Sample records for small-for-size fatty liver

  1. Successful Transplantation of Reduced Sized Rat Alcoholic Fatty Livers Made Possible by Mobilization of Host Stem Cells

    PubMed Central

    Hisada, Masayuki; Ota, Yoshihiro; Zhang, Xiuying; Cameron, Andrew M; Gao, Bin; Montgomery, Robert A; Williams, George Melville; Sun, Zhaoli

    2015-01-01

    Livers from Lewis rats fed with 7% alcohol for 5 weeks were used for transplantation. Reduced sized (50%) livers or whole livers were transplanted into normal DA recipients, which, in this strain combination, survive indefinitely when the donor has not been fed alcohol. However, none of the rats survived a whole fatty liver transplant while six of seven recipients of reduced sized alcoholic liver grafts survived long term. SDF-1 and HGF were significantly increased in reduced size liver grafts compared to whole liver grafts. Lineage-negative Thy-1+CXCR4+CD133+ stem cells were significantly increased in the peripheral blood and in allografts after reduced size fatty liver transplantation. In contrast, there were meager increases in cells reactive with anti Thy-1, CXCR4 and CD133 in peripheral blood and allografts in whole alcoholic liver recipients. The provision of plerixafor, a stem cell mobilizer, salvaged 5 of 10 whole fatty liver grafts. Conversely, blocking SDF-1 activity with neutralizing antibodies diminished stem cell recruitment and four of five reduced sized fatty liver recipients died. Thus chemokine insuficiency was associated with transplant failure of whole grafts which was overcome by the increased regenerative requirements promoted by the small grafts and mediated by SDF-1 resulting in stem cell influx. PMID:22994609

  2. Small for Size and Flow (SFSF) syndrome: An alternative description for posthepatectomy liver failure.

    PubMed

    Golriz, Mohammad; Majlesara, Ali; El Sakka, Saroa; Ashrafi, Maryam; Arwin, Jalal; Fard, Nassim; Raisi, Hanna; Edalatpour, Arman; Mehrabi, Arianeb

    2016-06-01

    Small for Size Syndrome (SFSS) syndrome is a recognizable clinical syndrome occurring in the presence of a reduced mass of liver, which is insufficient to maintain normal liver function. A definition has yet to be fully clarified, but it is a common clinical syndrome following partial liver transplantation and extended hepatectomy, which is characterized by postoperative liver dysfunction with prolonged cholestasis and coagulopathy, portal hypertension, and ascites. So far, this syndrome has been discussed with focus on the remnant size of the liver after partial liver transplantation or extended hepatectomy. However, the current viewpoints believe that the excessive flow of portal vein for the volume of the liver parenchyma leads to over-pressure, sinusoidal endothelial damages and haemorrhage. The new hypothesis declares that in both extended hepatectomy and partial liver transplantation, progression of Small for Size Syndrome is not determined only by the "size" of the liver graft or remnant, but by the hemodynamic parameters of the hepatic circulation, especially portal vein flow. Therefore, we suggest the term "Small for Size and Flow (SFSF)" for this syndrome. We believe that it is important for liver surgeons to know the pathogenesis and manifestation of this syndrome to react early enough preventing non-reversible tissue damages. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  3. Size and oxidative susceptibility of low-density lipoprotein particles in breast cancer patients with tamoxifen-induced fatty liver.

    PubMed

    Wakatsuki, Akihiko; Ogawa, Yasuhiro; Saibara, Toshiji; Okatani, Yuji; Fukaya, Takao

    2002-08-01

    The purpose of the present study was to investigate the effects of tamoxifen on the size and oxidative susceptibility of low-density lipoprotein (LDL) particles in breast cancer patients with tamoxifen-induced fatty liver. We investigated the following breast cancer patients: 13 receiving no tamoxifen (group A), 13 receiving tamoxifen 40 mg daily but without fatty liver (group B), and 13 receiving tamoxifen 40 mg daily with fatty liver (group C). Plasma lipids and diameter of LDL particles were measured. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO(4) while monitoring conjugated diene formation and assaying thiobarbituric acid reactive substances (TBARS). Plasma total and LDL cholesterol concentrations in groups B and C were significantly lower than those in group A. In group C, concentrations of plasma triglyceride (TG) and TBARS were significantly greater, but LDL particle diameter and lag time for LDL oxidation were significantly smaller than those in groups A and B. Plasma TG concentrations correlated negatively with computed tomography ratio of liver to spleen (r = -0.76; P < 0.001). LDL particle diameter correlated negatively with plasma TG (r = -0.62; P < 0.001) and TBARS (r = -0.44; P < 0.01), but positively with LDL lag time (r = 0.47; P < 0.01). Tamoxifen-induced fatty liver in breast cancer patients may be atherogenic, via increased TG and consequent small, easily oxidized LDL particles.

  4. Fatty Liver Disease

    MedlinePlus

    ... fatty liver disease that is not related to heavy alcohol use. There are two kinds: Simple fatty ... disease? Alcoholic fatty liver disease is due to heavy alcohol use. Your liver breaks down most of ...

  5. External Validation of Fatty Liver Index for Identifying Ultrasonographic Fatty Liver in a Large-Scale Cross-Sectional Study in Taiwan

    PubMed Central

    Fang, Kuan-Chieh; Wang, Yuan-Chen; Huo, Teh-Ia; Huang, Yi-Hsiang; Yang, Hwai-I; Su, Chien-Wei; Lin, Han-Chieh; Lee, Fa-Yauh; Wu, Jaw-Ching; Lee, Shou-Dong

    2015-01-01

    Background and Aims The fatty liver index (FLI) is an algorithm involving the waist circumference, body mass index, and serum levels of triglyceride and gamma-glutamyl transferase to identify fatty liver. Although some studies have attempted to validate the FLI, few studies have been conducted for external validation among Asians. We attempted to validate FLI to predict ultrasonographic fatty liver in Taiwanese subjects. Methods We enrolled consecutive subjects who received health check-up services at the Taipei Veterans General Hospital from 2002 to 2009. Ultrasonography was applied to diagnose fatty liver. The ability of the FLI to detect ultrasonographic fatty liver was assessed by analyzing the area under the receiver operating characteristic (AUROC) curve. Results Among the 29,797 subjects enrolled in this study, fatty liver was diagnosed in 44.5% of the population. Subjects with ultrasonographic fatty liver had a significantly higher FLI than those without fatty liver by multivariate analysis (odds ratio 1.045; 95% confidence interval, CI 1.044–1.047, p< 0.001). Moreover, FLI had the best discriminative ability to identify patients with ultrasonographic fatty liver (AUROC: 0.827, 95% confidence interval, 0.822–0.831). An FLI < 25 (negative likelihood ratio (LR−) 0.32) for males and <10 (LR− 0.26) for females rule out ultrasonographic fatty liver. Moreover, an FLI ≥ 35 (positive likelihood ratio (LR+) 3.12) for males and ≥ 20 (LR+ 4.43) for females rule in ultrasonographic fatty liver. Conclusions FLI could accurately identify ultrasonographic fatty liver in a large-scale population in Taiwan but with lower cut-off value than the Western population. Meanwhile the cut-off value was lower in females than in males. PMID:25781622

  6. Fatty liver in children

    PubMed Central

    Rafeey, Mandana; Mortazavi, Fakhrossadat; Mogaddasi, Nafiseh; Robabeh, Ghergherehchi; Ghaffari, Shamsi; Hasani, Alka

    2009-01-01

    Aims: The aim of this study is to investigate the clinical and laboratory characteristics of nonalcoholic fatty liver disease (NAFLD) in a referral center of pediatrics in the northwest of Iran. Methods: In this cross-sectional study all subjects aged between six months to 15 years that were referred to the sonography unit, were investigated for fatty liver from March 2005 to August 2006. Patients with fatty liver change underwent detailed clinical and laboratory evaluation. Results: From 1500 children who were investigated, 34 subjects with sonographic evidence of fatty liver were enrolled in this study (2.3%). The mean age was 6.53 ± 3.07 years. Elevated aspartate aminotransferase and alanine aminotransferase was detected in 38.2% and 47.1% of patients, respectively. The mean level of cholesterol was 461 ± 182.23 mg/dl and 94.1% of patients had hypercholesterolemia. Total cholesterol level and serum aminotransferase levels had a significant positive correlation with severity of fatty liver (p < 0.05). Mean body mass index was significantly higher in patients with severe fatty liver (p < 0.05). Conclusion: The epidemiology of pediatric NAFLD should inform future attempts to develop evaluated screening protocols. Moreover, these data should guide efforts to delineate the pathophysiology of fatty liver in children. PMID:19536316

  7. Ultrasound image texture processing for evaluating fatty liver in peripartal dairy cows

    NASA Astrophysics Data System (ADS)

    Amin, Viren R.; Bobe, Gerd; Young, Jerry; Ametaj, Burim; Beitz, Donald

    2001-07-01

    The objective of this work is to characterize the liver ultrasound texture as it changes in diffuse disease of fatty liver. This technology could allow non-invasive diagnosis of fatty liver, a major metabolic disorder in early lactation dairy cows. More than 100 liver biopsies were taken from fourteen dairy cows, as a part of the USDA-funded study for effects of glucagon on prevention and treatment of fatty liver. Up to nine liver biopsies were taken from each cow during peripartal period of seven weeks and total lipid content was determined chemically. Just before each liver biopsy was taken, ultrasonic B-mode images were digitally captured using a 3.5 or 5 MHz transducer. Effort was made to capture images that were non-blurred, void of large blood vessels and multiple echoes, and of consistent texture. From each image, a region-of-interest of size 100-by-100 pixels was processed. Texture parameters were calculated using algorithms such as first and second order statistics, 2D Fourier transformation, co-occurrence matrix, and gradient analysis. Many cows had normal liver (3% to 6% total lipid) and a few had developed fatty liver with total lipid up to 15%. The selected texture parameters showed consistent change with changing lipid content and could potentially be used to diagnose early fatty liver non-invasively. The approach of texture analysis algorithms and initial results on their potential in evaluating total lipid percentage is presented here.

  8. Nonalcoholic Fatty Liver Disease

    MedlinePlus

    ... fatty liver, alcoholic steatohepatitis, ascites, choline deficiency, cirrhosis, drug-induced fatty liver, edema, encephalopathy, glycogen storage disorder, gynecomastia, hepatic steatosis, hepatomegaly, hereditary fructose intolerance, homocystinuria, hyperlipidemia, ...

  9. Fish oil prevents sucrose-induced fatty liver but exacerbates high-safflower oil-induced fatty liver in ddy mice.

    PubMed

    Yamazaki, Tomomi; Nakamori, Akiko; Sasaki, Eriko; Wada, Satoshi; Ezaki, Osamu

    2007-12-01

    Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). We analyzed the effects of dietary fish oil on fatty liver induced by sucrose, safflower oil, and butter in ddY mice. In experiment I, mice were fed a high-starch diet [70 energy% (en%) starch] plus 20% (wt/wt) sucrose in the drinking water or fed a high-safflower oil diet (60 en%) for 11 weeks. As a control, mice were fed a high-starch diet with drinking water. Fish oil (10 en%) was either supplemented or not. Mice supplemented with sucrose or fed safflower oil showed a 1.7-fold or 2.2-fold increased liver triglyceride content, respectively, compared with that of control mice. Fish oil completely prevented sucrose-induced fatty liver, whereas it exacerbated safflower oil-induced fatty liver. Sucrose increased SREBP-1c and target gene messenger RNAs (mRNAs), and fish oil completely inhibited these increases. In experiment II, mice were fed a high-safflower oil or a high-butter diet, with or without fish oil supplementation. Fish oil exacerbated safflower oil-induced fatty liver but did not affect butter-induced fatty liver. Fish oil increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and target CD36 mRNA in safflower oil-fed mice. These increases were not observed in sucrose-supplemented or butter-fed mice. The effects of dietary fish oil on fatty liver differ according to the cause of fatty liver; fish oil prevents sucrose-induced fatty liver but exacerbates safflower oil-induced fatty liver. The exacerbation of fatty liver may be due, at least in part, to increased expression of liver PPARgamma.

  10. Current treatment for non-alcoholic fatty liver disease.

    PubMed

    Moctezuma-Velázquez, C

    Non-alcoholic fatty liver disease is the most prevalent hepatopathy, estimated at 30% in the general population. In the coming years, it will likely be the most common indication for liver transplantation and the most frequent cause of hepatocellular carcinoma. Current treatment for non-alcoholic fatty liver disease is based on dietary and exercise interventions that have been shown to be efficacious, even for reverting fibrosis. Unfortunately, compliance with general measures involving lifestyle modifications is very poor, making pharmacologic strategies a necessary option. At present, there are no treatments for non-alcoholic fatty liver disease approved by regulatory agencies, and the only ones with sufficient evidence and recommended by international societies are treatments with pioglitazone and vitamin E, which are not exempt from adverse effects. We review herein the current management of non-alcoholic fatty liver disease, including dietary and physical activity interventions, available treatments, equivocal therapies, emerging treatments, and treatments presently in clinical trials. Copyright © 2018 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.

  11. Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers.

    PubMed

    Anavi, Sarit; Madar, Zecharia; Tirosh, Oren

    2017-10-01

    Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  12. Fatty liver promotes fibrosis in monkeys consuming high fructose.

    PubMed

    Cydylo, Michael A; Davis, Ashley T; Kavanagh, Kylie

    2017-02-01

    Nonalcoholic fatty liver diseases (NAFLD) are related to development of liver fibrosis which currently has few therapeutic options. Rodent models of NAFLD inadequately model the fibrotic aspects of the disease and fail to demonstrate the spectrum of cardiometabolic diseases without genetic manipulation. This study aimed to document a monkey model of fatty liver and fibrosis, which naturally develop cardiometabolic disease pathophysiologies. Twenty-seven cynomolgus monkeys (Macaca fascicularis) fed diets either low or high in simple carbohydrates, supplied as fructose [control and high-fructose diet (HRr)], on low-fat, cholesterol-free background were studied. The HFr was consumed for up to 7 years, and liver tissue was histologically evaluated for fat and fibrosis extent. The HFr diet increased steatosis, and its extent was related to duration of fructose exposure. Lipid droplet size also increased with HFr duration; however, compared with control, the lipid droplets were smaller on average. Fibrosis extent was significantly greater with fructose feeding and was predicted by fructose exposure, extent of fatty liver, and age. These data are the first to demonstrate that high-carbohydrate diets alone can generate both liver fat and fibrosis and thus allow further study of mechanisms and therapeutic options in the translational animal model. © 2017 The Obesity Society.

  13. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis.

    PubMed

    Koo, Seung-Hoi

    2013-09-01

    Liver plays a central role in the biogenesis of major metabolites including glucose, fatty acids, and cholesterol. Increased incidence of obesity in the modern society promotes insulin resistance in the peripheral tissues in humans, and could cause severe metabolic disorders by inducing accumulation of lipid in the liver, resulting in the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD, which is characterized by increased fat depots in the liver, could precede more severe diseases such as non-alcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma. Accumulation of lipid in the liver can be traced by increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, or the increased incidence of de novo lipogenesis. In this review, I would like to focus on the roles of individual pathways that contribute to the hepatic steatosis as a precursor for the NAFLD.

  14. The Effects of Physical Exercise on Fatty Liver Disease

    PubMed Central

    van der Windt, Dirk J.; Sud, Vikas; Zhang, Hongji; Tsung, Allan; Huang, Hai

    2018-01-01

    The increasing prevalence of obesity has made nonalcoholic fatty liver disease (NAFLD) the most common chronic liver disease. As a consequence, NAFLD and especially its inflammatory form nonalcoholic steatohepatitis (NASH) are the fastest increasing etiology of end-stage liver disease and hepatocellular carcinoma. Physical inactivity is related to the severity of fatty liver disease irrespective of body weight, supporting the hypothesis that increasing physical activity through exercise can improve fatty liver disease. This review summarizes the evidence for the effects of physical exercise on NAFLD and NASH. Several clinical trials have shown that both aerobic and resistance exercise reduce the hepatic fat content. From clinical and basic scientific studies, it is evident that exercise affects fatty liver disease through various pathways. Improved peripheral insulin resistance reduces the excess delivery of free fatty acids and glucose for free fatty acid synthesis to the liver. In the liver, exercise increases fatty acid oxidation, decreases fatty acid synthesis, and prevents mitochondrial and hepatocellular damage through a reduction of the release of damage-associated molecular patterns. In conclusion, physical exercise is a proven therapeutic strategy to improve fatty liver disease. PMID:29212576

  15. Vegetarian diet, food substitution, and nonalcoholic fatty liver.

    PubMed

    Chiu, Tina H; Lin, Ming-Nan; Pan, Wen-Harn; Chen, Yen-Ching; Lin, Chin-Lon

    2018-01-01

    Vegetarian diets have been shown to improve insulin resistance and reduce body weight, but the effects on nonalcoholic fatty liver require further confirmation. We aim to investigate the association between vegetarian diets, major food groups, and nonalcoholic fatty liver, and to compare the degree of liver fibrosis between vegetarians and nonvegetarians in those with fatty liver. We analyzed cross-sectional data from the Tzu Chi Health Study which included 2127 nonvegetarians and 1273 vegetarians who did not smoke or habitually drink alcohol and had no hepatitis B or hepatitis C. Fatty liver and liver fibrosis were determined using ultrasonography and the nonalcoholic fatty liver disease fibrosis score, respectively. Diet was assessed through a validated food frequency questionnaire. Vegetarian diets were associated with lower odds of fatty liver (odds ratio = 0.79, 95% confidence interval: 0.68-0.91) after adjusting for age, gender, education, history of smoking and alcohol drinking. Adjustment for body mass index (BMI) attenuated the protective association. Vegetarians had less severe fibrosis than nonvegetarians. Replacing a serving of soy with a serving of meat or fish was associated with 12%-13% increased risk, and replacing a serving of whole grains with a serving of refined grains, fruits, and fruit juice was associated with 3%-12% increased the risk of fatty liver. Vegetarian diets, replacing meat and fish with soy, and replacing refined carbohydrates with whole grains, may be inversely associated with nonalcoholic fatty liver related to BMI.

  16. Fads1 and 2 are promoted to meet instant need for long-chain polyunsaturated fatty acids in goose fatty liver.

    PubMed

    Osman, Rashid H; Liu, Long; Xia, Lili; Zhao, Xing; Wang, Qianqian; Sun, Xiaoxian; Zhang, Yihui; Yang, Biao; Zheng, Yun; Gong, Daoqing; Geng, Tuoyu

    2016-07-01

    Global prevalence of non-alcoholic fatty liver disease (NAFLD) constitutes a threat to human health. Goose is a unique model of NAFLD for discovering therapeutic targets as its liver can develop severe steatosis without overt injury. Fatty acid desaturase (Fads) is a potential therapeutic target as Fads expression and mutations are associated with liver fat. Here, we hypothesized that Fads was promoted to provide a protection for goose fatty liver. To test this, goose Fads1 and Fads2 were sequenced. Fads1/2/6 expression was determined in goose liver and primary hepatocytes by quantitative PCR. Liver fatty acid composition was also analyzed by gas chromatography. Data indicated that hepatic Fads1/2/6 expression was gradually increased with the time of overfeeding. In contrast, trans-C18:1n9 fatty acid (Fads inhibitor) was reduced. However, enhanced Fads capacity for long-chain polyunsaturated fatty acid (LC-PUFA) synthesis was not sufficient to compensate for the depleted LC-PUFAs in goose fatty liver. Moreover, cell studies showed that Fads1/2/6 expression was regulated by fatty liver-associated factors. Together, these findings suggest Fads1/2 as protective components are promoted to meet instant need for LC-PUFAs in goose fatty liver, and we propose this is required for severe hepatic steatosis without liver injury.

  17. Genetics of nonalcoholic fatty liver disease.

    PubMed

    Dongiovanni, Paola; Valenti, Luca

    2016-08-01

    Epidemiological, familial, and twin studies indicate that non-alcoholic fatty liver disease, now the leading cause of liver damage in developed countries, has a strong heritability. The common I148M variant of PNPLA3 impairing hepatocellular lipid droplets remodeling is the major genetic determinant of hepatic fat content. The I148M variant has a strong impact on the full spectrum of liver damage related to fatty liver, encompassing non-alcoholic steatohepatitis, advanced fibrosis, and hepatocellular carcinoma, and influences the response to therapeutic approaches. Common variants in GCKR enhance de novo hepatic lipogenesis in response to glucose and liver inflammation. Furthermore, the low-frequency E167K variant of TM6SF2 and rare mutations in APOB, which impair very low-density lipoproteins secretion, predispose to progressive fatty liver. These and other recent findings reviewed here indicate that impaired lipid handling by hepatocytes has a major role in the pathogenesis of non-alcoholic fatty liver disease by triggering inflammation, fibrogenesis, and carcinogenesis. These discoveries have provided potential novel biomarkers for clinical use and have revealed intriguing therapeutic targets. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Vegetarian diet, food substitution, and nonalcoholic fatty liver

    PubMed Central

    Chiu, Tina H.; Lin, Ming-Nan; Pan, Wen-Harn; Chen, Yen-Ching; Lin, Chin-Lon

    2018-01-01

    Objectives: Vegetarian diets have been shown to improve insulin resistance and reduce body weight, but the effects on nonalcoholic fatty liver require further confirmation. We aim to investigate the association between vegetarian diets, major food groups, and nonalcoholic fatty liver, and to compare the degree of liver fibrosis between vegetarians and nonvegetarians in those with fatty liver. Materials and Methods: We analyzed cross-sectional data from the Tzu Chi Health Study which included 2127 nonvegetarians and 1273 vegetarians who did not smoke or habitually drink alcohol and had no hepatitis B or hepatitis C. Fatty liver and liver fibrosis were determined using ultrasonography and the nonalcoholic fatty liver disease fibrosis score, respectively. Diet was assessed through a validated food frequency questionnaire. Results: Vegetarian diets were associated with lower odds of fatty liver (odds ratio = 0.79, 95% confidence interval: 0.68–0.91) after adjusting for age, gender, education, history of smoking and alcohol drinking. Adjustment for body mass index (BMI) attenuated the protective association. Vegetarians had less severe fibrosis than nonvegetarians. Replacing a serving of soy with a serving of meat or fish was associated with 12%–13% increased risk, and replacing a serving of whole grains with a serving of refined grains, fruits, and fruit juice was associated with 3%–12% increased the risk of fatty liver. Conclusion: Vegetarian diets, replacing meat and fish with soy, and replacing refined carbohydrates with whole grains, may be inversely associated with nonalcoholic fatty liver related to BMI. PMID:29875591

  19. Omega-3 fatty acids and non-alcoholic fatty liver disease: Evidence of efficacy and mechanism of action.

    PubMed

    Scorletti, Eleonora; Byrne, Christopher D

    2018-03-22

    For many years it has been known that high doses of long chain omega-3 fatty acids are beneficial in the treatment of hypertriglyceridaemia. Over the last three decades, there has also been a wealth of in vitro and in vivo data that has accumulated to suggest that long chain omega-3 fatty acid treatment might be beneficial to decrease liver triacylglycerol. Several biological mechanisms have been identified that support this hypothesis; notably, it has been shown that long chain omega-3 fatty acids have a beneficial effect: a) on bioactive metabolites involved in inflammatory pathways, and b) on alteration of nuclear transcription factor activities such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP), involved in inflammatory pathways and liver lipid metabolism. Since the pathogenesis of non alcoholic fatty liver disease (NAFLD) begins with the accumulation of liver lipid and progresses with inflammation and then several years later with development of fibrosis; it has been thought in patients with NAFLD omega-3 fatty acid treatment would be beneficial in treating liver lipid and possibly also in ameliorating inflammation. Meta-analyses (of predominantly dietary studies and small trials) have tended to support the assertion that omega-3 fatty acids are beneficial in decreasing liver lipid, but recent randomised controlled trials have produced conflicting data. These trials have suggested that omega-3 fatty acid might be beneficial in decreasing liver triglyceride (docosahexanoic acid also possibly being more effective than eicosapentanoic acid) but not in decreasing other features of steatohepatitis (or liver fibrosis). The purpose of this review is to discuss recent evidence regarding biological mechanisms by which long chain omega-3 fatty acids might act to ameliorate liver disease in NAFLD; to consider the recent evidence from randomised

  20. Nonalcoholic fatty liver and the severity of acute pancreatitis.

    PubMed

    Mikolasevic, I; Orlic, L; Poropat, G; Jakopcic, I; Stimac, D; Klanac, A; Carovic, F; Milic, S

    2017-03-01

    To explore the effect of nonalcoholic fatty liver as a hepatic manifestation of metabolic syndrome on the severity of acute pancreatitis. We hypothesized that patients with nonalcoholic fatty liver would have a more severe form of acute pancreatitis. We retrospectively analyzed 822 patients hospitalized with acute pancreatitis. We diagnosed acute pancreatitis and determined its severity according the revised Atlanta classification criteria from 2012. We assessed nonalcoholic fatty liver with computed tomography. There were 198 (24.1%) patients out of 822 analyzed who had nonalcoholic fatty liver. Patients with nonalcoholic fatty liver had statistically higher incidence of moderately severe (35.4% vs. 14.6%; p=0.02) and severe acute pancreatitis (20.7% vs. 9.6%; p<0.001) compared to patients without nonalcoholic fatty liver. At the admission patients with nonalcoholic fatty liver had higher values of C-reactive protein as well as at day three, higher APACHE II score at admission and significantly higher incidence of organ failure and local complications as well as higher values of computed tomography severity index compared to patients without nonalcoholic fatty liver. We found independent association between the occurrence of moderately severe and severe acute pancreatitis and nonalcoholic fatty liver (OR 2.13, 95%CI 1.236-3.689). Compared to patients without nonalcoholic fatty liver, patients with nonalcoholic fatty liver had a higher death rate, however not statistically significant (5.6% vs. 4.3%; p=NS). Presence of nonalcoholic fatty liver at admission can indicate a higher risk for developing more severe forms of acute pancreatitis and could be used as an additional prognostic tool. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  1. Fatty liver disease and lifestyle in youngsters: diet, food intake frequency, exercise, sleep shortage and fashion.

    PubMed

    Trovato, Francesca M; Martines, Giuseppe Fabio; Brischetto, Daniela; Catalano, Daniela; Musumeci, Giuseppe; Trovato, Guglielmo M

    2016-03-01

    Fatty liver is associated with alcohol habits and/or overweight/obesity. We challenged several lifestyle features associated with fatty liver and, particularly, with non-alcoholic fatty liver disease (NAFLD). Among them, sleep shortage as a result of nightlife habits and a preference for plus-size fashion were assessed. The latter consists of fashionable plus-sized clothing for actual individuals' size and reflects a frequent attitude of some social or age groups, conceivably indicating more global and widespread trend and behaviour. We studied a group of 708 non-diabetic youngsters, 458 women and 250 men, 21.72 ± 3.71 years old (range 15-35 years), referred for minor digestive ailments for clinical assessment, ultrasound detection of fatty liver and nutritional counselling. Details of personal history regarding lifestyle, food intake frequency and alcohol intake, dietary and physical exercise profile, sleep duration and clothing preferences were recorded. The prevalence of NAFLD in this cohort of youngsters is 67/708 (9.4%). Even if it is quantitatively very low in both groups, the average alcohol intake, always below 20 g/day, is greater in NAFLD subjects (5.83 ± 4.32 g) vs. subjects with normal liver (2.02 ± 3.20 g). The number of meals/day and adherence to a Mediterranean diet profile are smaller in NAFLD subjects. By multiple regression, BMI, sedentary life, plus-sized clothing for their actual size, sleep shortage and lower frequency of daily food intake are associated with the presence of NAFLD. Onset and continuation of fatty liver disease, beyond food and exercise quantity and quality, with their effects on obesity, may also be associated with other aspects of lifestyle. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. FT-IR imaging for quantitative determination of liver fat content in non-alcoholic fatty liver.

    PubMed

    Kochan, K; Maslak, E; Chlopicki, S; Baranska, M

    2015-08-07

    In this work we apply FT-IR imaging of large areas of liver tissue cross-section samples (∼5 cm × 5 cm) for quantitative assessment of steatosis in murine model of Non-Alcoholic Fatty Liver (NAFLD). We quantified the area of liver tissue occupied by lipid droplets (LDs) by FT-IR imaging and Oil Red O (ORO) staining for comparison. Two alternative FT-IR based approaches are presented. The first, straightforward method, was based on average spectra from tissues and provided values of the fat content by using a PLS regression model and the reference method. The second one – the chemometric-based method – enabled us to determine the values of the fat content, independently of the reference method by means of k-means cluster (KMC) analysis. In summary, FT-IR images of large size liver sections may prove to be useful for quantifying liver steatosis without the need of tissue staining.

  3. Non-Alcoholic Fatty Liver Disease in HIV Infection.

    PubMed

    Macías, Juan; Pineda, Juan A; Real, Luis M

    2017-01-01

    Non-alcoholic fatty liver disease is one of the most frequent chronic hepatic conditions worldwide. The spectrum of non-alcoholic fatty liver disease goes from hepatic steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Risk factors for non-alcoholic fatty liver disease are metabolic, mainly obesity and the accompanying consequences. Treatment and prevention of non-alcoholic fatty liver disease should target those metabolic abnormalities. The frequency of and the factors associated with hepatic steatosis in HIV infection seem to be similar to those reported in the general population, though direct comparisons are lacking. Hepatic steatosis in HIV infection may also be secondary to antiretroviral drugs or HCV-related factors in HCV-coinfected subjects. However, more recent data suggest that hepatic steatosis in HIV infection represents true non-alcoholic fatty liver disease. As such, management of non-alcoholic fatty liver disease in HIV infection should follow the same principles as in the general population.

  4. Fatty Liver Index and Lipid Accumulation Product Can Predict Metabolic Syndrome in Subjects without Fatty Liver Disease

    PubMed Central

    Cheng, Yuan-Lung; Wang, Yuan-Jen; Lan, Keng-Hsin; Huo, Teh-Ia; Hsieh, Wei-Yao; Hou, Ming-Chih; Lee, Fa-Yauh; Wu, Jaw-Ching; Lee, Shou-Dong

    2017-01-01

    Background. Fatty liver index (FLI) and lipid accumulation product (LAP) are indexes originally designed to assess the risk of fatty liver and cardiovascular disease, respectively. Both indexes have been proven to be reliable markers of subsequent metabolic syndrome; however, their ability to predict metabolic syndrome in subjects without fatty liver disease has not been clarified. Methods. We enrolled consecutive subjects who received health check-up services at Taipei Veterans General Hospital from 2002 to 2009. Fatty liver disease was diagnosed by abdominal ultrasonography. The ability of the FLI and LAP to predict metabolic syndrome was assessed by analyzing the area under the receiver operating characteristic (AUROC) curve. Results. Male sex was strongly associated with metabolic syndrome, and the LAP and FLI were better than other variables to predict metabolic syndrome among the 29,797 subjects. Both indexes were also better than other variables to detect metabolic syndrome in subjects without fatty liver disease (AUROC: 0.871 and 0.879, resp.), and the predictive power was greater among women. Conclusion. Metabolic syndrome increases the cardiovascular disease risk. The FLI and LAP could be used to recognize the syndrome in both subjects with and without fatty liver disease who require lifestyle modifications and counseling. PMID:28194177

  5. Evaluation of fatty proportion in fatty liver using least squares method with constraints.

    PubMed

    Li, Xingsong; Deng, Yinhui; Yu, Jinhua; Wang, Yuanyuan; Shamdasani, Vijay

    2014-01-01

    Backscatter and attenuation parameters are not easily measured in clinical applications due to tissue inhomogeneity in the region of interest (ROI). A least squares method(LSM) that fits the echo signal power spectra from a ROI to a 3-parameter tissue model was used to get attenuation coefficient imaging in fatty liver. Since fat's attenuation value is higher than normal liver parenchyma, a reasonable threshold was chosen to evaluate the fatty proportion in fatty liver. Experimental results using clinical data of fatty liver illustrate that the least squares method can get accurate attenuation estimates. It is proved that the attenuation values have a positive correlation with the fatty proportion, which can be used to evaluate the syndrome of fatty liver.

  6. Effect of liver fatty acid binding protein on fatty acid movement between liposomes and rat liver microsomes.

    PubMed

    McCormack, M; Brecher, P

    1987-06-15

    Although movement of fatty acids between bilayers can occur spontaneously, it has been postulated that intracellular movement is facilitated by a class of proteins named fatty acid binding proteins (FABP). In this study we have incorporated long chain fatty acids into multilamellar liposomes made of phosphatidylcholine, incubated them with rat liver microsomes containing an active acyl-CoA synthetase, and measured formation of acyl-CoA in the absence or presence of FABP purified from rat liver. FABP increased about 2-fold the accumulation of acyl-CoA when liposomes were the fatty acid donor. Using fatty acid incorporated into liposomes made either of egg yolk lecithin or of dipalmitoylphosphatidylcholine, it was found that the temperature dependence of acyl-CoA accumulation in the presence of FABP correlated with both the physical state of phospholipid molecules in the liposomes and the binding of fatty acid to FABP, suggesting that fatty acid must first desorb from the liposomes before FABP can have an effect. An FABP-fatty acid complex incubated with microsomes, in the absence of liposomes, resulted in greater acyl-CoA formation than when liposomes were present, suggesting that desorption of fatty acid from the membrane is rate-limiting in the accumulation of acyl-CoA by this system. Finally, an equilibrium dialysis cell separating liposomes from microsomes on opposite sides of a Nuclepore filter was used to show that liver FABP was required for the movement and activation of fatty acid between the compartments. These studies show that liver FABP interacts with fatty acid that desorbs from phospholipid bilayers, and promotes movement to a membrane-bound enzyme, suggesting that FABP may act intracellularly by increasing net desorption of fatty acid from cell membranes.

  7. Targeting nuclear receptors for the treatment of fatty liver disease.

    PubMed

    Tanaka, Naoki; Aoyama, Toshifumi; Kimura, Shioko; Gonzalez, Frank J

    2017-11-01

    Ligand-activated nuclear receptors, including peroxisome proliferator-activated receptor alpha (PPARα), pregnane X receptor, and constitutive androstane receptor, were first identified as key regulators of the responses against chemical toxicants. However, numerous studies using mouse disease models and human samples have revealed critical roles for these receptors and others, such as PPARβ/δ, PPARγ, farnesoid X receptor (FXR), and liver X receptor (LXR), in maintaining nutrient/energy homeostasis in part through modulation of the gut-liver-adipose axis. Recently, disorders associated with disrupted nutrient/energy homeostasis, e.g., obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD), are increasing worldwide. Notably, in NAFLD, a progressive subtype exists, designated as non-alcoholic steatohepatitis (NASH) that is characterized by typical histological features resembling alcoholic steatohepatitis (ASH), and NASH/ASH are recognized as major causes of hepatitis virus-unrelated liver cirrhosis and hepatocellular carcinoma. Since hepatic steatosis is basically caused by an imbalance between fat/energy influx and utilization, abnormal signaling of these nuclear receptors contribute to the pathogenesis of fatty liver disease. Standard therapeutic interventions have not been fully established for fatty liver disease, but some new agents that activate or inhibit nuclear receptor signaling have shown promise as possible therapeutic targets. In this review, we summarize recent findings on the roles of nuclear receptors in fatty liver disease and discuss future perspectives to develop promising pharmacological strategies targeting nuclear receptors for NAFLD/NASH. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Fatty acid composition in serum correlates with that in the liver and non-alcoholic fatty liver disease activity scores in mice fed a high-fat diet.

    PubMed

    Wang, Xing-He; Li, Chun-Yan; Muhammad, Ishfaq; Zhang, Xiu-Ying

    2016-06-01

    In this study, we investigated the correlation between the serum fatty acid composition and hepatic steatosis, inflammation, hepatocellular ballooning scores, and liver fatty acids composition in mice fed a high-fat diet. Livers were collected for non-alcoholic fatty liver disease score analysis. Fatty acid compositions were analysed by gas chromatography. Correlations were determined by Pearson correlation coefficient. Exposed to a high-fat diet, mice developed fatty liver disease with varying severity without fibrosis. The serum fatty acid variation became more severe with prolonged exposure to a high-fat diet. This variation also correlated significantly with the variation in livers, with the types of fatty acids corresponding to liver steatosis, inflammation, and hepatocellular ballooning scores. Results of this study lead to the following hypothesis: the extent of serum fatty acid variation may be a preliminary biomarker of fatty liver disease caused by high-fat intake. Copyright © 2016. Published by Elsevier B.V.

  9. [Non-invasive assessment of fatty liver].

    PubMed

    Egresi, Anna; Lengyel, Gabriella; Hagymási, Krisztina

    2015-04-05

    As the result of various harmful effects (infectious agents, metabolic diseases, unhealthy diet, obesity, toxic agents, autoimmune processes) hepatic damage may develop, which can progress towards liver steatosis, and fibrosis as well. The most common etiological factors of liver damages are hepatitis B and C infection, alcohol consumption and non-alcoholic fatty liver disease. Liver biopsy is considered as the gold standard for the diagnosis of chronic liver diseases. Due to the dangers and complications of liver biopsy, studies are focused on non-invasive markers and radiological imaging for liver steatosis, progression of fatty liver, activity of the necroinflammation and the severity of the fibrosis. Authors review the possibilities of non-invasive assessment of liver steatosis. The statistical features of the probes (positive, negative predictive values, sensitivity, specificity) are reviewed. The role of radiological imaging is also discussed. Although the non-invasive methods discussed in this article are useful to assess liver steatosis, further studies are needed to validate to follow progression of the diseases and to control therapeutic response.

  10. Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity.

    PubMed

    Pavlides, Michael; Banerjee, Rajarshi; Tunnicliffe, Elizabeth M; Kelly, Catherine; Collier, Jane; Wang, Lai Mun; Fleming, Kenneth A; Cobbold, Jeremy F; Robson, Matthew D; Neubauer, Stefan; Barnes, Eleanor

    2017-07-01

    The diagnosis of non-alcoholic steatohepatitis and fibrosis staging are central to non-alcoholic fatty liver disease assessment. We evaluated multiparametric magnetic resonance in the assessment of non-alcoholic steatohepatitis and fibrosis using histology as standard in non-alcoholic fatty liver disease. Seventy-one patients with suspected non-alcoholic fatty liver disease were recruited within 1 month of liver biopsy. Magnetic resonance data were used to define the liver inflammation and fibrosis score (LIF 0-4). Biopsies were assessed for steatosis, lobular inflammation, ballooning and fibrosis and classified as non-alcoholic steatohepatitis or simple steatosis, and mild or significant (Activity ≥2 and/or Fibrosis ≥2 as defined by the Fatty Liver Inhibition of Progression consortium) non-alcoholic fatty liver disease. Transient elastography was also performed. Magnetic resonance success rate was 95% vs 59% for transient elastography (P<.0001). Fibrosis stage on biopsy correlated with liver inflammation and fibrosis (r s =.51, P<.0001). The area under the receiver operating curve using liver inflammation and fibrosis for the diagnosis of cirrhosis was 0.85. Liver inflammation and fibrosis score for ballooning grades 0, 1 and 2 was 1.2, 2.7 and 3.5 respectively (P<.05) with an area under the receiver operating characteristic curve of 0.83 for the diagnosis of ballooning. Patients with steatosis had lower liver inflammation and fibrosis (1.3) compared to patients with non-alcoholic steatohepatitis (3.0) (P<.0001); area under the receiver operating characteristic curve for the diagnosis of non-alcoholic steatohepatitis was 0.80. Liver inflammation and fibrosis scores for patients with mild and significant non-alcoholic fatty liver disease were 1.2 and 2.9 respectively (P<.0001). The area under the receiver operating characteristic curve of liver inflammation and fibrosis for the diagnosis of significant non-alcoholic fatty liver disease was 0

  11. AMPK Re-Activation Suppresses Hepatic Steatosis but its Downregulation Does Not Promote Fatty Liver Development.

    PubMed

    Boudaba, Nadia; Marion, Allison; Huet, Camille; Pierre, Rémi; Viollet, Benoit; Foretz, Marc

    2018-02-01

    Nonalcoholic fatty liver disease is a highly prevalent component of disorders associated with disrupted energy homeostasis. Although dysregulation of the energy sensor AMP-activated protein kinase (AMPK) is viewed as a pathogenic factor in the development of fatty liver its role has not been directly demonstrated. Unexpectedly, we show here that liver-specific AMPK KO mice display normal hepatic lipid homeostasis and are not prone to fatty liver development, indicating that the decreases in AMPK activity associated with hepatic steatosis may be a consequence, rather than a cause, of changes in hepatic metabolism. In contrast, we found that pharmacological re-activation of downregulated AMPK in fatty liver is sufficient to normalize hepatic lipid content. Mechanistically, AMPK activation reduces hepatic triglyceride content both by inhibiting lipid synthesis and by stimulating fatty acid oxidation in an LKB1-dependent manner, through a transcription-independent mechanism. Furthermore, the effect of the antidiabetic drug metformin on lipogenesis inhibition and fatty acid oxidation stimulation was enhanced by combination treatment with small-molecule AMPK activators in primary hepatocytes from mice and humans. Overall, these results demonstrate that AMPK downregulation is not a triggering factor in fatty liver development but in contrast, establish the therapeutic impact of pharmacological AMPK re-activation in the treatment of fatty liver disease. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  12. Imaging patterns and focal lesions in fatty liver: a pictorial review.

    PubMed

    Venkatesh, Sudhakar K; Hennedige, Tiffany; Johnson, Geoffrey B; Hough, David M; Fletcher, Joel G

    2017-05-01

    Non-alcoholic fatty liver disease is the most common cause of chronic liver disease and affects nearly one-third of US population. With the increasing trend of obesity in the population, associated fatty change in the liver will be a common feature observed in imaging studies. Fatty liver causes changes in liver parenchyma appearance on imaging modalities including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) and may affect the imaging characteristics of focal liver lesions (FLLs). The imaging characteristics of FLLs were classically described in a non-fatty liver. In addition, focal fatty change and focal fat sparing may also simulate FLLs. Knowledge of characteristic patterns of fatty change in the liver (diffuse, geographical, focal, subcapsular, and perivascular) and their impact on the detection and characterization of FLL is therefore important. In general, fatty change may improve detection of FLLs on MRI using fat suppression sequences, but may reduce sensitivity on a single-phase (portal venous) CT and conventional ultrasound. In patients with fatty liver, MRI is generally superior to ultrasound and CT for detection and characterization of FLL. In this pictorial essay, we describe the imaging patterns of fatty change in the liver and its effect on detection and characterization of FLLs on ultrasound, CT, MRI, and PET.

  13. Liver Fatty acid binding protein (L-Fabp) modulates murine stellate cell activation and diet induced nonalcoholic fatty liver disease

    PubMed Central

    Chen, Anping; Tang, Youcai; Davis, Victoria; Hsu, Fong-Fu; Kennedy, Susan M.; Song, Haowei; Turk, John; Brunt, Elizabeth M.; Newberry, Elizabeth P.; Davidson, Nicholas O.

    2013-01-01

    Activation of hepatic stellate cells (HSCs) is crucial to the development of fibrosis in nonalcoholic fatty liver disease. Quiescent HSCs contain lipid droplets (LDs), whose depletion upon activation induces a fibrogenic gene program. Here we show that liver fatty acid-binding protein (L-Fabp), an abundant cytosolic protein that modulates fatty acid (FA) metabolism in enterocytes and hepatocytes also modulates HSC FA utilization and in turn regulates the fibrogenic program. L-Fabp expression decreased 10-fold following HSC activation, concomitant with depletion of LDs. Primary HSCs isolated from L-FABP−/− mice contain fewer LDs than wild type (WT) HSCs, and exhibit upregulated expression of genes involved in HSC activation. Adenoviral L-Fabp transduction inhibited activation of passaged WT HSCs and increased both the expression of prolipogenic genes and also augmented intracellular lipid accumulation, including triglyceride and FA, predominantly palmitate. Freshly isolated HSCs from L-FABP−/− mice correspondingly exhibited decreased palmitate in the free FA pool. To investigate whether L-FABP deletion promotes HSC activation in vivo, we fed L-FABP−/− and WT mice a high fat diet supplemented with trans-fatty acids and fructose (TFF). TFF-fed L-FABP−/− mice exhibited reduced hepatic steatosis along with decreased LD abundance and size compared to WT mice. In addition, TFF-fed L-FABP−/− mice exhibited decreased hepatic fibrosis, with reduced expression of fibrogenic genes, compared to WT mice. Conclusion L-FABP deletion attenuates both diet-induced hepatic steatosis and fibrogenesis, despite the observation that L-Fabp paradoxically promotes FA and LD accumulation and inhibits HSC activation in vitro. These findings highlight the importance of cell-specific modulation of hepatic lipid metabolism in promoting fibrogenesis in nonalcoholic fatty liver disease. PMID:23401290

  14. Gut Microbiota of Nonalcoholic Fatty Liver Disease.

    PubMed

    Abdou, Reham M; Zhu, Lixin; Baker, Robert D; Baker, Susan S

    2016-05-01

    The prevalence of nonalcoholic fatty liver disease has been rapidly increasing worldwide. It has become a leading cause of liver transplantation. Accumulating evidence suggests a significant role for gut microbiota in its development and progression. Here we review the effect of gut microbiota on developing hepatic fatty infiltration and its progression. Current literature supports a possible role for gut microbiota in the development of liver steatosis, inflammation and fibrosis. We also review the literature on possible interventions for NAFLD that target the gut microbiota.

  15. Ischemia-reperfusion injury in rat fatty liver: role of nutritional status.

    PubMed

    Caraceni, P; Nardo, B; Domenicali, M; Turi, P; Vici, M; Simoncini, M; De Maria, N; Trevisani, F; Van Thiel, D H; Derenzini, M; Cavallari, A; Bernardi, M

    1999-04-01

    Fatty livers are more sensitive to the deleterious effects of ischemia-reperfusion than normal livers. Nutritional status greatly modulates this injury in normal livers, but its role in the specific setting of fatty liver is unknown. This study aimed to determine the effect of nutritional status on warm ischemia-reperfusion injury in rat fatty livers. Fed and fasted rats with normal or fatty liver induced by a choline deficient diet underwent 1 hour of lobar ischemia and reperfusion. Rat survival was determined for 7 days. Serum transaminases, liver histology and cell ultrastructure were assessed before and after ischemia, and at 30 minutes, 2 hours, 8 hours, and 24 hours after reperfusion. Survival was also determined in fatty fasted rats supplemented with glucose before surgery. The preischemic hepatic glycogen was measured in all groups. Whereas survival was similar in fasted and fed rats with normal liver (90% vs. 100%), fasting dramatically reduced survival in rats with fatty liver (14% vs. 64%, P <.01). Accordingly, fasting and fatty degeneration had a synergistic effect in exacerbating liver injury. Mitochondrial damage was a predominant feature of ultrastructural hepatocyte injury in fasted fatty livers. Glucose supplementation partially prevented the fasting-induced depletion of glycogen and improved the 7-day rat survival to 45%. These data indicate that rat fatty livers exposed to normothermic ischemia-reperfusion injury are much more sensitive to fasting than histologically normal livers. Because glucose supplementation improves both the hepatic glycogen stores and the rat survival, a nutritional repletion procedure may be part of a treatment strategy aimed to prevent ischemia-reperfusion injury in fatty livers.

  16. Serum paraoxonase-1 as biomarker for improved diagnosis of fatty liver in dairy cows.

    PubMed

    Farid, Ayman Samir; Honkawa, Kazuyuki; Fath, Eman Mohamed; Nonaka, Nariaki; Horii, Yoichiro

    2013-04-11

    Fatty liver is a major metabolic disorder in dairy cows and is believed to result in major economic losses in dairy farming due to decreased health status, reproductive performance and fertility. Currently, the definitive means for diagnosing fatty liver is determining the fat content of hepatic tissue by liver biopsy, which is an invasive and costly procedure, making it poorly suited to dairy farms. Therefore, the key aim of this study was to investigate the measurement of serum paraoxonase-1 (PON1), an enzyme exclusively synthesized by the liver, as a sensitive noninvasive biomarker for diagnosis of fatty liver in dairy cows. A comparative cohort study using serum specimens from Holstein-Friesian dairy cows (46 healthy and 46 fatty liver cases) was conducted. Serum PON1 (paraoxonase, lactonase and arylesterase) activity and other biochemical and hematological parameters were measured. We found that serum PON1 activity was lower (P<0.001) in cows suffering from fatty liver. The area under the receiver operating characteristic curve (AUC-ROC) of PON1 activity for diagnosis of fatty liver was 0.973-0.989 [95% confidence interval (CI) 0.941, 1.000] which was higher than the AUC-ROC of aspartate aminotransferase (AST), lecithin-cholesterol acyltransferase (LCAT), alkaline phosphatase (ALP), non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL). We found that adding serum PON1 measurement to different batteries of serum diagnostic panels showed a combination of high sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (+LR), negative likelihood ratio (-LR), diagnostic odd ratio (DOR) and overall diagnostic accuracy in diagnosing fatty liver. The present results indicate that addition of serum PON1 activity measurement to the biochemical profile could improve the diagnosis of fatty liver in dairy cows, which would

  17. Choline-Deficient-Diet-Induced Fatty Liver Is a Metastasis-Resistant Microenvironment.

    PubMed

    Nakamura, Miki; Suetsugu, Atsushi; Hasegawa, Kosuke; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Hoffman, Robert M

    2017-07-01

    Fatty liver disease is increasing in the developed and developing world. Liver metastasis from malignant lymphoma in the fatty liver is poorly understood. In a previous report, we developed color-coded imaging of the tumor microenvironment (TME) of the murine EL4-RFP malignant lymphoma during metastasis, including the lung. In the present report, we investigated the potential and microenvironment of the fatty liver induced by a choline-deficient diet as a metastatic site in this mouse lymphoma model. C57BL/6-GFP transgenic mice were fed with a choline-deficient diet in order to establish a fatty liver model. EL4-RFP cells were injected in the spleen of normal mice and fatty-liver mice. Metastases in mice with fatty liver or normal liver were imaged with the Olympus SZX7 microscope and the Olympus FV1000 confocal microscope. Metastases of EL4-RFP were observed in the liver, ascites and bone marrow. Primary tumors were imaged in the spleen at the injection site. The fewest metastases were observed in the fatty liver. In addition, the fewest cancer-associated fibroblasts (CAFs) were observed in the fatty liver. The relative metastatic resistance of the fatty liver may be due to the reduced number of CAFs in the fatty livers. The mechanism of the effect of the choline-deficient diet is discussed. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  18. Functional pitch of a liver: fatty liver disease diagnosis with photoacoustic spectrum analysis

    NASA Astrophysics Data System (ADS)

    Xu, Guan; Meng, Zhuoxian; Lin, Jiandie; Carson, Paul; Wang, Xueding

    2014-03-01

    To provide more information for classification and assessment of biological tissues, photoacoustic spectrum analysis (PASA) moves beyond the quantification of the intensities of the photoacoustic (PA) signals by the use of the frequency-domain power distribution, namely power spectrum, of broadband PA signals. The method of PASA quantifies the linear-fit to the power spectrum of the PA signals from a biological tissue with 3 parameters, including intercept, midband-fit and slope. Intercept and midband-fit reflect the total optical absorption of the tissues whereas slope reflects the heterogeneity of the tissue structure. Taking advantage of the optical absorption contrasts contributed by lipid and blood at 1200 and 532 nm, respectively and the heterogeneous tissue microstructure in fatty liver due to the lipid infiltration, we investigate the capability of PASA in identifying histological changes of fatty livers in mouse model. 6 and 9 pairs of normal and fatty liver tissues from rat models were examined by ex vivo experiment with a conventional rotational PA measurement system. One pair of rat models with normal and fatty livers was examined non-invasively and in situ with our recently developed ultrasound and PA parallel imaging system. The results support our hypotheses that the spectrum analysis of PA signals can provide quantitative measures of the differences between the normal and fatty liver tissues and that part of the PA power spectrum can suffice for characterization of microstructures in biological tissues. Experimental results also indicate that the vibrational absorption peak of lipid at 1200nm could facilitate fatty liver diagnosis.

  19. Effect of growth hormone on fatty liver in panhypopituitarism

    PubMed Central

    Takano, S.; Kanzaki, S.; Sato, M.; Kubo, T.; Seino, Y.

    1997-01-01

    Accepted 10 March 1997
 A 17 year old boy was admitted because of short stature and hepatomegaly. He was diagnosed with panhypopituitarism and fatty liver. The fatty liver improved, not with hydrocortisone or levothyroxine treatment, but with growth hormone administration. The fatty liver in this patient was attributable to a growth hormone deficient state.

 PMID:9245856

  20. Non-Alcoholic Fatty Liver Disease.

    PubMed

    Engin, Atilla

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is in parallel with the obesity epidemic and it is the most common cause of liver diseases. The development of hepatic steatosis in majority of patients is linked to dietary fat ingestion. NAFLD is characterized by excess accumulation of triglyceride in the hepatocyte due to both increased inflow of free fatty acids and de novo hepatic lipogenesis. Insulin resistance with the deficiency of insulin receptor substrate-2 (IRS-2)-associated phosphatidylinositol 3-kinase (PI3K) activity causes an increase in intracellular fatty acid-derived metabolites such as diacylglycerol, fatty acyl CoA or ceramides. Lipotoxicity-related mechanism of NAFLD could be explained still best by the "double-hit" hypothesis. Insulin resistance is the major mechanism in the development and progression of NAFLD/Non-alcoholic steatohepatitis (NASH). Metabolic oxidative stress, autophagy, and inflammation induce NASH progression. In the "first hit" the hepatic concentrations of diacylglycerol increase with rising saturated liver fat content in human NAFLD. Activities of mitochondrial respiratory chain complexes are decreased in liver tissue of patients with NASH. Furthermore, hepatocyte lipoapoptosis is a critical feature of NASH. In "second hit" reduced glutathione levels due to oxidative stress lead to overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling that induces cell death in the steatotic liver. Accumulation of toxic levels of reactive oxygen species (ROS) is caused by the ineffectual cycling of the endoplasmic reticulum (ER) oxidoreductin (Ero1)-protein disulfide isomerase oxidation cycle through the downstream of the inner membrane mitochondrial oxidative metabolism and Kelch like-ECH-associated protein 1 (Keap1)- Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.

  1. Probiotics in Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, and Cirrhosis.

    PubMed

    Qamar, Amir A

    2015-01-01

    With the growing epidemic of obesity, the incidence of both nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH) is increasing. The intestinal microbiota differs between individuals who are obese or have normal body mass indices. Animal studies have shown increased intestinal permeability in NAFL, NASH, and cirrhosis. This increases the risk of oxidative and inflammatory injury to the liver from intestinal microbacteria. It may also increase the risk of fatty acid injury and fatty deposition. Bacterial translocation is associated with increased portal hypertension and hepatic encephalopathy in cirrhosis. By preventing bacterial adhesion and translocation, probiotics may have a role in the management of patients with NAFL, NASH, and cirrhosis. Multiple small studies have suggested that probiotics improve some of the clinical markers of activity in patients with NAFL and NASH. Controlled studies have also shown improved outcomes in patients with cirrhosis who were treated with probiotics.

  2. Clinical characteristics of patients with diabetes mellitus and fatty liver diagnosed by liver/spleen Hounsfield units on CT scan.

    PubMed

    Sakitani, Kosuke; Enooku, Kenichiro; Kubo, Hirokazu; Tanaka, Akifumi; Arai, Hisakatsu; Kawazu, Shoji; Koike, Kazuhiko

    2017-06-01

    Objective The leading cause of liver injuries in diabetes mellitus may be associated with fatty liver. We aimed to elucidate the relationship between fatty liver and diabetes characteristics. Methods Retrospectively, 970 patients with diabetes were analysed. Fatty liver was diagnosed when the liver/spleen Hounsfield unit ratio by computed tomography was below 0.9. Clinical diabetes characteristics were compared between patients with and without fatty liver. Results Of 970 patients (717 male and 253 female; mean age 64.4 years), 175 males (24.4%) and 60 females (23.7%) had fatty liver. None of the 28 patients with type 1 diabetes had fatty liver. In male patients with type 2 diabetes, age, visceral adipose tissue (VAT), albumin, alanine amino-transferase (ALT), and triglycerides were independently associated with fatty liver. In females, age and bilirubin were associated with fatty liver. Conclusions Fatty liver is associated with type 2 diabetes characteristics, including younger age and elevated VAT, albumin, ALT, and triglycerides in males and younger age and elevated bilirubin levels in females.

  3. Clinical characteristics of patients with diabetes mellitus and fatty liver diagnosed by liver/spleen Hounsfield units on CT scan

    PubMed Central

    Sakitani, Kosuke; Enooku, Kenichiro; Kubo, Hirokazu; Tanaka, Akifumi; Arai, Hisakatsu; Kawazu, Shoji; Koike, Kazuhiko

    2017-01-01

    Objective The leading cause of liver injuries in diabetes mellitus may be associated with fatty liver. We aimed to elucidate the relationship between fatty liver and diabetes characteristics. Methods Retrospectively, 970 patients with diabetes were analysed. Fatty liver was diagnosed when the liver/spleen Hounsfield unit ratio by computed tomography was below 0.9. Clinical diabetes characteristics were compared between patients with and without fatty liver. Results Of 970 patients (717 male and 253 female; mean age 64.4 years), 175 males (24.4%) and 60 females (23.7%) had fatty liver. None of the 28 patients with type 1 diabetes had fatty liver. In male patients with type 2 diabetes, age, visceral adipose tissue (VAT), albumin, alanine amino-transferase (ALT), and triglycerides were independently associated with fatty liver. In females, age and bilirubin were associated with fatty liver. Conclusions Fatty liver is associated with type 2 diabetes characteristics, including younger age and elevated VAT, albumin, ALT, and triglycerides in males and younger age and elevated bilirubin levels in females. PMID:28553763

  4. Models of non-Alcoholic Fatty Liver Disease and Potential Translational Value: the Effects of 3,5-L-diiodothyronine.

    PubMed

    Grasselli, Elena; Canesi, Laura; Portincasa, Piero; Voci, Adriana; Vergani, Laura; Demori, Ilaria

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in industrialized countries and is associated with increased risk of cardiovascular, hepatic and metabolic diseases. Molecular mechanisms on the root of the disrupted lipid homeostasis in NAFLD and potential therapeutic strategies can benefit of in vivo and in vitro experimental models of fatty liver. Here, we describe the high fat diet (HFD)-fed rat in vivo model, and two in vitro models, the primary cultured rat fatty hepatocytes or the FaO rat hepatoma fatty cells, mimicking human NAFLD. Liver steatosis was invariably associated with increased number/size of lipid droplets (LDs) and modulation of expression of genes coding for key genes of lipid metabolism such as peroxisome proliferator-activated receptors (Ppars) and perilipins (Plins). In these models, we tested the anti-steatotic effects of 3,5-L-diiodothyronine (T2), a metabolite of thyroid hormones. T2 markedly reduced triglyceride content and LD size acting on mRNA expression of both Ppars and Plins. T2 also stimulated mitochondrial oxidative metabolism of fatty acids. We conclude that in vivo and especially in vitro models of NAFLD are valuable tools to screen a large number of compounds counteracting the deleterious effect of liver steatosis. Because of the high and negative impact of liver steatosis on human health, ongoing experimental studies from our group are unravelling the ultimate translational value of such cellular models of NAFLD.

  5. Biphasic effect of alcohol intake on the development of fatty liver disease.

    PubMed

    Takahashi, Hirokazu; Ono, Masafumi; Hyogo, Hideyuki; Tsuji, Chika; Kitajima, Yoichiro; Ono, Naofumi; Eguchi, Takahisa; Fujimoto, Kazuma; Chayama, Kazuaki; Saibara, Toshiji; Anzai, Keizo; Eguchi, Yuichiro

    2015-11-01

    Fatty liver is an important clinical feature not only in alcoholic and non-alcoholic fatty liver diseases, but in other chronic liver diseases as well. Our aim was to elucidate the effect and relationship between habitual alcohol intake and obesity in the development of fatty liver disease. We enrolled 8,029 subjects undergoing abdominal ultrasonography with general medical examinations, and analyzed the factors associated with fatty liver based on daily alcohol intake, body mass index (BMI), and waist circumference. For fatty liver, BMI, waist circumference, total cholesterol, triglycerides, and fasting plasma glucose were significant and independent risk factors. Heavy alcohol intake (50 g/day) was a significant risk factor for fatty liver in women (odds ratio [OR], 3.35). Analysis based on the presence or absence of obesity revealed that moderate alcohol intake was a significant negative risk factor for fatty liver in both male and female obese (BMI ≥25 kg/m(2)) subjects (OR, 0.74 for non-obese and 0.39 for obese patients, respectively). Heavy alcohol intake was also a significant negative risk factor in obese males (0.62). In contrast, heavy alcohol intake was a risk factor in non-obese males (OR, 1.29) and in all females (OR, 2.22 for non-obese and 6.6 for obese patients, respectively). The influence of alcohol intake on fatty liver differed depending on the level of alcohol consumption, gender, and the presence of obesity, and showed biphasic effects.

  6. Thiamine and fatty acid content of Lake Michigan Chinook salmon

    USGS Publications Warehouse

    Honeyfield, D.C.; Peters, A.K.; Jones, M.L.

    2008-01-01

    Nutritional status of Lake Michigan Chinook salmon (Oncorhynchus tshawytscha) is inadequately documented. An investigation was conducted to determine muscle and liver thiamine content and whole body fatty acid composition in small, medium and large Chinook salmon. Muscle and liver thiamine concentrations were highest in small salmon, and tended to decrease with increasing fish size. Muscle thiamine was higher in fall than spring in large salmon. The high percentage of Chinook salmon (24-32% in fall and 58-71% in spring) with muscle thiamine concentration below 500 pmol/g, which has been associated with loss of equilibrium and death in other Great Lake salmonines, suggest that Chinook appear to rely less on thiamine than other Great Lakes species for which such low concentrations would be associated with thiamine deficiency (Brown et al. 2005b). A positive correlation was observed between liver total thiamine and percent liver lipids (r = 0.53, P < 0.0001, n = 119). In medium and large salmon, liver lipids were observed to be low in fish with less than 4,000 pmol/g liver total thiamine. In individuals with greater than 4,000 pmol/g liver thiamine, liver lipid increased with thiamine concentration. Individual fatty acids declined between fall and spring. Essential omega-3 fatty acids appear to be conserved as lipid content declined. Arachidonic acid (C20:4n6), an essential omega-6 fatty acid was not different between fall and spring, although the sum of omega-6 (Sw6) fatty acids declined over winter. Elevated concentrations of saturated fatty acids (sum) were observed in whole body tissue lipid. In summary, thiamine, a dietary essential vitamin, and individual fatty acids were found to vary in Lake Michigan Chinook salmon by fish size and season of the year.

  7. Subclassification of fatty liver by its pathogenesis: cIEFing is believing.

    PubMed

    Byrne, Frances L; Hoehn, Kyle L

    2016-05-01

    Fatty liver, also termed hepatic steatosis or fatty liver disease, is a condition characterized by excess fat accumulation in the liver. Common causes of fatty liver include obesity, ageing, medications, genetic disorders, viral hepatitis, excess alcohol or toxins. This diversity in pathogenesis is matched by an equally diverse spectrum of consequences, whereby some individuals remain asymptomatic yet others progress through a series of inflammatory, fibrotic and metabolic disorders that can lead to liver failure, cancer or diabetes. Current treatment approaches for fatty liver do not differ by disease aetiology and primarily involve weight loss strategies or management of co-morbidities. In a recent paper published in this journal, Urasaki et al used capillary isoelectric focusing (cIEF) to create profiles of protein post-translational modifications that distinguish four different models of fatty liver in mice. Importantly, this new cIEF approach has the potential to provide rapid individualized diagnosis of fatty liver pathogenesis that may enable more accurate and personalized treatment strategies. Further testing and optimization of cIEF as a diagnostic screening tool in humans is warranted. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  8. Assessment of liver size by ultrasonography.

    PubMed

    Patzak, Monika; Porzner, Marc; Oeztuerk, Suemeyra; Mason, Richard Andrew; Wilhelm, Manfred; Graeter, Tilmann; Kratzer, Wolfgang; Haenle, Mark Martin; Akinli, Atilla Serif

    2014-09-01

    To determine liver span sonographically in a randomly selected population sample and identify factors that affect liver size. A total of 1,789 subjects (963 females, 826 males; mean age 41.8 ± 12.8 years) underwent sonographic examination of the liver in the midclavicular line to determine liver span. Subjects underwent physical examination and blood tests and completed a standardized interview questionnaire. The average liver span in the midclavicular line for the overall collective was 15.0 ± 1.5 cm; the average for females was 14.9 ± 1.6 cm and 15.1 ± 1.5 cm for males. Liver span exceeded 16 cm in 24.3% of subjects. Results of the multivariate analysis showed that, of the factors potentially influencing liver span, gender, age, body mass index, body height, fatty liver (p < 0.0001), waist-to-hip ratio (p = 0.015), and metabolic syndrome (p = 0.032) are significant. By contrast, diabetes mellitus, alcohol consumption, tobacco consumption, physical activity, and laboratory findings showed no influence. Sonographic measurement of liver span in the midclavicular line is a simple method for routine clinical use. Gender, age, body mass index, waist-to-hip ratio, body height, hepatic steatosis, and metabolic syndrome are factors associated with liver span. © 2014 Wiley Periodicals, Inc.

  9. Emerging roles of SIRT1 in fatty liver diseases

    PubMed Central

    Ding, Ren-Bo; Bao, Jiaolin; Deng, Chu-Xia

    2017-01-01

    Fatty liver diseases, which are commonly associated with high-fat/calorie diet, heavy alcohol consumption and/or other metabolic disorder causes, lead to serious medical concerns worldwide in recent years. It has been demonstrated that metabolic homeostasis disruption is most likely to be responsible for this global epidemic. Sirtuins are a group of conserved nicotinamide adenine dinucleotide (NAD+) dependent histone and/or protein deacetylases belonging to the silent information regulator 2 (Sir2) family. Among seven mammalian sirtuins, sirtuin 1 (SIRT 1) is the most extensively studied one and is involved in both alcoholic and nonalcoholic fatty liver diseases. SIRT1 plays beneficial roles in regulating hepatic lipid metabolism, controlling hepatic oxidative stress and mediating hepatic inflammation through deacetylating some transcriptional regulators against the progression of fatty liver diseases. Here we summarize the latest advances of the biological roles of SIRT1 in regulating lipid metabolism, oxidative stress and inflammation in the liver, and discuss the potential of SIRT1 as a therapeutic target for treating alcoholic and nonalcoholic fatty liver diseases. PMID:28808418

  10. Hydroxypropyl methylcellulose, a viscous soluble fiber, reduces insulin resistance and decreases fatty liver in Zucker Diabetic Fatty rats.

    PubMed

    Brockman, David A; Chen, Xiaoli; Gallaher, Daniel D

    2012-11-12

    Diets producing a high glycemic response result in exaggerated insulin secretion which induces hepatic lipogenesis, contributing to development of insulin resistance and fatty liver. Viscous dietary fibers blunt the postprandial rise in blood glucose, however their effect on type 2 diabetes and obesity are not entirely known. This study examined the effect of chronic consumption of the viscous, non-fermentable dietary fiber, hydroxypropyl methylcellulose (HPMC), on glucose control, insulin resistance and liver lipids in an obese diabetic rat model. Three groups of Zucker Diabetic Fatty (ZDF) rats were fed diets containing either 5% non-viscous cellulose (control), low viscosity HPMC (LV-HPMC) or high viscosity HPMC (HV- HPMC) for six weeks. Zucker lean littermates consuming cellulose served as a negative control. Markers of glucose control, including oral glucose tolerance test, glycated hemoglobin and urinary glucose, were measured as well as adiposity and the accumulation of liver lipids. The HPMC diets increased the viscosity of the small intestinal contents and reduced the postprandial rise in blood glucose. The food efficiency ratio was greater with HPMC feeding compared to the obese control and urinary excretion of glucose and ketone bodies was reduced. The two HPMC groups had lower glycated hemoglobin and kidney weights and a reduced area under the curve during a glucose tolerance test, indicating improved glucose control. Epididymal fat pad weight as percent of body weight was reduced in the HV-HPMC group compared to the obese control group. The HV-HPMC group also had lower concentrations of liver lipid and cholesterol and reduced liver weight. However, HV-HPMC feeding did not affect hepatic gene expression of SREBP-1c or FAS. Muscle concentration of acylcarnitines, a lipid intermediate in fatty acid β-oxidation, was not different between the HPMC groups and obese control, suggesting no change in muscle fatty acid oxidation by HPMC. Consumption of the

  11. Development of coaxial ultrasonic probe for fatty liver diagnostic system using ultrasonic velocity change

    NASA Astrophysics Data System (ADS)

    Hori, Makoto; Yokota, Daiki; Aotani, Yuhei; Kumagai, Yuta; Wada, Kenji; Matsunaka, Toshiyuki; Morikawa, Hiroyasu; Horinaka, Hiromichi

    2017-07-01

    A diagnostic system for fatty liver at an early stage is needed because fatty liver is linked to metabolic syndrome. We have already proposed a fatty liver diagnosis method based on the temperature coefficient of ultrasonic velocity. In this study, we fabricated a coaxial ultrasonic probe by integrating two kinds of transducers for warming and signal detection. The diagnosis system equipped with the coaxial probe was applied to tissue-mimicking phantoms including the fat area. The fat content rates corresponding to the set rates of the phantoms were estimated by the ultrasonic velocity-change method.

  12. Pediatric fatty liver disease: Role of ethnicity and genetics

    PubMed Central

    Marzuillo, Pierluigi; Miraglia del Giudice, Emanuele; Santoro, Nicola

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs’ group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver. PMID:24966605

  13. Adenosine signaling contributes to ethanol-induced fatty liver in mice

    PubMed Central

    Peng, Zhongsheng; Borea, Pier Andrea; Wilder, Tuere; Yee, Herman; Chiriboga, Luis; Blackburn, Michael R.; Azzena, Gianfranco; Resta, Giuseppe; Cronstein, Bruce N.

    2009-01-01

    Fatty liver is commonly associated with alcohol ingestion and abuse. While the molecular pathogenesis of these fatty changes is well understood, the biochemical and pharmacological mechanisms by which ethanol stimulates these molecular changes remain unknown. During ethanol metabolism, adenosine is generated by the enzyme ecto-5′-nucleotidase, and adenosine production and adenosine receptor activation are known to play critical roles in the development of hepatic fibrosis. We therefore investigated whether adenosine and its receptors play a role in the development of alcohol-induced fatty liver. WT mice fed ethanol on the Lieber-DeCarli diet developed hepatic steatosis, including increased hepatic triglyceride content, while mice lacking ecto-5′-nucleotidase or adenosine A1 or A2B receptors were protected from developing fatty liver. Similar protection was also seen in WT mice treated with either an adenosine A1 or A2B receptor antagonist. Steatotic livers demonstrated increased expression of genes involved in fatty acid synthesis, which was prevented by blockade of adenosine A1 receptors, and decreased expression of genes involved in fatty acid metabolism, which was prevented by blockade of adenosine A2B receptors. In vitro studies supported roles for adenosine A1 receptors in promoting fatty acid synthesis and for A2B receptors in decreasing fatty acid metabolism. These results indicate that adenosine generated by ethanol metabolism plays an important role in ethanol-induced hepatic steatosis via both A1 and A2B receptors and suggest that targeting adenosine receptors may be effective in the prevention of alcohol-induced fatty liver. PMID:19221436

  14. Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice

    PubMed Central

    Yang, Hao; Wang, Shu Pei; Mitchell, Grant A.

    2017-01-01

    Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency. PMID:29232702

  15. Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice.

    PubMed

    Xia, Bo; Cai, Guo He; Yang, Hao; Wang, Shu Pei; Mitchell, Grant A; Wu, Jiang Wei

    2017-12-01

    Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency.

  16. Evaluation of fatty liver fibrosis in rabbits using real-time shear wave elastography

    PubMed Central

    LU, YONGPING; WEI, JIA; TANG, YUEYUE; YUAN, YUAN; HUANG, YANLING; ZHANG, YONG; LI, YUNYAN

    2014-01-01

    The aim of the present study was to detect the elastic modulus (stiffness) of the livers of rabbits with non-alcoholic and alcoholic fatty liver disease using real-time shear wave elastography (SWE), and to investigate the fibrosis development process in the formation of fatty liver. The stiffness of the fatty livers in rabbit models prepared via feeding with alcohol or a high-fat diet were measured using a real-time SWE ultrasound system and a 4–15-MHz linear array probe, and the liver stiffness was compared with the pathological staging of the disease. The stiffness of the liver was positively correlated with the degree of pathological change in fatty liver disease (P<0.01). The stiffness of the liver in the alcoholic fatty liver group was higher compared with that in the non-alcoholic fatty liver and control groups, and the stiffness in the non-alcoholic fatty liver group was higher than that in the control group (P<0.01). Real-time SWE objectively identified the trend in the changing stiffness of the liver and noninvasively detected the development of fibrosis in the progression of non-alcoholic and alcoholic fatty liver disease. PMID:25009583

  17. Quantitative characterization of fatty liver disease using x-ray scattering

    NASA Astrophysics Data System (ADS)

    Elsharkawy, Wafaa B.; Elshemey, Wael M.

    2013-11-01

    Nonalcoholic fatty liver disease (NAFLD) is a dynamic condition in which fat abnormally accumulates within the hepatocytes. It is believed to be a marker of risk of later chronic liver diseases, such as liver cirrhosis and carcinoma. The fat content in liver biopsies determines its validity for liver transplantation. Transplantation of livers with severe NAFLD is associated with a high risk of primary non-function. Moreover, NAFLD is recognized as a clinically important feature that influences patient morbidity and mortality after hepatic resection. Unfortunately, there is a lack in a precise, reliable and reproducible method for quantification of NAFLD. This work suggests a method for the quantification of NAFLD. The method is based on the fact that fatty liver tissue would have a characteristic x-ray scattering profile with a relatively intense fat peak at a momentum transfer value of 1.1 nm-1 compared to a soft tissue peak at 1.6 nm-1. The fat content in normal and fatty liver is plotted against three profile characterization parameters (ratio of peak intensities, ratio of area under peaks and ratio of area under fat peak to total profile area) for measured and Monte Carlo simulated x-ray scattering profiles. Results show a high linear dependence (R2>0.9) of the characterization parameters on the liver fat content with a reported high correlation coefficient (>0.9) between measured and simulated data. These results indicate that the current method probably offers reliable quantification of fatty liver disease.

  18. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of nonalcoholic fatty liver disease

    USDA-ARS?s Scientific Manuscript database

    Obesity is often associated with a cluster of increased health risks collectively known as "Metabolic Syndrome" (MS). MS is often accompanied by development of fatty liver. Sometimes fatty liver results in damage leading to reduced liver function, and need for a transplant. This condition is known...

  19. Validity criteria for the diagnosis of fatty liver by M probe-based controlled attenuation parameter.

    PubMed

    Wong, Vincent Wai-Sun; Petta, Salvatore; Hiriart, Jean-Baptiste; Cammà, Calogero; Wong, Grace Lai-Hung; Marra, Fabio; Vergniol, Julien; Chan, Anthony Wing-Hung; Tuttolomondo, Antonino; Merrouche, Wassil; Chan, Henry Lik-Yuen; Le Bail, Brigitte; Arena, Umberto; Craxì, Antonio; de Lédinghen, Victor

    2017-09-01

    Controlled attenuation parameter (CAP) can be performed together with liver stiffness measurement (LSM) by transient elastography (TE) and is often used to diagnose fatty liver. We aimed to define the validity criteria of CAP. CAP was measured by the M probe prior to liver biopsy in 754 consecutive patients with different liver diseases at three centers in Europe and Hong Kong (derivation cohort, n=340; validation cohort, n=414; 101 chronic hepatitis B, 154 chronic hepatitis C, 349 non-alcoholic fatty liver disease, 37 autoimmune hepatitis, 49 cholestatic liver disease, 64 others; 277 F3-4; age 52±14; body mass index 27.2±5.3kg/m 2 ). The primary outcome was the diagnosis of fatty liver, defined as steatosis involving ≥5% of hepatocytes. The area under the receiver-operating characteristics curve (AUROC) for CAP diagnosis of fatty liver was 0.85 (95% CI 0.82-0.88). The interquartile range (IQR) of CAP had a negative correlation with CAP (r=-0.32, p<0.001), suggesting the IQR-to-median ratio of CAP would be an inappropriate validity parameter. In the derivation cohort, the IQR of CAP was associated with the accuracy of CAP (AUROC 0.86, 0.89 and 0.76 in patients with IQR of CAP <20 [15% of patients], 20-39 [51%], and ≥40dB/m [33%], respectively). Likewise, the AUROC of CAP in the validation cohort was 0.90 and 0.77 in patients with IQR of CAP <40 and ≥40dB/m, respectively (p=0.004). The accuracy of CAP in detecting grade 2 and 3 steatosis was lower among patients with body mass index ≥30kg/m 2 and F3-4 fibrosis. The validity of CAP for the diagnosis of fatty liver is lower if the IQR of CAP is ≥40dB/m. Lay summary: Controlled attenuation parameter (CAP) is measured by transient elastography (TE) for the detection of fatty liver. In this large study, using liver biopsy as a reference, we show that the variability of CAP measurements based on its interquartile range can reflect the accuracy of fatty liver diagnosis. In contrast, other clinical factors such

  20. The nutritional geometry of liver disease including non-alcoholic fatty liver disease.

    PubMed

    Simpson, Stephen J; Raubenheimer, David; Cogger, Victoria C; Macia, Laurence; Solon-Biet, Samantha M; Le Couteur, David G; George, Jacob

    2018-02-01

    Nutrition has a profound effect on chronic liver disease, especially non-alcoholic fatty liver disease (NAFLD). Most observational studies and clinical trials have focussed on the effects of total energy intake, or the intake of individual macronutrients and certain micronutrients, such as vitamin D, on liver disease. Although these studies have shown the importance of nutrition on hepatic outcomes, there is not yet any unifying framework for understanding the relationship between diet and liver disease. The Geometric Framework for Nutrition (GFN) is an innovative model for designing nutritional experiments or interpreting nutritional data that can determine the effects of nutrients and their interactions on animal behaviour and phenotypes. Recently the GFN has provided insights into the relationship between dietary energy and macronutrients on obesity and ageing in mammals including humans. Mouse studies using the GFN have disentangled the effects of macronutrients on fatty liver and the gut microbiome. The GFN is likely to play a significant role in disentangling the effects of nutrients on liver disease, especially NAFLD, in humans. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  1. Gut-liver axis and probiotics: Their role in non-alcoholic fatty liver disease

    PubMed Central

    Paolella, Giulia; Mandato, Claudia; Pierri, Luca; Poeta, Marco; Di Stasi, Martina; Vajro, Pietro

    2014-01-01

    The incidence of obesity and its related conditions, including non-alcoholic fatty liver disease (NAFLD), has dramatically increased in all age groups worldwide. Given the health consequences of these conditions, and the subsequent economic burden on healthcare systems, their prevention and treatment have become major priorities. Because standard dietary and lifestyle changes and pathogenically-oriented therapies (e.g., antioxidants, oral hypoglycemic agents, and lipid-lowering agents) often fail due to poor compliance and/or lack of efficacy, novel approaches directed toward other pathomechanisms are needed. Here we present several lines of evidence indicating that, by increasing energy extraction in some dysbiosis conditions or small intestinal bacterial overgrowth, specific gut microbiota and/or a “low bacterial richness” may play a role in obesity, metabolic syndrome, and fatty liver. Under conditions involving a damaged intestinal barrier (“leaky gut”), the gut-liver axis may enhance the natural interactions between intestinal bacteria/bacterial products and hepatic receptors (e.g., toll-like receptors), thus promoting the following cascade of events: oxidative stress, insulin-resistance, hepatic inflammation, and fibrosis. We also discuss the possible modulation of gut microbiota by probiotics, as attempted in NAFLD animal model studies and in several pilot pediatric and adult human studies. Globally, this approach appears to be a promising and innovative add-on therapeutic tool for NAFLD in the context of multi-target therapy. PMID:25400436

  2. An extended fatty liver index to predict non-alcoholic fatty liver disease.

    PubMed

    Kantartzis, K; Rettig, I; Staiger, H; Machann, J; Schick, F; Scheja, L; Gastaldelli, A; Bugianesi, E; Peter, A; Schulze, M B; Fritsche, A; Häring, H-U; Stefan, N

    2017-06-01

    In clinical practice, there is a strong interest in non-invasive markers of non-alcoholic fatty liver disease (NAFLD). Our hypothesis was that the fold-change in plasma triglycerides (TG) during a 2-h oral glucose tolerance test (fold-change TG OGTT ) in concert with blood glucose and lipid parameters, and the rs738409 C>G single nucleotide polymorphism (SNP) in PNPLA3 might improve the power of the widely used fatty liver index (FLI) to predict NAFLD. The liver fat content of 330 subjects was quantified by 1 H-magnetic resonance spectroscopy. Blood parameters were measured during fasting and after a 2-h OGTT. A subgroup of 213 subjects underwent these measurements before and after 9 months of a lifestyle intervention. The fold-change TG OGTT was closely associated with liver fat content (r=0.51, P<0.0001), but had less power to predict NAFLD (AUROC=0.75) than the FLI (AUROC=0.79). Not only was the fold-change TG OGTT independently associated with liver fat content and NAFLD, but so also were the 2-h blood glucose level and rs738409 C>G SNP in PNPLA3. In fact, a novel index (extended FLI) generated from these and the usual FLI parameters considerably increased its power to predict NAFLD (AUROC=0.79-0.86). The extended FLI also increased the power to predict changes in liver fat content with a lifestyle intervention (n=213; standardized beta coefficient: 0.23-0.29). This study has provided novel data confirming that the OGTT-derived fold-change TG OGTT and 2-h glucose level, together with the rs738409 C>G SNP in PNPLA3, allow calculation of an extended FLI that considerably improves its power to predict NAFLD. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Moro orange juice prevents fatty liver in mice.

    PubMed

    Salamone, Federico; Li Volti, Giovanni; Titta, Lucilla; Puzzo, Lidia; Barbagallo, Ignazio; La Delia, Francesco; Zelber-Sagi, Shira; Malaguarnera, Michele; Pelicci, Pier Giuseppe; Giorgio, Marco; Galvano, Fabio

    2012-08-07

    To establish if the juice of Moro, an anthocyanin-rich orange, may improve liver damage in mice with diet-induced obesity. Eight-week-old mice were fed a high-fat diet (HFD) and were administrated water or Moro juice for 12 wk. Liver morphology, gene expression of lipid transcription factors, and metabolic enzymes were assessed. Mice fed HFD displayed increased body weight, insulin resistance and dyslipidemia. Moro juice administration limited body weight gain, enhanced insulin sensitivity, and decreased serum triglycerides and total cholesterol. Mice fed HFD showed liver steatosis associated with ballooning. Dietary Moro juice markedly improved liver steatosis by inducing the expression of peroxisome proliferator-activated receptor-α and its target gene acylCoA-oxidase, a key enzyme of lipid oxidation. Consistently, Moro juice consumption suppressed the expression of liver X receptor-α and its target gene fatty acid synthase, and restored liver glycerol-3-phosphate acyltransferase 1 activity. Moro juice counteracts liver steatogenesis in mice with diet-induced obesity and thus may represent a promising dietary option for the prevention of fatty liver.

  4. Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research

    PubMed Central

    Willebrords, Joost; Pereira, Isabel Veloso Alves; Maes, Michaël; Yanguas, Sara Crespo; Colle, Isabelle; Van Den Bossche, Bert; Da silva, Tereza Cristina; Oliveira, Cláudia P; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Cogliati, Bruno; Vinken, Mathieu

    2015-01-01

    Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and ‘-omics’-based read-outs are still in their infancy, but show great promise. . In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed. PMID:26073454

  5. Small-for-size syndrome in live donor liver transplantation-Pathways of injury and therapeutic strategies.

    PubMed

    Goldaracena, Nicolas; Echeverri, Juan; Selzner, Markus

    2017-02-01

    Due to the severe organ shortage and the increasing gap between the supply and demand for donor grafts, live donor liver transplantation (LDLT) has become an accepted and alternative technique for the expansion of the donor pool. However, donor safety and good recipient outcomes must be balanced regarding risk stratification and decision-making within this patient population. Small-for-size syndrome (SFSS) is one of the complications encountered after LDLT, thus increasing the burden of optimizing donor graft selection and effective treatments during its occurrence. A graft-to-recipient weight ratio (GRWR) <0.8 predisposes the graft to SFSS. However, other factors may induce this complication even without a graft-to-patient size mismatch. Several strategies to prevent this complication include portal vein flow and liver outflow modulation, as well as pharmacological treatment. Also, as an entity with a multifactorial etiology, outcomes vary between right-lobe, left-lobe, and posterior-lobe donation among series encountered in the literature. In this review, we analyze the pathophysiology and classification of this complication, the state-of-the-art on management of SFSS, and the outcomes regarding the best treatment strategy on this patient population. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. New Insights from Rodent Models of Fatty Liver Disease

    PubMed Central

    2011-01-01

    Abstract Rodent models of fatty liver disease are essential research tools that provide a window into disease pathogenesis and a testing ground for prevention and treatment. Models come in many varieties involving dietary and genetic manipulations, and sometimes both. High-energy diets that induce obesity do not uniformly cause fatty liver disease; this has prompted close scrutiny of specific macronutrients and nutrient combinations to determine which have the greatest potential for hepatotoxicity. At the same time, diets that do not cause obesity or the metabolic syndrome but do cause severe steatohepatitis have been exploited to study factors important to progressive liver injury, including cell death, oxidative stress, and immune activation. Rodents with a genetic predisposition to overeating offer yet another model in which to explore the evolution of fatty liver disease. In some animals that overeat, steatohepatitis can develop even without resorting to a high-energy diet. Importantly, these models and others have been used to document that aerobic exercise can prevent or reduce fatty liver disease. This review focuses primarily on lessons learned about steatohepatitis from manipulations of diet and eating behavior. Numerous additional insights about hepatic lipid metabolism, which have been gained from genetically engineered mice, are also mentioned. Antioxid. Redox Signal. 15, 535–550. PMID:21126212

  7. Auxiliary partial orthotopic living donor liver transplantation with a small-for-size graft for congenital absence of the portal vein.

    PubMed

    Matsuura, Toshiharu; Soejima, Yuji; Taguchi, Tomoaki

    2010-12-01

    Congenital absence of the portal vein (CAPV) with an extrahepatic portosystemic shunt is a rare malformation; the completely absent type, Abernethy malformation type I, is especially rare. Liver transplantation for CAPV type I has been recently recognized as the only curative operation, but few reports have been published so far; meanwhile, auxiliary partial orthotopic liver transplantation (APOLT) has been proposed to be a very effective option, especially for pediatric patients. Here we present an 18-year-old adult patient with CAPV, asplenia, and an iliac shunt vessel who was managed successfully with APOLT using a small-for-size graft. To the best of our knowledge, this is the first adult patient who has experienced success with APOLT for CAPV. This is a feasible procedure: it not only fulfills the metabolic demands of the liver for adult patients but also potentially cures CAPV. Copyright © 2010 American Association for the Study of Liver Diseases.

  8. Assessment of Liver Viscoelasticity for the Diagnosis of Early Stage Fatty Liver Disease Using Transient Elastography

    NASA Astrophysics Data System (ADS)

    Remenieras, Jean-Pierre; Dejobert, Maelle; Bastard, Cécile; Miette, Véronique; Perarnau, Jean-Marc; Patat, Frédéric

    Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of fat within the Liver. The main objective of this work is (1) to evaluate the feasibility of measuring in vivo in the liver the shear wave phase velocity dispersion cs(ω) between 20 Hz and 90 Hz using vibration-controlled transient elastography (VCTE); (2) to estimate through the rheological Kelvin-Voigt model the shear elastic μ and shear viscosity η modulus; (3) to correlate the evolution of these viscoelastic parameters on two patients at Tours Hospital with the hepatic fat percentage measured with T1-weighted gradient-echo in-and out-phase MRI sequence. For the first volunteer who has 2% of fat in the liver, we obtained μ = 1233 ± 133 Pa and η = 0.5 ± 0.4 Pa.s. For the patient with 22% of fat, we measure μ = 964 ± 91 Pa and η = 1.77 ± 0.3 Pa.s. In conclusion, this novel method showed to be sensitive in characterizing the visco-elastic properties of fatty liver.

  9. Treatment options for nonalcoholic Fatty liver disease.

    PubMed

    Chitturi, Shivakumar

    2008-11-01

    Nonalcoholic fatty liver disease comprises a range of disorders from steatosis and steatohepatitis through to cirrhosis. Nonalcoholic steatohepatitis can progress to cirrhosis and liver-related death. Therefore, managing this common disorder is becoming an important public health issue. Lifestyle measures are commonly suggested but robust data are lacking. Trials with antioxidants (vitamin E, betaine) as well as cytoprotectants (ursodeoxycholic acid) have been disappointing. While data for insulin sensitizers such as metformin are less conclusive, thiazolidinediones appear promising. However, not all patients respond to thiazolidinediones. Moreover, issues related to weight gain, cardiovascular risk need to be addressed. The use of endocannabinoid antagonists and insulin secretagogues are novel strategies to combat this disorder.

  10. Curcumin improves alcoholic fatty liver by inhibiting fatty acid biosynthesis.

    PubMed

    Guo, Chang; Ma, Jingfan; Zhong, Qionghong; Zhao, Mengyuan; Hu, Tianxing; Chen, Tong; Qiu, Longxin; Wen, Longping

    2017-08-01

    Alcoholic fatty liver is a threat to human health. It has been long known that abstinence from alcohol is the most effective therapy, other effective therapies are not available for the treatment in humans. Curcumin has a great potential for anti-oxidation and anti-inflammation, but the effect on metabolic reconstruction remains little known. Here we performed metabolomic analysis by gas chromatography/mass spectrometry and explored ethanol pathogenic insight as well as curcumin action pattern. We identified seventy-one metabolites in mouse liver. Carbohydrates and lipids were characteristic categories. Pathway analysis results revealed that ethanol-induced pathways including biosynthesis of unsaturated fatty acids, fatty acid biosynthesis and pentose and glucuronate interconversions were suppressed by curcumin. Additionally, ethanol enhanced galactose metabolism and pentose phosphate pathway. Glyoxylate and dicarboxylate metabolism and pyruvate metabolism were inhibited in mice fed ethanol diet plus curcumin. Stearic acid, oleic acid and linoleic acid were disease biomarkers and therapical biomarkers. These results reflect the landscape of hepatic metabolism regulation. Our findings illustrate ethanol pathological pathway and metabolic mechanism of curcumin therapy. Copyright © 2017. Published by Elsevier Inc.

  11. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

    PubMed Central

    Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

    2017-01-01

    Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

  12. Metabolic profiling of fatty liver in young and middle‐aged adults: Cross‐sectional and prospective analyses of the Young Finns Study

    PubMed Central

    Würtz, Peter; Suomela, Emmi; Lehtovirta, Miia; Kangas, Antti J.; Jula, Antti; Mikkilä, Vera; Viikari, Jorma S.A.; Juonala, Markus; Rönnemaa, Tapani; Hutri‐Kähönen, Nina; Kähönen, Mika; Lehtimäki, Terho; Soininen, Pasi; Ala‐Korpela, Mika; Raitakari, Olli T.

    2016-01-01

    Nonalcoholic fatty liver is associated with obesity‐related metabolic disturbances, but little is known about the metabolic perturbations preceding fatty liver disease. We performed comprehensive metabolic profiling to assess how circulating metabolites, such as lipoprotein lipids, fatty acids, amino acids, and glycolysis‐related metabolites, reflect the presence of and future risk for fatty liver in young adults. Sixty‐eight lipids and metabolites were quantified by nuclear magnetic resonance metabolomics in the population‐based Young Finns Study from serum collected in 2001 (n = 1,575), 2007 (n = 1,509), and 2011 (n = 2,002). Fatty liver was diagnosed by ultrasound in 2011 when participants were aged 34‐49 years (19% prevalence). Cross‐sectional associations as well as 4‐year and 10‐year risks for fatty liver were assessed by logistic regression. Metabolites across multiple pathways were strongly associated with the presence of fatty liver (P < 0.0007 for 60 measures in age‐adjusted and sex‐adjusted cross‐sectional analyses). The strongest direct associations were observed for extremely large very‐low‐density lipoprotein triglycerides (odds ratio [OR] = 4.86 per 1 standard deviation, 95% confidence interval 3.48‐6.78), other very‐low‐density lipoprotein measures, and branched‐chain amino acids (e.g., leucine OR = 2.94, 2.51‐3.44). Strong inverse associations were observed for high‐density lipoprotein measures, e.g., high‐density lipoprotein size (OR = 0.36, 0.30‐0.42) and several fatty acids including omega‐6 (OR = 0.37, 0.32‐0.42). The metabolic associations were attenuated but remained significant after adjusting for waist, physical activity, alcohol consumption, and smoking (P < 0.0007). Similar aberrations in the metabolic profile were observed already 10 years before fatty liver diagnosis. Conclusion: Circulating lipids, fatty acids, and amino acids reflect fatty liver independently of routine metabolic risk

  13. Physical activity as a protective factor for development of non-alcoholic fatty liver in men

    PubMed Central

    Pinto, Carla Giuliano de Sá; Marega, Marcio; de Carvalho, José Antonio Maluf; Carmona, Felipe Gambetta; Lopes, Carlos Eduardo Felix; Ceschini, Fabio Luis; Bocalini, Danilo Sales; Figueira, Aylton José

    2015-01-01

    Objective To determine the impact of physical activity on the prevalence of fatty liver, metabolic and cardiovascular disease in adult men. Methods This study evaluated 1,399 men (40.7±8.18 years) with body mass index of 26.7kg/m2 (±3.4) who participated in the Protocol of Preventive Health Check-up at Hospital Israelita Albert Einstein from January to October 2011. We conducted tests of serum blood glucose, total cholesterol, LDL, HDL, triglycerides, reactive c-protein, aspartate transaminase, alanine transaminase and gamma-glutamyl transpeptidase. The statistical analysis comprised in the comparison of mean and standard deviation. The analysis of variance was based in two paths of two way ANOVA, Student’s t-test, Mann Whitney U test, Wald test and χ2. We considered a significance level at p<0.05 and correlation of univariate Poison with 95% confidence interval. Results :Fatty liver was diagnosed in 37.0% of the sample. Triglyceride levels of active men with fatty liver were 148.2±77.6mg/dL while inactive men with fatty liver had 173.4±15.6mg/dL. The remaining serum levels were normal. Inactive individuals showed higher values than active. In addition, inactive individuals have 10.68 times higher risk of developing fatty liver compared with active. Conclusion Physical activity improves metabolic parameters such as triglycerides, weight control, HDL, which interfere in the development of fatty liver. Physically active individuals had lower fatty liver prevalence regardless of values of body composition and lipid profile, leading the conclusion that physical activity has a protective role against development of fatty liver. PMID:25993066

  14. Comparison of fatty liver index with noninvasive methods for steatosis detection and quantification

    PubMed Central

    Zelber-Sagi, Shira; Webb, Muriel; Assy, Nimer; Blendis, Laurie; Yeshua, Hanny; Leshno, Moshe; Ratziu, Vlad; Halpern, Zamir; Oren, Ran; Santo, Erwin

    2013-01-01

    AIM: To compare noninvasive methods presently used for steatosis detection and quantification in nonalcoholic fatty liver disease (NAFLD). METHODS: Cross-sectional study of subjects from the general population, a subgroup from the First Israeli National Health Survey, without excessive alcohol consumption or viral hepatitis. All subjects underwent anthropometric measurements and fasting blood tests. Evaluation of liver fat was performed using four noninvasive methods: the SteatoTest; the fatty liver index (FLI); regular abdominal ultrasound (AUS); and the hepatorenal ultrasound index (HRI). Two of the noninvasive methods have been validated vs liver biopsy and were considered as the reference methods: the HRI, the ratio between the median brightness level of the liver and right kidney cortex; and the SteatoTest, a biochemical surrogate marker of liver steatosis. The FLI is calculated by an algorithm based on triglycerides, body mass index, γ-glutamyl-transpeptidase and waist circumference, that has been validated only vs AUS. FLI < 30 rules out and FLI ≥ 60 rules in fatty liver. RESULTS: Three hundred and thirty-eight volunteers met the inclusion and exclusion criteria and had valid tests. The prevalence rate of NAFLD was 31.1% according to AUS. The FLI was very strongly correlated with SteatoTest (r = 0.91, P < 0.001) and to a lesser but significant degree with HRI (r = 0.55, P < 0.001). HRI and SteatoTest were significantly correlated (r = 0.52, P < 0.001). The κ between diagnosis of fatty liver by SteatoTest (≥ S2) and by FLI (≥ 60) was 0.74, which represented good agreement. The sensitivity of FLI vs SteatoTest was 85.5%, specificity 92.6%, positive predictive value (PPV) 74.7%, and negative predictive value (NPV) 96.1%. Most subjects (84.2%) with FLI < 60 had S0 and none had S3-S4. The κ between diagnosis of fatty liver by HRI (≥ 1.5) and by FLI (≥ 60) was 0.43, which represented only moderate agreement. The sensitivity of FLI vs HRI was 56

  15. Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

    PubMed Central

    Yki-Järvinen, Hannele

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance. PMID:26556368

  16. 1H-Nuclear Magnetic Resonance-Based Plasma Metabolic Profiling of Dairy Cows with Fatty Liver

    PubMed Central

    Xu, Chuang; Sun, Ling-wei; Xia, Cheng; Zhang, Hong-you; Zheng, Jia-san; Wang, Jun-song

    2016-01-01

    Fatty liver is a common metabolic disorder of dairy cows during the transition period. Historically, the diagnosis of fatty liver has involved liver biopsy, biochemical or histological examination of liver specimens, and ultrasonographic imaging of the liver. However, more convenient and noninvasive methods would be beneficial for the diagnosis of fatty liver in dairy cows. The plasma metabolic profiles of dairy cows with fatty liver and normal (control) cows were investigated to identify new biomarkers using 1H nuclear magnetic resonance. Compared with the control group, the primary differences in the fatty liver group included increases in β-hydroxybutyric acid, acetone, glycine, valine, trimethylamine-N-oxide, citrulline, and isobutyrate, and decreases in alanine, asparagine, glucose, γ-aminobutyric acid glycerol, and creatinine. This analysis revealed a global profile of endogenous metabolites, which may present potential biomarkers for the diagnosis of fatty liver in dairy cows. PMID:26732447

  17. PNPLA3 I148M variant in nonalcoholic fatty liver disease: demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis.

    PubMed

    Chen, Li-Zhen; Xin, Yong-Ning; Geng, Ning; Jiang, Man; Zhang, Ding-Ding; Xuan, Shi-Ying

    2015-01-21

    Patatin-like phospholipase domain-containing 3 (PNPLA3 or adiponutrin) displays anabolic and catabolic activities in lipid metabolism, and has been reported to be significantly associated with liver fat content. Various studies have established a strong link between the 148 isoleucine to methionine protein variant (I148M) of PNPLA3 and liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, detailed demographic and ethnic characteristics of the I148M variant and its role in the development of nonalcoholic fatty liver fibrosis have not been fully elucidated. The present review summarizes the current knowledge on the association between the PNPLA3 I148M variant and NAFLD, and especially its role in the development of nonalcoholic fatty liver fibrosis. First, we analyze the impact of demographic and ethnic characteristics of the PNPLA3 I148M variant and the presence of metabolic syndrome on the association between PNPLA3 I148M and NAFLD. Then, we explore the role of the PNPLA3 I148M in the development of nonalcoholic fatty liver fibrosis, and hypothesize the underlying mechanisms by speculating a pro-fibrogenic network. Finally, we briefly highlight future research that may elucidate the specific mechanisms of the PNPLA3 I148M variant in fibrogenesis, which, in turn, provides a theoretical foundation and valuable experimental data for the clinical management of nonalcoholic fatty liver fibrosis.

  18. PNPLA3 I148M variant in nonalcoholic fatty liver disease: Demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis

    PubMed Central

    Chen, Li-Zhen; Xin, Yong-Ning; Geng, Ning; Jiang, Man; Zhang, Ding-Ding; Xuan, Shi-Ying

    2015-01-01

    Patatin-like phospholipase domain-containing 3 (PNPLA3 or adiponutrin) displays anabolic and catabolic activities in lipid metabolism, and has been reported to be significantly associated with liver fat content. Various studies have established a strong link between the 148 isoleucine to methionine protein variant (I148M) of PNPLA3 and liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, detailed demographic and ethnic characteristics of the I148M variant and its role in the development of nonalcoholic fatty liver fibrosis have not been fully elucidated. The present review summarizes the current knowledge on the association between the PNPLA3 I148M variant and NAFLD, and especially its role in the development of nonalcoholic fatty liver fibrosis. First, we analyze the impact of demographic and ethnic characteristics of the PNPLA3 I148M variant and the presence of metabolic syndrome on the association between PNPLA3 I148M and NAFLD. Then, we explore the role of the PNPLA3 I148M in the development of nonalcoholic fatty liver fibrosis, and hypothesize the underlying mechanisms by speculating a pro-fibrogenic network. Finally, we briefly highlight future research that may elucidate the specific mechanisms of the PNPLA3 I148M variant in fibrogenesis, which, in turn, provides a theoretical foundation and valuable experimental data for the clinical management of nonalcoholic fatty liver fibrosis. PMID:25624712

  19. Effects of Fatty Liver Induced by Excess Orotic Acid on B-Group Vitamin Concentrations of Liver, Blood, and Urine in Rats.

    PubMed

    Shibata, Katsumi; Morita, Nobuya; Kawamura, Tomoyo; Tsuji, Ai; Fukuwatari, Tsutomu

    2015-01-01

    Fatty liver is caused when rats are given orotic acid of the pyrimidine base in large quantities. The lack of B-group vitamins suppresses the biosynthesis of fatty acids. We investigated how orotic acid-induced fatty liver affects the concentrations of liver, blood, and urine B-group vitamins in rats. The vitamin B6 and B12 concentrations of liver, blood, and urine were not affected by orotic acid-induced fatty liver. Vitamin B2 was measured only in the urine, but was unchanged. The liver, blood, and urine concentrations of niacin and its metabolites fell dramatically. Niacin and its metabolites in the liver, blood, and urine were affected as expected. Although the concentrations of vitamin B1, pantothenic acid, folate, and biotin in liver and blood were decreased by orotic acid-induced fatty liver, these urinary excretion amounts showed a specific pattern toward increase. Generally, as for the typical urinary excretion of B-group vitamins, these are excreted when the body is saturated. However, the ability to sustain vitamin B1, pantothenic acid, folate, and biotin decreased in fatty liver, which is hypothesized as a specific phenomenon. This metabolic response might occur to prevent an abnormally increased biosynthesis of fatty acids by orotic acid.

  20. Plasma phospholipids and fatty acid composition differ between liver biopsy-proven nonalcoholic fatty liver disease and healthy subjects

    PubMed Central

    Ma, D W L; Arendt, B M; Hillyer, L M; Fung, S K; McGilvray, I; Guindi, M; Allard, J P

    2016-01-01

    Background: There is growing evidence that nonalcoholic fatty liver disease (NAFLD) is associated with perturbations in liver lipid metabolism. Liver phospholipid and fatty acid composition have been shown to be altered in NAFLD. However, detailed profiles of circulating lipids in the pathogenesis of NAFLD are lacking. Objective: Therefore, the objective of the present study was to examine circulating lipids and potential mechanisms related to hepatic gene expression between liver biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH) and healthy subjects. Subjects: Plasma phospholipid and fatty acid composition were determined in 31 healthy living liver donors as healthy controls (HC), 26 patients with simple hepatic steatosis (SS) and 20 with progressive NASH. Hepatic gene expression was analyzed by Illumina microarray in a subset of 22 HC, 16 SS and 14 NASH. Results: Concentrations of phosphatidylethanolamine (PE) increased relative to disease progression, HCFatty acid composition of phospholipids was also remodeled. In particular, docosahexaenoic and arachidonic acid were higher (P<0.05) in SS and NASH relative to HC in PS. Differentially expressed hepatic genes included ETNK1 and PLSCR1 that are involved in PE synthesis and PS transport, respectively. Conclusions: The present study demonstrates that there is a disruption in phospholipid metabolism that is present in SS, but more pronounced in NASH. Intervention studies targeted at lipid metabolism could benefit SS and NASH. PMID:27428872

  1. Digital liver biopsy: Bio-imaging of fatty liver for translational and clinical research

    PubMed Central

    Mancini, Marcello; Summers, Paul; Faita, Francesco; Brunetto, Maurizia R; Callea, Francesco; De Nicola, Andrea; Di Lascio, Nicole; Farinati, Fabio; Gastaldelli, Amalia; Gridelli, Bruno; Mirabelli, Peppino; Neri, Emanuele; Salvadori, Piero A; Rebelos, Eleni; Tiribelli, Claudio; Valenti, Luca; Salvatore, Marco; Bonino, Ferruccio

    2018-01-01

    The rapidly growing field of functional, molecular and structural bio-imaging is providing an extraordinary new opportunity to overcome the limits of invasive liver biopsy and introduce a “digital biopsy” for in vivo study of liver pathophysiology. To foster the application of bio-imaging in clinical and translational research, there is a need to standardize the methods of both acquisition and the storage of the bio-images of the liver. It can be hoped that the combination of digital, liquid and histologic liver biopsies will provide an innovative synergistic tri-dimensional approach to identifying new aetiologies, diagnostic and prognostic biomarkers and therapeutic targets for the optimization of personalized therapy of liver diseases and liver cancer. A group of experts of different disciplines (Special Interest Group for Personalized Hepatology of the Italian Association for the Study of the Liver, Institute for Biostructures and Bio-imaging of the National Research Council and Bio-banking and Biomolecular Resources Research Infrastructure) discussed criteria, methods and guidelines for facilitating the requisite application of data collection. This manuscript provides a multi-Author review of the issue with special focus on fatty liver. PMID:29527259

  2. Digital liver biopsy: Bio-imaging of fatty liver for translational and clinical research.

    PubMed

    Mancini, Marcello; Summers, Paul; Faita, Francesco; Brunetto, Maurizia R; Callea, Francesco; De Nicola, Andrea; Di Lascio, Nicole; Farinati, Fabio; Gastaldelli, Amalia; Gridelli, Bruno; Mirabelli, Peppino; Neri, Emanuele; Salvadori, Piero A; Rebelos, Eleni; Tiribelli, Claudio; Valenti, Luca; Salvatore, Marco; Bonino, Ferruccio

    2018-02-27

    The rapidly growing field of functional, molecular and structural bio-imaging is providing an extraordinary new opportunity to overcome the limits of invasive liver biopsy and introduce a "digital biopsy" for in vivo study of liver pathophysiology. To foster the application of bio-imaging in clinical and translational research, there is a need to standardize the methods of both acquisition and the storage of the bio-images of the liver. It can be hoped that the combination of digital, liquid and histologic liver biopsies will provide an innovative synergistic tri-dimensional approach to identifying new aetiologies, diagnostic and prognostic biomarkers and therapeutic targets for the optimization of personalized therapy of liver diseases and liver cancer. A group of experts of different disciplines (Special Interest Group for Personalized Hepatology of the Italian Association for the Study of the Liver, Institute for Biostructures and Bio-imaging of the National Research Council and Bio-banking and Biomolecular Resources Research Infrastructure) discussed criteria, methods and guidelines for facilitating the requisite application of data collection. This manuscript provides a multi-Author review of the issue with special focus on fatty liver.

  3. Non-alcoholic fatty liver and the gut microbiota.

    PubMed

    Bashiardes, Stavros; Shapiro, Hagit; Rozin, Shachar; Shibolet, Oren; Elinav, Eran

    2016-09-01

    Non-alcoholic fatty liver (NAFLD) is a common, multi-factorial, and poorly understood liver disease whose incidence is globally rising. NAFLD is generally asymptomatic and associated with other manifestations of the metabolic syndrome. Yet, up to 25% of NAFLD patients develop a progressive inflammatory liver disease termed non-alcoholic steatohepatitis (NASH) that may progress towards cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. In recent years, several lines of evidence suggest that the gut microbiome represents a significant environmental factor contributing to NAFLD development and its progression into NASH. Suggested microbiome-associated mechanisms contributing to NAFLD and NASH include dysbiosis-induced deregulation of the gut endothelial barrier function, which facilitates systemic bacterial translocation, and intestinal and hepatic inflammation. Furthermore, increased microbiome-modulated metabolites such as lipopolysaccharides, short chain fatty acids (SCFAs), bile acids, and ethanol, may affect liver pathology through multiple direct and indirect mechanisms. Herein, we discuss the associations, mechanisms, and clinical implications of the microbiome's contribution to NAFLD and NASH. Understanding these contributions to the development of fatty liver pathogenesis and its clinical course may serve as a basis for development of therapeutic microbiome-targeting approaches for treatment and prevention of NAFLD and NASH. Intestinal host-microbiome interactions play diverse roles in the pathogenesis and progression of NAFLD and NASH. Elucidation of the mechanisms driving these microbial effects on the pathogenesis of NAFLD and NASH may enable to identify new diagnostic and therapeutic targets of these common metabolic liver diseases. This article is part of a special issue on microbiota.

  4. Large-for-size liver transplant: a single-center experience.

    PubMed

    Akdur, Aydincan; Kirnap, Mahir; Ozcay, Figen; Sezgin, Atilla; Ayvazoglu Soy, Hatice Ebru; Karakayali Yarbug, Feza; Yildirim, Sedat; Moray, Gokhan; Arslan, Gulnaz; Haberal, Mehmet

    2015-04-01

    The ideal ratio between liver transplant graft mass and recipient body weight is unknown, but the graft probably must weigh 0.8% to 2.0% recipient weight. When this ratio > 4%, there may be problems due to large-for-size transplant, especially in recipients < 10 kg. This condition is caused by discrepancy between the small abdominal cavity and large graft and is characterized by decreased blood supply to the liver graft and graft dysfunction. We evaluated our experience with large-for-size grafts. We retrospectively evaluated 377 orthotopic liver transplants that were performed from 2001-2014 in our center. We included 188 pediatric transplants in our study. There were 58 patients < 10 kg who had living-donor living transplant with graft-to-bodyweight ratio > 4%. In 2 patients, the abdomen was closed with a Bogota bag. In 5 patients, reoperation was performed due to vascular problems and abdominal hypertension, and the abdomen was closed with a Bogota bag. All Bogota bags were closed in 2 weeks. After closing the fascia, 10 patients had vascular problems that were diagnosed in the operating room by Doppler ultrasonography, and only the skin was closed without fascia closure. No graft loss occurred due to large-for-size transplant. There were 8 patients who died early after transplant (sepsis, 6 patients; brain death, 2 patients). There was no major donor morbidity or donor mortality. Large-for-size graft may cause abdominal compartment syndrome due to the small size of the recipient abdominal cavity, size discrepancies in vascular caliber, insufficient portal circulation, and disturbance of tissue oxygenation. Abdominal closure with a Bogota bag in these patients is safe and effective to avoid abdominal compartment syndrome. Early diagnosis by ultrasonography in the operating room after fascia closure and repeated ultrasonography at the clinic may help avoid graft loss.

  5. Gut-Liver Axis, Nutrition, and Non Alcoholic Fatty Liver Disease

    PubMed Central

    Kirpich, Irina A.; Marsano, Luis S.; McClain, Craig J.

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases involving hepatic fat accumulation, inflammation with the potential progression to fibrosis and cirrhosis over time. NAFLD is often associated with obesity, insulin resistance, and diabetes. The interactions between the liver and the gut, the so-called ”gut-liver axis”, play a critical role in NAFLD onset and progression. Compelling evidence links the gut microbiome, intestinal barrier integrity, and NAFLD. The dietary factors may alter the gut microbiota and intestinal barrier function, favoring the occurrence of metabolic endotoxemia and low grade inflammation, thereby contributing to the development of obesity and obesity-associated fatty liver disease. Therapeutic manipulations with prebiotics and probiotics to modulate the gut microbiota and maintain intestinal barrier integrity are potential agents for NAFLD management. This review summarizes the current knowledge regarding the complex interplay between the gut microbiota, intestinal barrier, and dietary factors in NAFLD pathogenesis. The concepts addressed in this review have important clinical implications, although more work needs to be done to understand how dietary factors affect the gut barrier and microbiota, and to comprehend how microbe-derived components may interfere with the host’s metabolism contributing to NAFLD development. PMID:26151226

  6. The Natural Course of Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Calzadilla Bertot, Luis; Adams, Leon Anton

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from “bland steatosis” to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death. PMID:27213358

  7. A disease-specific quality of life instrument for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: CLDQ-NAFLD.

    PubMed

    Younossi, Zobair M; Stepanova, Maria; Henry, Linda; Racila, Andrei; Lam, Brian; Pham, Huong T; Hunt, Sharon

    2017-08-01

    Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are the most common causes of chronic liver disease with known negative impact on patients' health-related quality of life. Our aim was to validate a disease-specific health-related quality of life instrument useful for efficacy trials involving patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. From a long item selection questionnaire, we selected relevant items which, by factor analysis, were grouped into domains constituting Chronic Liver Disease Questionnaire-Non-Alcoholic Fatty Liver Disease version. The developed instrument was subjected to internal validity, test-retest reliability and construct validity assessment using standard methods. For development of the Chronic Liver Disease Questionnaire-Non-Alcoholic Fatty Liver Disease version instrument, a 75-item-long item selection questionnaire was administered to 25 patients with non-alcoholic fatty liver disease. After item reduction, factor analysis found that 98.7% of variance in the remaining items would be explained by six factors. Thus, the resulting Chronic Liver Disease Questionnaire-Non-Alcoholic Fatty Liver Disease version instrument had 36 items grouped into six domains: Abdominal Symptoms, Activity, Emotional, Fatigue, Systemic Symptoms, and Worry. The independent validation group included another 104 patients with non-alcoholic fatty liver disease. The Cronbach's alphas of 0.74-0.90 suggested good to excellent internal consistency of the domains. Furthermore, the presence of obesity and history of depression were discriminated best by Chronic Liver Disease Questionnaire-Non-Alcoholic Fatty Liver Disease version scores (P<.05). The domains' correlations with the most relevant domains of Short Form-36 exceeded 0.70. Test-retest reliability in a subgroup of patients (N=27) demonstrated no significant within-patient variability with multiple administrations (all median differences were zero, all P>.15

  8. Experimental study of osthole on treatment of hyperlipidemic and alcoholic fatty liver in animals

    PubMed Central

    Song, Fang; Xie, Mei-Lin; Zhu, Lu-Jia; Zhang, Ke-Ping; Xue, Jie; Gu, Zhen-Lun

    2006-01-01

    AIM: To evaluate the effects of osthole on fatty liver, and investigate the possible mechanism. METHODS: A quail model with hyperlipidemic fatty liver and rat model with alcoholic fatty liver were set up by feeding high fat diet and alcohol, respectively. These experimental animals were then treated with osthole 5-20 mg/kg for 6 wk, respectively. Whereafter, the lipid in serum and hepatic tissue, and coefficient of hepatic weight were measured. RESULTS: After treatment with osthole the levels of serum total cholesterol (TC), triglyceride (TG), lower density lipoprotein-cholesterol (LDL-C), coefficient of hepatic weight, and the hepatic tissue contents of TC and TG were significantly decreased. The activity of superoxide dismutase (SOD) in liver was improved. In alcohol-induced fatty liver rats, the level of malondialdehyde (MDA) in liver was decreased. In high fat-induced fatty liver quails, glutathione peroxidase (GSH-PX) in liver was significantly improved. The histological evaluation of liver specimens demonstrated that the osthole dramatically decreased lipid accumulation. CONCLUSION: These results suggested that osthole had therapeutic effects on both alcohol and high fat-induced fatty liver. The mechanism might be associated with its antioxidation. PMID:16865778

  9. Prevention of alcoholic fatty liver and mitochondrial dysfunction in the rat by long-chain polyunsaturated fatty acids

    PubMed Central

    Song, Byoung-Joon; Moon, Kwan-Hoon; Olsson, Nils U.; Salem, Norman

    2008-01-01

    Background/Aims We reported that reduced dietary intake of polyunsaturated fatty acids (PUFA) such as arachidonic (AA,20:4n6, omega-6) and docosahexaenoic (DHA,22:6n3, omega-3) acids led to alcohol-induced fatty liver and fibrosis. This study was aimed at studying the mechanisms by which a DHA/AA-supplemented diet prevents alcohol-induced fatty liver. Methods Male Long-Evans rats were fed an ethanol or control liquid-diet with or without DHA/AA for 9 weeks. Plasma transaminase levels, liver histology, oxidative/nitrosative stress markers, and activities of oxidatively-modified mitochondrial proteins were evaluated. Results Chronic alcohol administration increased the degree of fatty liver but fatty liver decreased significantly in rats fed the alcohol-DHA/AA-supplemented diet. Alcohol exposure increased oxidative/nitrosative stress with elevated levels of ethanol-inducible CYP2E1, nitric oxide synthase, nitrite and mitochondrial hydrogen peroxide. However, these increments were normalized in rats fed the alcohol-DHA/AA-supplemented diet. The number of oxidatively-modified mitochondrial proteins was markedly increased following alcohol exposure but significantly reduced in rats fed the alcohol-DHA/AA-supplemented diet. The suppressed activities of mitochondrial aldehyde dehydrogenase, ATP synthase, and 3-ketoacyl-CoA thiolase in ethanol-exposed rats were also recovered in animals fed the ethanol-DHA/AA-supplemented diet. Conclusions Addition of DHA/AA prevents alcohol-induced fatty liver and mitochondrial dysfunction in an animal model by protecting various mitochondrial enzymes most likely through reducing oxidative/nitrosative stress. PMID:18571270

  10. Estimation of fish and omega-3 fatty acid intake in pediatric nonalcoholic fatty liver disease

    PubMed Central

    St-Jules, David E; Watters, Corilee A; Brunt, Elizabeth M; Wilkens, Lynne R; Novotny, Rachel; Belt, Patricia; Lavine, Joel E

    2013-01-01

    Introduction Fish and omega-3 fatty acids are reported to be beneficial in pediatric nonalcoholic fatty liver disease (NAFLD), but no studies have assessed their relation to histological severity. The objectives of this study were to evaluate the dietary intake of fish and omega-3 fatty acids in children with biopsy-proven NAFLD, and examine their association with serological and histological indicators of disease. Materials and Methods This was a cross-sectional analysis of 223 children (6–18 years) that participated in the Treatment of Nonalcoholic Fatty Liver Disease in Children trial or the NAFLD Database study conducted by the Nonalcoholic Steatohepatitis Clinical Research Network. The distribution of fish and omega-3 fatty acid intake were determined from responses to the Block Brief 2000 Food Frequency Questionnaire, and analyzed for associations with serum alanine aminotransferase, histological features of fatty liver disease, and diagnosis of steatohepatitis after adjusting for demographic, anthropometric and dietary variables. Results The minority of subjects consumed the recommended eight ounces of fish per week (22/223 (10%)) and 200 mg of long-chain omega-3 fatty acids per day (12/223 (5%)). Lack of fish and long-chain omega-3 fatty acid intake was associated with greater portal (p=0.03 and p=0.10, respectively) and lobular inflammation (p=0.09 and p=0.004, respectively) after controlling for potential confounders. Discussion Fish and omega-3 fatty acid intake were insufficient in children with NAFLD, which may increase susceptibility to hepatic inflammation. Patients with pediatric NAFLD should be encouraged to consume the recommended amount of fish per week. PMID:24177784

  11. Novel circulating biomarkers for non-alcoholic fatty liver disease: A systematic review.

    PubMed

    Sahebkar, Amirhossein; Sancho, Elena; Abelló, David; Camps, Jordi; Joven, Jorge

    2018-02-01

    Currently, a liver biopsy remains the only reliable way to precisely diagnose non-alcoholic fatty liver disease (NAFLD) and establish the severity of liver injury, presence of fibrosis, and architecture remodeling. However, the cost and the intrinsic invasive procedure of a liver biopsy rules it out as a gold standard diagnostic test, and the imaging test are not the best choice due to the price, and currently is being refined. The lack of a biomarker of NAFLD pushes to develop this new line of research. The aim of the present systematic review is to clarify and update all the NAFLD biomarkers described in the literature until recently. We highlight α-ketoglutarate and CK18-F as currently the best potential biomarker of NAFLD. However, due to methodological differences, we propose the implementation of international, multicenter, multiethnic studies with larger population size, and biopsy proven NAFLD diagnosis to analyze and compare α-ketoglutarate and CK18-F as potential biomarkers of the silent evolution of NAFLD. © 2017 Wiley Periodicals, Inc.

  12. Potential for Dietary ω-3 Fatty Acids to Prevent Nonalcoholic Fatty Liver Disease and Reduce the Risk of Primary Liver Cancer123

    PubMed Central

    Jump, Donald B; Depner, Christopher M; Tripathy, Sasmita; Lytle, Kelli A

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity, and its prevalence is anticipated to increase as the obesity epidemic remains unabated. NAFLD is now the most common cause of chronic liver disease in developed countries and is defined as excessive lipid accumulation in the liver, that is, hepatosteatosis. NAFLD ranges in severity from benign fatty liver to nonalcoholic steatohepatitis (NASH), and NASH is characterized by hepatic injury, inflammation, oxidative stress, and fibrosis. NASH can progress to cirrhosis, and cirrhosis is a risk factor for primary hepatocellular carcinoma (HCC). The prevention of NASH will lower the risk of cirrhosis and NASH-associated HCC. Our studies have focused on NASH prevention. We developed a model of NASH by using mice with the LDL cholesterol receptor gene ablated fed the Western diet (WD). The WD induces a NASH phenotype in these mice that is similar to that seen in humans and includes robust induction of hepatic steatosis, inflammation, oxidative stress, and fibrosis. With the use of transcriptomic, lipidomic, and metabolomic approaches, we examined the capacity of 2 dietary ω-3 (n–3) polyunsaturated fatty acids, eicosapentaenoic acid (20:5ω-3; EPA) and docosahexaenoic acid (22:6ω-3; DHA), to prevent WD-induced NASH. Dietary DHA was superior to EPA at attenuating WD-induced changes in plasma lipids and hepatic injury and at reversing WD effects on hepatic metabolism, oxidative stress, and fibrosis. The outcome of these studies suggests that DHA may be useful in preventing NASH and reducing the risk of HCC. PMID:26567194

  13. Effects of fatty infiltration in human livers on the backscattered statistics of ultrasound imaging.

    PubMed

    Wan, Yung-Liang; Tai, Dar-In; Ma, Hsiang-Yang; Chiang, Bing-Hao; Chen, Chin-Kuo; Tsui, Po-Hsiang

    2015-06-01

    Ultrasound imaging has been widely applied to screen fatty liver disease. Fatty liver disease is a condition where large vacuoles of triglyceride fat accumulate in liver cells, thereby altering the arrangement of scatterers and the corresponding backscattered statistics. In this study, we used ultrasound Nakagami imaging to explore the effects of fatty infiltration in human livers on the statistical distribution of backscattered signals. A total of 107 patients volunteered to participate in the experiments. The livers were scanned using a clinical ultrasound scanner to obtain the raw backscattered signals for ultrasound B-mode and Nakagami imaging. Clinical scores of fatty liver disease for each patient were determined according to a well-accepted sonographic scoring system. The results showed that the Nakagami image can visualize the local backscattering properties of liver tissues. The Nakagami parameter increased from 0.62 ± 0.11 to 1.02 ± 0.07 as the fatty liver disease stage increased from normal to severe, indicating that the backscattered statistics vary from pre-Rayleigh to Rayleigh distributions. A significant positive correlation (correlation coefficient ρ = 0.84; probability value (p value) < 0.0001) exists between the degree of fatty infiltration and the Nakagami parameter, suggesting that ultrasound Nakagami imaging has potentials in future applications in fatty liver disease diagnosis. © IMechE 2015.

  14. Metabolic Syndrome: Nonalcoholic Fatty Liver Disease.

    PubMed

    Williams, Tracy

    2015-08-01

    Although nonalcoholic fatty liver disease (NAFLD) is not one of the defining criteria for metabolic syndrome, it is a common hepatic manifestation. NAFLD includes a spectrum of histologic findings ranging from simple steatosis, known as nonalcoholic fatty liver, to nonalcoholic steatohepatitis (NASH). To make the diagnosis of NAFLD, other etiologies of steatosis or hepatitis, such as hepatotoxic drugs, excessive alcohol intake, congenital errors of metabolism, or viral hepatitis, must be ruled out. After ruling out other conditions, the diagnosis of NAFLD often is made clinically, but a definitive diagnosis of NASH requires liver biopsy. As with other complications of metabolic syndrome, insulin resistance is thought to be an underlying etiology of NAFLD. Management strategies attempt to reverse or improve insulin resistance while minimizing liver damage. The strongest evidence supports lifestyle modifications with weight loss, but there is some evidence to support bariatric surgery, medical therapy with insulin-sensitizing agents, and/or pharmacotherapy to promote weight loss. Cardiovascular disease is the major cause of mortality in patients with NAFLD, so management must include modification of cardiovascular risk factors. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

  15. The role of nutraceuticals for the treatment of non-alcoholic fatty liver disease.

    PubMed

    Del Ben, Maria; Polimeni, Licia; Baratta, Francesco; Pastori, Daniele; Angelico, Francesco

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to liver fibrosis and to cirrhosis. NAFLD is considered as the hepatic component of the metabolic syndrome but mechanisms underlying the onset and progression of NAFLD are still under investigation. The traditional 'two hit hypothesis' has been developed within a more complex 'multiple parallel hit hypothesis' which comprises a wide spectrum of parallel hits. Many therapeutic approaches have been proposed so far and several types of nutraceuticals have been suggested for the treatment of NAFLD and non-alcoholic steatohepatitis (NASH), the most promising of which are those with antioxidant effects. In particular, vitamin E appears to be effective for the treatment of nondiabetic subjects with more advanced NASH, although the high suggested daily dosages are a matter of concern. Moreover, polyphenols reduce liver fat accumulation, mainly by inhibiting lipogenesis. At present, there are insufficient data to support the use of vitamin C supplements in patients with NAFLD. Data on polyunsaturated fatty acid (PUFA) supplementation are heterogeneous, and no well-designed randomized controlled studies (RCTs) of adequate size, with histological assessment of steatosis, have been conducted. Based on the available data, silymarin supplementation for the treatment of NAFLD seems to have a favourable effect. The results with anti-inflammatory agents, such as vitamin D and carnitine are uncertain. In conclusion, there are insufficient data either to support or refute the use of nutraceuticals for subjects with NAFLD. Further RTCs, with histological changes as an outcome measure, are needed. © 2016 The British Pharmacological Society.

  16. [Non-alcoholic fatty liver disease--new view].

    PubMed

    Raszeja-Wyszomirska, Joanna; Lawniczak, Małgorzata; Marlicz, Wojciech; Miezyńska-Kurtycz, Joanna; Milkiewicz, Piotr

    2008-06-01

    Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology--from steatosis alone, through the necroinflammatory disorder of non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. NAFLD/NASH is mostly related with visceral adiposity, obesity, type 2 diabetes melitus (DM t.2) and metabolic syndrome. Pathogenetic concepts of NAFLD include overnutrition and underactivity, insulin resistance (IR) and genetic factor. The prevalence of NAFLD has been estimated to be 17-33% in some countries, NASH may be present in about 1/3 of such cases, while 20-25% of NASH cases could progress to cirrhosis. NAFLD is now recognized as one of the most frequent reason of liver tests elevation without clinical symptoms. Insulin resistance is considering as having a central role in NAFLD pathogenesis. In hepatocytes, IR is related to hyperglycaemia and hyperinsulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. Early stages of fatty liver are clinically silent and include elevation of ALT and GGTP, hyperechogenic liver in USG and/or hepatomegaly. Among clinical symptoms, abdominal discomfort is relatively common as well as chronic fatigue. NAFLD/NASH is not a benign disease, progressive liver biopsy have shown histological progression of fibrosis in 32%, the estimated rate of cirrhosis development is 20% and a liver--related death is 12% over 10 years. No treatment has scientifically proved to ameliorate NAFLD or to avoid its progression. The various therapeutic alternatives are aimed at interfering with the risk factors involved in the pathogenesis of the disorder in order to prevent the progression to end-stage liver disease. The most important therapeutic measure is increasing insulin sensitivity by an attempt to change a lifestyle mostly by dieting and physical activity in order to loose weight. The most used agent is metformin, the others

  17. Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease.

    PubMed

    Reilly, Norelle R; Lebwohl, Benjamin; Hultcrantz, Rolf; Green, Peter H R; Ludvigsson, Jonas F

    2015-06-01

    Non-alcoholic fatty liver disease is a common cause of chronic liver disease. Celiac disease alters intestinal permeability and treatment with a gluten-free diet often causes weight gain, but so far there are few reports of non-alcoholic fatty liver disease in patients with celiac disease. Population-based cohort study. We compared the risk of non-alcoholic fatty liver disease diagnosed from 1997 to 2009 in individuals with celiac disease (n = 26,816) to matched reference individuals (n = 130,051). Patients with any liver disease prior to celiac disease were excluded, as were individuals with a lifetime diagnosis of alcohol-related disorder to minimize misclassification of non-alcoholic fatty liver disease. Cox regression estimated hazard ratios for non-alcoholic fatty liver disease were determined. During 246,559 person-years of follow-up, 53 individuals with celiac disease had a diagnosis of non-alcoholic fatty liver disease (21/100,000 person-years). In comparison, we identified 85 reference individuals diagnosed with non-alcoholic fatty liver disease during 1,488,413 person-years (6/100,000 person-years). This corresponded to a hazard ratio of 2.8 (95% CI 2.0-3.8), with the highest risk estimates seen in children (HR = 4.6; 95% CI 2.3-9.1). The risk increase in the first year after celiac disease diagnosis was 13.3 (95% CI 3.5-50.3) but remained significantly elevated even beyond 15 years after the diagnosis of celiac disease (HR = 2.5; 95% CI 1.0-5.9). Individuals with celiac disease are at increased risk of non-alcoholic fatty liver disease compared to the general population. Excess risks were highest in the first year after celiac disease diagnosis, but persisted through 15 years after diagnosis with celiac disease. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  18. An increase in liver PPARγ2 is an initial event to induce fatty liver in response to a diet high in butter: PPARγ2 knockdown improves fatty liver induced by high-saturated fat.

    PubMed

    Yamazaki, Tomomi; Shiraishi, Sayaka; Kishimoto, Kyoko; Miura, Shinji; Ezaki, Osamu

    2011-06-01

    The effects of a diet rich in saturated fat on fatty liver formation and the related mechanisms that induce fatty liver were examined. C57BL/6J mice were fed butter or safflower oil as a high-fat (HF) diet (40% fat calories) for 2, 4, 10, or 17 weeks. Although both HF diets induced similar levels of obesity, HF butter-fed mice showed a two to threefold increase in liver triacylglycerol (TG) concentration compared to HF safflower oil-fed mice at 4 or 10 weeks without hyperinsulinemia. At 4 weeks, increases in peroxisome proliferator-activated receptor γ2 (PPARγ2), CD36, and adipose differentiation-related protein (ADRP) mRNAs were observed in HF butter-fed mice; at 10 weeks, an increase in sterol regulatory element-binding protein-1c (SREBP-1c) was observed; at 17 weeks, these increases were attenuated. At 4 weeks, a single injection of adenoviral vector-based short hairpin interfering RNA against PPARγ2 in HF butter-fed mice reduced PPARγ protein and mRNA of its target genes (CD36 and ADRP) by 43%, 43%, and 39%, respectively, with a reduction in liver TG concentration by 38% in 5 days. PPARγ2 knockdown also reduced mRNAs in lipogenic genes (fatty-acid-synthase, stearoyl-CoA desaturase 1, acetyl-CoA carboxylase 1) without alteration of SREBP-1c mRNA. PPARγ2 knockdown reduced mRNAs in genes related to inflammation (CD68, interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein-1). In conclusion, saturated fatty acid-rich oil induced fatty liver in mice, and this was triggered initially by an increase in PPARγ2 protein in the liver, which led to increased expression of lipogenic genes. Inactivation of PPARγ2 may improve fatty liver induced by HF saturated fat. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

    PubMed Central

    Ibdah, Jamal A.

    2018-01-01

    Acute fatty liver of pregnancy (AFLP), a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is highly associated with a fetal homozygous mutation (1528G>C) in the gene that encodes for mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD). The mutation in LCHAD results in the accumulation of 3-hydroxy fatty acids, such as 3-hydroxy myristic acid, 3-hydroxy palmitic acid and 3-hydroxy dicarboxylic acid in the placenta, which are then shunted to the maternal circulation leading to the development of acute liver injury observed in patients with AFLP. In this review, we will discuss the mechanistic role of increased 3-hydroxy fatty acid in causing lipotoxicity to the liver and in inducing oxidative stress, mitochondrial dysfunction and hepatocyte lipoapoptosis. Further, we also review the role of 3-hydroxy fatty acids in causing placental damage, pancreatic islet β-cell glucolipotoxicity, brain damage, and retinal epithelial cells lipoapoptosis in patients with LCHAD deficiency. PMID:29361796

  20. Altered plasma lipidome profile of dairy cows with fatty liver disease.

    PubMed

    Gerspach, C; Imhasly, S; Gubler, M; Naegeli, H; Ruetten, M; Laczko, E

    2017-02-01

    Fatty liver disease is a common health problem of dairy cows occurring during the transition from pregnancy to lactation. It is a direct response to fat mobilization due to negative energy balance. Accumulation of lipids in the liver occurs if the uptake of non-esterified fatty acids by the liver exceeds the capacity of lipid oxidation or secretion by the liver. Currently, the diagnosis of fatty liver disease requires confirmation through biopsies to determine the hepatic lipid content. In view of this lack of a practical diagnostic tool, we compared the plasma lipidome of diseased dairy cows using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Multivariate data analysis yielded 20 m/z values that were able to distinguish between dairy cows with no hepatic lipidosis and those exhibiting different stages of the disease. Based on the chromatography retention time and m/z ratios, we identified phosphatidylcholines with reduced plasma abundances in cows with fatty liver disease. The abundances of different bile acids tended to be increased. In addition, we detected two metabolites related to inflammation, resolvin E1 and palmitoyl-ethanolamine (PEA), which need to be further investigated in cattle. These results indicate that the measurement of specific representatives of phosphatidylcholines in plasma may provide a novel diagnostic biomarker of fatty liver disease in dairy cows. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Non-alcoholic Fatty Liver Disease (NAFLD)--A Review.

    PubMed

    Karim, M F; Al-Mahtab, M; Rahman, S; Debnath, C R

    2015-10-01

    Non-alcoholic fatty liver disease (NAFLD) is an emerging problem in Hepatology clinics. It is closely related to the increased frequency of overweight or obesity. It has recognised association with metabolic syndrome. Central obesity, diabetes mellitus, dyslipidemia are commonest risk factors. Association with hepatitis C genotype 3 is also recognised. NAFLD is an important cause of cyptogenic cirrhosis of liver. It affects all populations and all age groups. Most patients with NAFLD are asymptomatic or vague upper abdominal pain. Liver function tests are mostly normal or mild elevation of aminotranferases. Histological features almost identical to those of alcohol-induced liver damage and can range from mild steatosis to cirrhosis. Two hit hypothesis is prevailing theory for the development of NAFLD. Diagnosis is usually made by imaging tools like ultrasonogram which reveal a bright liver while liver biopsy is gold standard for diagnosis as well as differentiating simple fatty liver and non-alcoholic steatohepatitis (NASH). Prognosis is variable. Simple hepatic steatosis generally has a benign long-term prognosis. However, one to two third of NASH progress to fibrosis or cirrhosis and may have a similar prognosis as cirrhosis from other liver diseases. Treatment is mostly control of underlying disorders and dietary advice, exercise, insulin sensitizers, antioxidants, or cytoprotective agents. The prevalence of NAFLD is increasing. So it needs more research to address this problem.

  2. Evaluation of nonalcoholic fatty liver disease using magnetic resonance in obese children and adolescents.

    PubMed

    Benetolo, Patrícia O; Fernandes, Maria I M; Ciampo, Ieda R L Del; Elias-Junior, Jorge; Sawamura, Regina

    2018-02-10

    To determine the frequency of nonalcoholic fatty liver disease using nuclear magnetic resonance as a noninvasive method. This was a cross-sectional study conducted on 50 children and adolescents followed up at an outpatient obesity clinic. The subjects were submitted to physical examination, laboratory tests (transaminases, liver function tests, lipid profile, glycemia, and basal insulin) and abdominal nuclear magnetic resonance (calculation of hepatic, visceral, and subcutaneous fat). Nonalcoholic fatty liver disease was diagnosed in 14 (28%) participants, as a severe condition in eight (percent fat >18%), and as non-severe in four (percent fat from 9% to 18%). Fatty liver was associated with male gender, triglycerides, AST, ALT, AST/ALT ratio, and acanthosis nigricans. Homeostasis model assessment of insulin resistance and metabolic syndrome did not show an association with fatty liver. The frequency of nonalcoholic fatty liver disease in the present population of children and adolescents was lower than that reported in the international literature. It is suggested that nuclear magnetic resonance is an imaging exam that can be applied to children and adolescents, thus representing an effective noninvasive tool for the diagnosis of nonalcoholic fatty liver disease in this age range. However, further national multicenter studies with longitudinal design are needed for a better analysis of the correlation between nonalcoholic fatty liver disease and its risk factors, as well as its consequences. Copyright © 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  3. Inverse Association between Hepatitis B Virus Infection and Fatty Liver Disease: A Large-Scale Study in Populations Seeking for Check-Up

    PubMed Central

    Cheng, Yuan-Lung; Wang, Yuan-Jen; Kao, Wei-Yu; Chen, Ping-Hsien; Huo, Teh-Ia; Huang, Yi-Hsiang; Lan, Keng-Hsin; Su, Chien-Wei; Chan, Wan-Leong; Lin, Han-Chieh; Lee, Fa-Yauh; Wu, Jaw-Ching

    2013-01-01

    Background Although many studies have attempted to clarify the association between hepatitis B virus (HBV) infection and fatty liver disease, no prior studies have emphasized the relationship of HBV and fatty liver regarding different demographics of age and body mass index (BMI). Aim To investigate the correlation of HBV and fatty liver in the different demographics of age and BMI. Methods We enrolled consecutive subjects who had received health check-up services at the Taipei Veterans General Hospital from 2002 to 2009 and ultrasonography was used to diagnose fatty liver according to the practice guidelines of the American Gastroenterological Association. Results Among the 33,439 subjects enrolled in this study, fatty liver was diagnosed in 43.9% of the population and 38.9% of patients with chronic HBV infection. Multivariate analysis showed that BMI, age, waist circumference, systolic blood pressure, fasting glucose, cholesterol, alanine aminotransferase (ALT) levels, and platelet counts were positively associated, while hepatitis B surface antigen (HBsAg) positivity was inversely associated with fatty liver, especially for subjects with BMI>22.4 kg/m2 and age>50 years. On the contrary, HBV infection was positively correlated with the presence of elevated serum ALT levels in subjects with fatty liver disease regardless of their age and BMI. Conclusions Metabolic factors are important determinants for the prevalence of fatty liver. Patients with HBV infection were inversely associated with fatty liver disease than the general population, especially in older and obese patients. Furthermore, metabolic factors and HBV infection were associated with elevated serum ALT levels in fatty liver disease. PMID:23991037

  4. Fatty acids of glycerophosphatides in developing chick embryonic brain and liver.

    PubMed

    Miyamoto, K; Stephanides, L M; Bernsohn, J

    1966-09-01

    Fatty acid compositions of glycerophosphatides of developing chick embryonic brain and liver were compared. In brain, ethanolamine and serine glycerophosphatides contained 30-40% polyunsaturated fatty acids, lecithin almost none (except for arachidonic). In the liver, these acids were equally distributed in the phospholipid fractions. The principal polyunsaturated fatty acids of the ethanolamine and serine glycerophosphatides in brain, liver, and yolk were 22:6, 20:4, and 18:2, respectively. During embryonic development of brain from the 8th day of incubation to hatching, the fatty acid composition of individual glycerophosphatide fractions remained constant. Because of the relative increase of ethanolamine glycerophosphatides and decrease of lecithin, total glycerophosphatides showed a decrease in 16:0 and an increase in 18:0. Substantial amounts of palmitaldehyde and stearaldehyde were present on the 8th day of incubation in the brain ethanolamine glycerophosphatide fraction. During the 3rd week of incubation, the liver showed a two-fold increase in the relative amount of 18:2 in all glycerophosphatide fractions. A decrease of 16:0 in the lecithin fraction and consequently in total glycerophosphatides was also observed during this period. No significant changes in glycerophosphatide fatty acids were observed in the yolk throughout incubation.

  5. Identification of Plants That Inhibit Lipid Droplet Formation in Liver Cells: Rubus suavissimus Leaf Extract Protects Mice from High-Fat Diet-Induced Fatty Liver by Directly Affecting Liver Cells

    PubMed Central

    Takahashi, Tomohiro; Sugawara, Wataru; Takiguchi, Yuya; Takizawa, Kento; Nakabayashi, Ami; Nakamura, Mitsuo; Nagano-Ito, Michiyo; Ichikawa, Shinichi

    2016-01-01

    Fatty liver disease is a condition in which abnormally large numbers of lipid droplets accumulate in liver cells. Fatty liver disease induces inflammation under conditions of oxidative stress and may result in cancer. To identify plants that protect against fatty liver disease, we examined the inhibitory effects of plant extracts on lipid droplet formation in mouse hepatoma cells. A screen of 98 water extracts of plants revealed 4 extracts with inhibitory effects. One of these extracts, Rubus suavissimus S. Lee (Tien-cha or Chinese sweet tea) leaf extract, which showed strong inhibitory effects, was tested in a mouse fatty liver model. In these mouse experiments, intake of the plant extract significantly protected mice against fatty liver disease without affecting body weight gain. Our results suggest that RSE directly affects liver cells and protects them from fatty liver disease. PMID:27429636

  6. Clinical approaches to non-alcoholic fatty liver disease

    PubMed Central

    Schwenger, Katherine JP; Allard, Johane P

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients. PMID:24587650

  7. Managing non-alcoholic fatty liver disease

    PubMed Central

    Ngu, Jing Hieng; Goh, George Boon Bee; Poh, Zhongxian; Soetikno, Roy

    2016-01-01

    The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly with the obesity and diabetes mellitus epidemics. It is rapidly becoming the most common cause of liver disease worldwide. NAFLD can progress to serious complications such as cirrhosis, hepatocellular carcinoma and death. Therefore, it is important to recognise this condition so that early intervention can be implemented. Lifestyle modifications and strict control of metabolic risk factors are the mainstay of treatment. As disease progression is slow in the majority of NAFLD patients, most can be managed well by primary care physicians. NAFLD patients with advanced liver fibrosis should be referred to specialist care for further assessment. PMID:27439352

  8. Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease.

    PubMed

    Lee, Yun-Hee; Kim, Sou Hyun; Kim, Sang-Nam; Kwon, Hyun-Jung; Kim, Jeong-Dong; Oh, Ji Youn; Jung, Young-Suk

    2016-07-26

    Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease.

  9. Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease

    PubMed Central

    Lee, Yun-Hee; Kim, Sou Hyun; Kim, Sang-Nam; Kwon, Hyun-Jung; Kim, Jeong-Dong; Oh, Ji Youn; Jung, Young-Suk

    2016-01-01

    Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease. PMID:27409675

  10. Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age?

    PubMed Central

    Firneisz, Gábor

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients. PMID:25083080

  11. Non-alcoholic fatty liver disease and type 2 diabetes mellitus: the liver disease of our age?

    PubMed

    Firneisz, Gábor

    2014-07-21

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.

  12. Serum adipokines might predict liver histology findings in non-alcoholic fatty liver disease.

    PubMed

    Jamali, Raika; Razavizade, Mohsen; Arj, Abbas; Aarabi, Mohammad Hossein

    2016-06-07

    To assess significance of serum adipokines to determine the histological severity of non-alcoholic fatty liver disease. Patients with persistent elevation in serum aminotransferase levels and well-defined characteristics of fatty liver at ultrasound were enrolled. Individuals with a history of alcohol consumption, hepatotoxic medication, viral hepatitis or known liver disease were excluded. Liver biopsy was performed to confirm non-alcoholic liver disease (NAFLD). The degrees of liver steatosis, lobular inflammation and fibrosis were determined based on the non-alcoholic fatty liver activity score (NAS) by a single expert pathologist. Patients with a NAS of five or higher were considered to have steatohepatitis. Those with a NAS of two or lower were defined as simple fatty liver. Binary logistic regression was used to determine the independent association of adipokines with histological findings. Receiver operating characteristic (ROC) analysis was employed to determine cut-off values of serum adipokines to discriminate the grades of liver steatosis, lobular inflammation and fibrosis. Fifty-four participants aged 37.02 ± 9.82 were enrolled in the study. Higher serum levels of visfatin, IL-8, TNF-α levels were associated independently with steatosis grade of more than 33% [β = 1.08 (95%CI: 1.03-1.14), 1.04 (95%CI: 1.008-1.07), 1.04 (95%CI: 1.004-1.08), P < 0.05]. Elevated serum IL-6 and IL-8 levels were associated independently with advanced lobular inflammation [β = 1.4 (95%CI: 1.09-1.8), 1.07 (95%CI: 1.003-1.15), P < 0.05]. Similarly, higher TNF-α, resistin, and hepcidin levels were associated independently with advanced fibrosis stage [β = 1.06 (95%CI: 1.002-1.12), 19.86 (95%CI: 2.79-141.19), 560.72 (95%CI: 5.98-5255.33), P < 0.05]. Serum IL-8 and TNF-α values were associated independently with the NAS score, considering a NAS score of 5 as the reference value [β = 1.05 (95%CI: 1.01-1.1), 1.13 (95%CI: 1.04-1.22), P < 0.05]. Certain adipokines may

  13. Risk of Colorectal Neoplasia According to Fatty Liver Severity and Presence of Gall Bladder Polyps.

    PubMed

    Lee, Taeyoung; Yun, Kyung Eun; Chang, Yoosoo; Ryu, Seungho; Park, Dong Il; Choi, Kyuyong; Jung, Yoon Suk

    2016-01-01

    Fatty liver is the hepatic manifestation of metabolic syndrome (MetS) and is a known risk factor for colorectal neoplasia (CRN). Gallbladder (GB) polyps share many common risk factors with CRN. However, studies evaluating CRN risk according to fatty liver severity and the presence of GB polyps are rare. To investigate CRN risk according to the fatty liver severity and the presence of GB polyps. A retrospective cross-sectional study was performed on 44,220 participants undergoing colonoscopy and abdominal ultrasonography (US) as part of a health-screening program. Of the participants, fatty liver was diagnosed as mild in 27.7 %, moderate in 5.1 %, and severe in 0.4 % and 13.4 % were diagnosed with GB polyps. Mean age of participants was 42.7 years. In adjusted models, risk of overall CRN and non-advanced CRN increased with worsening fatty liver severity (P for trend = 0.007 and 0.020, respectively). Adjusted odd ratios for overall CRN and non-advanced CRN comparing participants with mild, moderate, and severe fatty liver to participants without fatty liver were 1.13 and 1.12 for mild, 1.12 and 1.10 for moderate, and 1.56 and 1.65 for severe. The presence of GB polyps did not correlate with CRN risk after adjusting for confounders. CRN risk increased with worsening fatty liver severity. However the association between GB polyp and CRN was not significant in the presence of other variables. Considering that many people undergo noninvasive abdominal US as a health screen, our study will contribute to colonoscopy screening strategies in people undergoing abdominal US.

  14. Exercise improves adipose function and inflammation and ameliorates fatty liver disease in obese diabetic mice.

    PubMed

    Haczeyni, Fahrettin; Barn, Vanessa; Mridha, Auvro R; Yeh, Matthew M; Estevez, Emma; Febbraio, Mark A; Nolan, Christopher J; Bell-Anderson, Kim S; Teoh, Narci C; Farrell, Geoffrey C

    2015-09-01

    Adipose inflammation and dysfunction underlie metabolic obesity. Exercise improves glycemic control and metabolic indices, but effects on adipose function and inflammation are less clear. Accordingly, it was hypothesized that exercise improves adipose morphometry to reduce adipose inflammation in hyperphagic obese mice. Alms1 mutant foz/foz mice housed in pairs were fed an atherogenic or chow diet; half the cages were fitted with a computer-monitored wheel for voluntary exercise. Insulin-induced AKT-phosphorylation, adipocyte size distribution, and inflammatory recruitment were studied in visceral versus subcutaneous depots, and severity of fatty liver disease was determined. Exercise prevented obesity and diabetes development in chow-fed foz/foz mice and delayed their onset in atherogenic-fed counterparts. Insulin-stimulated phospho-AKT levels in muscle were improved with exercise, but not in adipose or liver. Exercise suppressed adipose inflammatory recruitment, particularly in visceral adipose, associated with an increased number of small adipocyte subpopulations, and enhanced expression of beige adipocyte factor PRDM16 in subcutaneous fat. In atherogenic-fed foz/foz mice liver, exercise suppressed development of nonalcoholic steatohepatitis and related liver fibrosis. Exercise confers metabo-protective effects in atherogenic-fed hyperphagic mice by preventing early onset of obesity and diabetes in association with enhanced muscle insulin sensitivity, improved adipose morphometry, and suppressed adipose and liver inflammation. © 2015 The Obesity Society.

  15. The cheating liver: imaging of focal steatosis and fatty sparing.

    PubMed

    Dioguardi Burgio, Marco; Bruno, Onorina; Agnello, Francesco; Torrisi, Chiara; Vernuccio, Federica; Cabibbo, Giuseppe; Soresi, Maurizio; Petta, Salvatore; Calamia, Mauro; Papia, Giovanni; Gambino, Angelo; Ricceri, Viola; Midiri, Massimo; Lagalla, Roberto; Brancatelli, Giuseppe

    2016-06-01

    Focal steatosis and fatty sparing are a frequent finding in liver imaging, and can mimic solid lesions. Liver regional variations in the degree of fat accumulation can be related to vascular anomalies, metabolic disorders, use of certain drugs or coexistence of hepatic masses. CT and MRI are the modalities of choice for the noninvasive diagnosis of hepatic steatosis. Knowledge of CT and MRI appearance of focal steatosis and fatty sparing is crucial for an accurate diagnosis, and to rule-out other pathologic processes. This paper will review the CT and MRI techniques for the diagnosis of hepatic steatosis and the CT and MRI features of common and uncommon causes of focal steatosis and fatty sparing.

  16. Assessment of the fatty liver index as an indicator of hepatic steatosis for predicting incident diabetes independently of insulin resistance in a Korean population.

    PubMed

    Jung, C H; Lee, W J; Hwang, J Y; Yu, J H; Shin, M S; Lee, M J; Jang, J E; Leem, J; Park, J-Y; Kim, H-K

    2013-04-01

    Fatty liver disease, especially non-alcoholic fatty liver disease, is considered to be the hepatic manifestation of the metabolic syndrome, both closely associated with insulin resistance. Furthermore, fatty liver disease assessed by ultrasonography is known to be a predictor of the development of Type 2 diabetes mellitus. However, it remains unclear whether fatty liver disease plays a role in the pathogenesis of Type 2 diabetes independently of insulin resistance. In this study, we investigated whether fatty liver disease assessed by the fatty liver index can predict the development of Type 2 diabetes independently of systemic insulin resistance. We examined the clinical and laboratory data of 7860 subjects without diabetes who underwent general routine health evaluations at the Asan Medical Center in 2007 and had returned for follow-up examinations in 2011. Fatty liver index was calculated using an equation that considers serum triglyceride levels, γ-glutamyltransferase, waist circumference and BMI. During a 4-year period, 457 incident diabetes cases (5.8%) were identified. The odds ratios for the development of Type 2 diabetes were significantly higher in the group with a fatty liver index ≥ 60 (fatty liver index-positive) than in the group with a fatty liver index < 20 (fatty liver index-negative) after adjusting for various confounding variables including homeostasis model assessment of insulin resistance. Odds ratios were significant regardless of the insulin resistance status at baseline. Our results suggest that fatty liver index as a simple surrogate indicator of hepatic steatosis is valuable in identifying subjects at high risk for Type 2 diabetes. In addition, fatty liver disease itself contributes to the development of Type 2 diabetes independently of systemic insulin resistance. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  17. Alteration of Hepatic Gene Expression along with the Inherited Phenotype of Acquired Fatty Liver in Chicken

    PubMed Central

    Zhang, Yonghong; Liu, Zhen; Liu, Ranran; Wang, Jie; Zheng, Maiqing; Li, Qinghe; Cui, Huanxian; Zhao, Guiping; Wen, Jie

    2018-01-01

    Fatty liver is a widespread disease in chickens that causes a decrease in egg production and even death. The characteristics of the inherited phenotype of acquired fatty liver and the molecular mechanisms underlying it, however, are largely unknown. In the current study, fatty liver was induced in 3 breeds by a high-fat (HF) diet and a methionine choline-deficient (MCD) diet. The results showed that the dwarf Jingxing-Huang (JXH) chicken was more susceptible to fatty liver compared with the layer White Leghorns (WL) and local Beijing-You (BJY) breeds. In addition, it was found that the paternal fatty livers induced by HF diet in JXH chickens were inherited. Compared to birds without fatty liver in the control group, both offsprings and their sires with fatty livers in the paternal group exhibited altered hepatic gene expression profiles, including upregulation of several key genes involved in fatty acid metabolism, lipid metabolism and glucose metabolism (ACACA, FASN, SCD, ACSL5, FADS2, FABP1, APOA4 and ME1). This study uniquely revealed that acquired fatty liver in cocks can be inherited. The hepatic gene expression profiles were altered in chickens with the inherited phenotype of acquired paternal fatty liver and several genes could be candidate biomarkers. PMID:29642504

  18. Alteration of Hepatic Gene Expression along with the Inherited Phenotype of Acquired Fatty Liver in Chicken.

    PubMed

    Zhang, Yonghong; Liu, Zhen; Liu, Ranran; Wang, Jie; Zheng, Maiqing; Li, Qinghe; Cui, Huanxian; Zhao, Guiping; Wen, Jie

    2018-04-08

    Fatty liver is a widespread disease in chickens that causes a decrease in egg production and even death. The characteristics of the inherited phenotype of acquired fatty liver and the molecular mechanisms underlying it, however, are largely unknown. In the current study, fatty liver was induced in 3 breeds by a high-fat (HF) diet and a methionine choline-deficient (MCD) diet. The results showed that the dwarf Jingxing-Huang (JXH) chicken was more susceptible to fatty liver compared with the layer White Leghorns (WL) and local Beijing-You (BJY) breeds. In addition, it was found that the paternal fatty livers induced by HF diet in JXH chickens were inherited. Compared to birds without fatty liver in the control group, both offsprings and their sires with fatty livers in the paternal group exhibited altered hepatic gene expression profiles, including upregulation of several key genes involved in fatty acid metabolism, lipid metabolism and glucose metabolism ( ACACA , FASN , SCD , ACSL5 , FADS2 , FABP1 , APOA4 and ME1 ). This study uniquely revealed that acquired fatty liver in cocks can be inherited. The hepatic gene expression profiles were altered in chickens with the inherited phenotype of acquired paternal fatty liver and several genes could be candidate biomarkers.

  19. Rice endosperm protein slows progression of fatty liver and diabetic nephropathy in Zucker diabetic fatty rats.

    PubMed

    Kubota, Masatoshi; Watanabe, Reiko; Yamaguchi, Miki; Hosojima, Michihiro; Saito, Akihiko; Fujii, Mikio; Fujimura, Shinobu; Kadowaki, Motoni

    2016-10-01

    We previously reported that rice endosperm protein (REP) has renoprotective effects in Goto-Kakizaki rats, a non-obese diabetic model. However, whether these effects occur in obese diabetes remains unclear. This study aimed to clarify the effects of REP on obese diabetes, especially on fatty liver and diabetic nephropathy, using the obese diabetic model Zucker diabetic fatty (ZDF) rats. In total, 7-week-old male ZDF rats were fed diets containing 20 % REP or casein (C) for 8 weeks. Changes in fasting blood glucose levels and urinary markers were monitored during the experimental period. Hepatic lipids and metabolites were measured and renal glomeruli were observed morphologically. HbA1c levels were significantly lower in rats fed REP, compared with C (P<0·05). Compared with C in the liver, REP prevented lipid accumulation (total lipid, TAG and total cholesterol, P<0·01). Liver metabolome analysis indicated that levels of metabolites associated with glycolysis, the pentose phosphate pathway and carnitine metabolism were significantly greater in the REP group than in the C group (P<0·05), suggesting activation of both glucose catabolism and fatty acid oxidation. The metabolite increases promoted by REP may contribute to suppression of liver lipid accumulation. Urinary excretion of albumin and N-acetyl-β-d-glucosaminidase was significantly reduced in rats fed REP for 8 weeks (P<0·01). In addition, there was a distinct suppression of mesangial matrix expansion and glomerular hypertrophy in response to REP (P<0·01). Thus, REP had preventive effects on obese diabetes, fatty liver and diabetic nephropathy.

  20. Altered Hepatic Transport by Fetal Arsenite Exposure in Diet-Induced Fatty Liver Disease.

    PubMed

    Ditzel, Eric J; Li, Hui; Foy, Caroline E; Perrera, Alec B; Parker, Patricia; Renquist, Benjamin J; Cherrington, Nathan J; Camenisch, Todd D

    2016-07-01

    Non-alcoholic fatty liver disease can result in changes to drug metabolism and disposition potentiating adverse drug reactions. Furthermore, arsenite exposure during development compounds the severity of diet-induced fatty liver disease. This study examines the effects of arsenite potentiated diet-induced fatty liver disease on hepatic transport in male mice. Changes were detected for Mrp2/3/4 hepatic transporter gene expression as well as for Oatp1a4/2b1/1b2. Plasma concentrations of Mrp and Oatp substrates were increased in arsenic exposure groups compared with diet-only controls. In addition, murine embryonic hepatocytes and adult primary hepatocytes show significantly altered transporter expression after exposure to arsenite alone: a previously unreported phenomenon. These data indicate that developmental exposure to arsenite leads to changes in hepatic transport which could increase the risk for ADRs during fatty liver disease. © 2016 Wiley Periodicals, Inc.

  1. Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts.

    PubMed

    Ma, Jiantao; Fox, Caroline S; Jacques, Paul F; Speliotes, Elizabeth K; Hoffmann, Udo; Smith, Caren E; Saltzman, Edward; McKeown, Nicola M

    2015-08-01

    Non-alcoholic fatty liver disease affects ∼30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/day, and ⩾1 serving/day) of sugar-sweetened beverages or diet soda. After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend=0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend=0.007). We observed no significant association between diet soda intake and measures of fatty liver disease. In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease. Copyright © 2015 European Association for the Study of the Liver. All rights reserved.

  2. Molecular classification of fatty liver by high-throughput profiling of protein post-translational modifications.

    PubMed

    Urasaki, Yasuyo; Fiscus, Ronald R; Le, Thuc T

    2016-04-01

    We describe an alternative approach to classifying fatty liver by profiling protein post-translational modifications (PTMs) with high-throughput capillary isoelectric focusing (cIEF) immunoassays. Four strains of mice were studied, with fatty livers induced by different causes, such as ageing, genetic mutation, acute drug usage, and high-fat diet. Nutrient-sensitive PTMs of a panel of 12 liver metabolic and signalling proteins were simultaneously evaluated with cIEF immunoassays, using nanograms of total cellular protein per assay. Changes to liver protein acetylation, phosphorylation, and O-N-acetylglucosamine glycosylation were quantified and compared between normal and diseased states. Fatty liver tissues could be distinguished from one another by distinctive protein PTM profiles. Fatty liver is currently classified by morphological assessment of lipid droplets, without identifying the underlying molecular causes. In contrast, high-throughput profiling of protein PTMs has the potential to provide molecular classification of fatty liver. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  3. Isolation and characterization of fatty acid binding protein in the liver of the nurse shark, Ginglymostoma cirratum.

    PubMed

    Bass, N M; Manning, J A; Luer, C A

    1991-01-01

    1. A 14.5 kDa fatty acid binding protein was isolated from the liver of the nurse shark, Ginglymostoma cirratum. 2. Purified shark liver FABP (pI = 5.4) bound oleic acid at a single site with an affinity similar to that of mammalian FABP. 3. The apparent size, pI and amino acid composition of shark liver FABP indicate a close structural relationship between this protein and mammalian heart FABP.

  4. Fatty liver index vs waist circumference for predicting non-alcoholic fatty liver disease.

    PubMed

    Motamed, Nima; Sohrabi, Masoudreza; Ajdarkosh, Hossein; Hemmasi, Gholamreza; Maadi, Mansooreh; Sayeedian, Fatemeh Sima; Pirzad, Reza; Abedi, Khadijeh; Aghapour, Sivil; Fallahnezhad, Mojtaba; Zamani, Farhad

    2016-03-14

    To determine the discriminatory performance of fatty liver index (FLI) for non-alcoholic fatty liver disease (NAFLD). The data of 5052 subjects aged over 18 years were analyzed. FLI was calculated from body mass index, waist circumference (WC), triglyceride, and gamma glutamyl transferase data. Logistic regression analysis was conducted to determine the association between FLI and NAFLD. The discriminatory performance of FLI in the diagnosis of NAFLD was evaluated by receiver operating characteristic analysis. Area under the curves (AUCs) and related confidence intervals were estimated. Optimal cutoff points of FLI in the diagnosis of NAFLD were determined based on the maximum values of Youden's index. The mean age of men and women in the study population were 44.8 ± 16.8 and 43.78 ± 15.43, respectively (P = 0.0216). The prevalence of NAFLD was 40.1% in men and 44.2% in women (P < 0.0017). FLI was strongly associated with NAFLD, so that even a one unit increase in FLI increased the chance of developing NAFLD by 5.8% (OR = 1.058, 95%CI: 1.054-1.063, P < 0.0001). Although FLI showed good performance in the diagnosis of NAFLD (AUC = 0.8656 (95%CI: 0.8548-0.8764), there was no significant difference with regards to WC (AUC = 0.8533, 95%CI: 0.8419-0.8646). The performance of FLI was not significantly different between men (AUC = 0.8648, 95%CI: 0.8505-0.8791) and women (AUC = 0.8682, 95%CI: 0.8513-0.8851). The highest performance with regards to age was related to the 18-39 age group (AUC = 0.8930, 95%CI: 0.8766-0.9093). The optimal cutoff points of FLI were 46.9 in men (sensitivity = 0.8242, specificity = 0.7687, Youden's index = 0.5929) and 53.8 in women (sensitivity = 0.8233, specificity = 0.7655, Youden's index = 0.5888). Although FLI had acceptable discriminatory power in the diagnosis of NAFLD, WC was a simpler and more accessible index with a similar performance.

  5. ω-3 Fatty acids reverse lipotoxity through induction of autophagy in nonalcoholic fatty liver disease.

    PubMed

    Chen, Yi; Xu, Chengfu; Yan, Tianlian; Yu, Chaohui; Li, Youming

    2015-01-01

    The aim of this study was to evaluate the effect of ω-3 fatty acids on nonalcoholic fatty liver disease concerning hepatocyte lipid accumulation as well as apoptosis induced by free fatty acids (FFAs) and to explore the underlying mechanism involving autophagy. Hepatocytes were incubated with a mixture of free fatty acids (FFAs) to mimic in vitro lipotoxicity in the pathogenesis of nonalcoholic fatty liver disease, presented by lipid accumulation and cellular apoptosis. Chemical inhibitor or inducer of autophagy and genetic deficit cells, as well as ω-3 fatty acids were used as intervention. The autophagic role of ω-3 fatty acids was investigated using Western blot and immunofluorescence. The underlying mechanism of ω-3 fatty acids involving autophagy was preliminarily explored by quantitative real-time polymerase chain reaction and Western blot. FFAs induce lipid accumulation and apoptosis in hepatocytes. Inhibition or genetic defect of autophagy increases lipid accumulation induced by FFA, whereas induction acts inversely. ω-3 Fatty acids reduced lipid accumulation and inhibited apoptosis induced by FFA. ω-3 Fatty acids induced autophagy by downregulating stearoyl-CoA desaturase 1 expression in hepatocytes. ω-3 Fatty acids exert protective effects on hepatocytes against lipotoxicity through induction of autophagy, as demonstrated by inhibition of lipid accumulation and apoptosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Prevalence and features of fatty liver detected by physical examination in Guangzhou.

    PubMed

    Liao, Xian-Hua; Cao, Xu; Liu, Jie; Xie, Xiao-Hua; Sun, Yan-Hong; Zhong, Bi-Hui

    2013-08-28

    To investigate the prevalence of fatty liver discovered upon physical examination of Chinese patients and determine the associated clinical characteristics. A total of 3433 consecutive patients who received physical examinations at the Huangpu Division of the First Affiliated Hospital at Sun Yat-sen University in Guangzhou, China from June 2010 to December 2010 were retrospectively enrolled in the study. Results of biochemical tests, abdominal ultrasound, electrocardiography, and chest X-ray were collected. The diagnosis of fatty liver was made if a patient met any two of the three following ultrasonic criteria: (1) liver and kidney echo discrepancy and presence of an increased liver echogenicity (bright); (2) unclear intrahepatic duct structure; and (3) liver far field echo decay. The study population consisted of 2201 males and 1232 females, with a mean age of 37.4 ± 12.8 years. When all 3433 patients were considered, the overall prevalence of hyperlipidemia was 38.1%, of fatty liver was 26.0%, of increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels was 11.9%, of gallstone was 11.4%, of hyperglycemia was 7.3%, of hypertension was 7.1%, and of hyperuricemia was 6.2%. Of the 2605 patients who completed the abdominal ultrasonography exam, 677 (26.0%) were diagnosed with fatty liver and the prevalence was higher in males (32.5% vs females: 15.3%, P < 0.001). The overall prevalence of fatty liver increased with age, with the peak prevalence (39.5%) found in the 60 to 70-year-old age group. Among patients between the ages of 18 to 50-year-old, the prevalence of fatty liver was significantly higher in males (20.2% vs females: 8.7%, P < 0.001); the difference in prevalence between the two sexes in patients > 50-year-old did not reach statistical significance. Only 430 of the patients diagnosed with fatty liver had complete information; among those, increased ALT and/or AST levels were detected in only 30%, with all disturbances being

  7. OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease.

    PubMed

    Akie, Thomas E; Liu, Lijun; Nam, Minwoo; Lei, Shi; Cooper, Marcus P

    2015-01-01

    OXPHOS is believed to play an important role in non-alcoholic fatty liver disease (NAFLD), however, precise mechanisms whereby OXPHOS influences lipid homeostasis are incompletely understood. We previously reported that ectopic expression of LRPPRC, a protein that increases cristae density and OXPHOS, promoted fatty acid oxidation in cultured primary hepatocytes. To determine the biological significance of that observation and define underlying mechanisms, we have ectopically expressed LRPPRC in mouse liver in the setting of NAFLD. Interestingly, ectopic expression of LRPPRC in mouse liver completely interdicted NAFLD, including inflammation. Consistent with mitigation of NAFLD, two markers of hepatic insulin resistance--ROS and PKCε activity--were both modestly reduced. As reported by others, improvement of NAFLD was associated with improved whole-body insulin sensitivity. Regarding hepatic lipid homeostasis, the ratio of NAD+ to NADH was dramatically increased in mouse liver replete with LRPPRC. Pharmacological activators and inhibitors of the cellular respiration respectively increased and decreased the [NAD+]/[NADH] ratio, indicating respiration-mediated control of the [NAD+]/[NADH] ratio. Supporting a prominent role for NAD+, increasing the concentration of NAD+ stimulated complete oxidation of fatty acids. Importantly, NAD+ rescued impaired fatty acid oxidation in hepatocytes deficient for either OXPHOS or SIRT3. These data are consistent with a model whereby augmented hepatic OXPHOS increases NAD+, which in turn promotes complete oxidation of fatty acids and protects against NAFLD.

  8. [Prevalence of no alcohol fatty liver disease (NAFLD) in a population of obese children in Valencia, Venezuela].

    PubMed

    Pontiles de Sánchez, Milagros; Morón de Salim, Alba; Rodríguez de Perdomo, Henny; Perdomo Oramas, Germán

    2014-06-01

    No Alcoholic Fatty Liver Disease (NAFLD) is characterized by an abnormal accumulation of fat in hepatocytes, without alcohol, where overweight and obesity are determinants. Ecosonografia evaluated the prevalence of fatty liver in obese pediatric patients and its relation to nutritional assessment. The sample consisted of 85 children (51 females, 34 males), age 3-17. The abdominal ecosonography, BMI, waist circumference were performed; Godard Test for physical activity, history of diabetes, dyslipidemia, obesity and cardiovascular disease were questioned. Lipid profile, glucose and insulin resistance were determined. Data analyzed from descriptive and comparative tables. We obtained: mean age 9.8 ± 2.7 females and males 9.6 ± 2.7 years. The ecosonography indicated 50% and 50% fatty liver-pancreas fatty liver in children aged 3-6 years; 7-11 years 39.7% fatty liver-pancreas; 12-17yrs 31.6% fatty liver-pancreas (p > 0.05); BMI > 26 kg/m2 42.9% fatty liver-pancreas; 21 to 25 kg/m2 44.7% fatty liver; 15 to 20 kg/m2 60%fatty liver-pancreas (p> 0.05). 97.6% with high CC; 68.2% with inadequate physical activity; high frequency of history of chronic non-communicable diseases. We concluded that this population had predominantly fatty liver fatty replacement of the pancreas (HG-RGP) in the groups with higher BMI, CC and high male unrelated insulin resistance, altered lipid profile and diagnosis HG. We inferred that the anthropometric assessment of waist circumference and abdominal ecosonography indicate the presence of visceral obesity, a condition that predisposes to hepatic steatosis, pancreas and/or liver-pancreas.

  9. Gender and racial differences in nonalcoholic fatty liver disease.

    PubMed

    Pan, Jen-Jung; Fallon, Michael B

    2014-05-27

    Due to the worldwide epidemic of obesity, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of elevated liver enzymes. NAFLD represents a spectrum of liver injury ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may progress to advanced fibrosis and cirrhosis. Individuals with NAFLD, especially those with metabolic syndrome, have higher overall mortality, cardiovascular mortality, and liver-related mortality compared with the general population. According to the population-based studies, NAFLD and NASH are more prevalent in males and in Hispanics. Both the gender and racial ethnic differences in NAFLD and NASH are likely attributed to interaction between environmental, behavioral, and genetic factors. Using genome-wide association studies, several genetic variants have been identified to be associated with NAFLD/NASH. However, these variants account for only a small amount of variation in hepatic steatosis among ethnic groups and may serve as modifiers of the natural history of NAFLD. Alternatively, these variants may not be the causative variants but simply markers representing a larger body of genetic variations. In this article, we provide a concise review of the gender and racial differences in the prevalence of NAFLD and NASH in adults. We also discuss the possible mechanisms for these disparities.

  10. Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice.

    PubMed

    Zimmers, Teresa A; Jin, Xiaoling; Zhang, Zongxiu; Jiang, Yanlin; Koniaris, Leonidas G

    2017-10-01

    Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice ( P < 0.05). Gene expression profiling showed decreased epidermal growth factor receptor (EGFR) in fatty liver. Meta-analysis of expression studies in mice, rats, and patients also demonstrated reduction of EGFR in fatty liver. In mice, both EGFR and phosphorylated EGFR decreased with increasing percent body fat. Hydrodynamic transfection of EGFR plasmids in mice corrected fatty liver regeneration, reducing liver injury, increasing proliferation, and improving survival after 80% resection. Loss of EGFR expression is rate limiting for liver regeneration in obesity. Therapies directed at increasing EGFR in steatosis might promote liver regeneration and survival following hepatic resection or transplantation. Copyright © 2017 the American Physiological Society.

  11. Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts

    PubMed Central

    Ma, Jiantao; Fox, Caroline S.; Jacques, Paul F.; Speliotes, Elizabeth K.; Hoffmann, Udo; Smith, Caren E.; Saltzman, Edward; McKeown, Nicola M.

    2016-01-01

    Background & Aims Non-alcoholic fatty liver disease affects ~30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar-sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. Methods Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/-day, and ⩾1 serving/day) of sugar-sweetened beverages or diet soda. Results After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend = 0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend = 0.007). We observed no significant association between diet soda intake and measures of fatty liver disease. Conclusion In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease. PMID:26055949

  12. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal.

    PubMed

    Machado, Mariana V; Cortez-Pinto, Helena

    2013-05-01

    Non-alcoholic fatty liver disease (NAFLD) affects one in every three subjects in the occidental world. The vast majority will not progress, but a relevant minority will develop liver cirrhosis and its complications. The classical gold standard for diagnosing and staging NAFLD and assessing fibrosis is liver biopsy (LB). However, it has important sample error issues and subjectivity in the interpretation, apart from a small but real risk of complications. The decision to perform an LB is even harder in a condition so prevalent such as NAFLD, in which the probability of finding severe liver injury is low. In an attempt to overcome LB and to subcategorize patients with NAFLD in different prognoses allowing better management decisions, several non-invasive methods have been studied in the last decade. The literature is vast and confusing. This review will summarize which methods have been tested and how they perform, which tests are adequate for clinical practice and how they can change the management of these patients. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  13. Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Kahali, Bratati; Halligan, Brian; Speliotes, Elizabeth K.

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future. PMID:26676813

  14. The intersection of nonalcoholic fatty liver disease and obesity.

    PubMed

    Woo Baidal, Jennifer A; Lavine, Joel E

    2016-01-27

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and recently emerged as the most rapidly increasing indication for liver transplant. Although obesity is a risk factor for NAFLD, overlap between these two entities is incompletely understood. We highlight recent insights into the pathogenesis of human NAFLD in relation to obesity and discuss advances in the diagnosis and treatment of NAFLD. Copyright © 2016, American Association for the Advancement of Science.

  15. Durability of small-for-size living donor allografts.

    PubMed

    Au, Kin Pan; Chan, See Ching; Chok, Kenneth Siu Ho; Chan, Albert Chi Yan; Wong, Tiffany Cho Lam; Sharr, William Wei; Lo, Chung Mau

    2015-11-01

    Our aim was to study the long-term outcomes of living donor liver transplantation using small-for-size (SFS) grafts. From July 2002 to July 2009, 233 patients received a right liver graft with a middle hepatic vein from a living donor in our center. Recipients were stratified according to the graft weight to recipient standard liver volume (GW/SLV) ratio into 4 groups: >50% (n = 89), >40% to 50% (n = 85), >35% to 40% (n = 38), and ≤ 35% (n = 21). They were compared in terms of graft survivals, biliary stricture rates, renal function in terms of estimated glomerular filtration rate (eGFR), platelet counts, and graft function in terms of serum bilirubin and international normalized ratio (INR). The 5-year graft survivals for patients with GW/SLV of >50%, >40% to 50%, >35% to 40% and ≤ 35% were 88.8%, 88.2%, 81.5%, and 81.0%, respectively. Transplantation for hepatocellular carcinoma affected graft survivals (P = 0.02), but graft size did not (P = 0.66). There were no differences in frequency of biliary stricture (21.3% versus 17.1% versus 21.1% versus 28.6%; P = 0.75). At each year after transplant, their platelet counts (P = 0.12-0.65), eGFR (P = 0.49-0.91), bilirubin (P = 0.14-0.51), and INR (P = 0.20-0.98) remained comparable. SFS grafts with GW/SLV ≤ 35% and >35% to 40% had comparable long-term outcomes with larger liver grafts. Graft size did not affect long-term graft survivals. © 2015 American Association for the Study of Liver Diseases.

  16. Nonalcoholic fatty liver disease - A multisystem disease?

    PubMed Central

    Mikolasevic, Ivana; Milic, Sandra; Turk Wensveen, Tamara; Grgic, Ivana; Jakopcic, Ivan; Stimac, Davor; Wensveen, Felix; Orlic, Lidija

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most common comorbidities associated with overweight and metabolic syndrome (MetS). Importantly, NAFLD is one of its most dangerous complications because it can lead to severe liver pathologies, including fibrosis, cirrhosis and hepatic cellular carcinoma. Given the increasing worldwide prevalence of obesity, NAFLD has become the most common cause of chronic liver disease and therefore is a major global health problem. Currently, NAFLD is predominantly regarded as a hepatic manifestation of MetS. However, accumulating evidence indicates that the effects of NAFLD extend beyond the liver and are negatively associated with a range of chronic diseases, most notably cardiovascular disease (CVD), diabetes mellitus type 2 (T2DM) and chronic kidney disease (CKD). It is becoming increasingly clear that these diseases are the result of the same underlying pathophysiological processes associated with MetS, such as insulin resistance, chronic systemic inflammation and dyslipidemia. As a result, they have been shown to be independent reciprocal risk factors. In addition, recent data have shown that NAFLD actively contributes to aggravation of the pathophysiology of CVD, T2DM, and CKD, as well as several other pathologies. Thus, NAFLD is a direct cause of many chronic diseases associated with MetS, and better detection and treatment of fatty liver disease is therefore urgently needed. As non-invasive screening methods for liver disease become increasingly available, detection and treatment of NAFLD in patients with MetS should therefore be considered by both (sub-) specialists and primary care physicians. PMID:27920470

  17. Non-alcoholic fatty liver disease: An expanded review

    PubMed Central

    Benedict, Mark; Zhang, Xuchen

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/supplements are being used in the treatment of NAFLD; however, none seem to be the “magic bullet” in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients. PMID:28652891

  18. Prevalence and features of fatty liver detected by physical examination in Guangzhou

    PubMed Central

    Liao, Xian-Hua; Cao, Xu; Liu, Jie; Xie, Xiao-Hua; Sun, Yan-Hong; Zhong, Bi-Hui

    2013-01-01

    AIM: To investigate the prevalence of fatty liver discovered upon physical examination of Chinese patients and determine the associated clinical characteristics. METHODS: A total of 3433 consecutive patients who received physical examinations at the Huangpu Division of the First Affiliated Hospital at Sun Yat-sen University in Guangzhou, China from June 2010 to December 2010 were retrospectively enrolled in the study. Results of biochemical tests, abdominal ultrasound, electrocardiography, and chest X-ray were collected. The diagnosis of fatty liver was made if a patient met any two of the three following ultrasonic criteria: (1) liver and kidney echo discrepancy and presence of an increased liver echogenicity (bright); (2) unclear intrahepatic duct structure; and (3) liver far field echo decay. RESULTS: The study population consisted of 2201 males and 1232 females, with a mean age of 37.4 ± 12.8 years. When all 3433 patients were considered, the overall prevalence of hyperlipidemia was 38.1%, of fatty liver was 26.0%, of increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels was 11.9%, of gallstone was 11.4%, of hyperglycemia was 7.3%, of hypertension was 7.1%, and of hyperuricemia was 6.2%. Of the 2605 patients who completed the abdominal ultrasonography exam, 677 (26.0%) were diagnosed with fatty liver and the prevalence was higher in males (32.5% vs females: 15.3%, P < 0.001). The overall prevalence of fatty liver increased with age, with the peak prevalence (39.5%) found in the 60 to 70-year-old age group. Among patients between the ages of 18 to 50-year-old, the prevalence of fatty liver was significantly higher in males (20.2% vs females: 8.7%, P < 0.001); the difference in prevalence between the two sexes in patients > 50-year-old did not reach statistical significance. Only 430 of the patients diagnosed with fatty liver had complete information; among those, increased ALT and/or AST levels were detected in only 30%, with

  19. The effects of TIS and MI on the texture features in ultrasonic fatty liver images

    NASA Astrophysics Data System (ADS)

    Zhao, Yuan; Cheng, Xinyao; Ding, Mingyue

    2017-03-01

    Nonalcoholic fatty liver disease (NAFLD) is prevalent and has a worldwide distribution now. Although ultrasound imaging technology has been deemed as the common method to diagnose fatty liver, it is not able to detect NAFLD in its early stage and limited by the diagnostic instruments and some other factors. B-scan image feature extraction of fatty liver can assist doctor to analyze the patient's situation and enhance the efficiency and accuracy of clinical diagnoses. However, some uncertain factors in ultrasonic diagnoses are often been ignored during feature extraction. In this study, the nonalcoholic fatty liver rabbit model was made and its liver ultrasound images were collected by setting different Thermal index of soft tissue (TIS) and mechanical index (MI). Then, texture features were calculated based on gray level co-occurrence matrix (GLCM) and the impacts of TIS and MI on these features were analyzed and discussed. Furthermore, the receiver operating characteristic (ROC) curve was used to evaluate whether each feature was effective or not when TIS and MI were given. The results showed that TIS and MI do affect the features extracted from the healthy liver, while the texture features of fatty liver are relatively stable. In addition, TIS set to 0.3 and MI equal to 0.9 might be a better choice when using a computer aided diagnosis (CAD) method for fatty liver recognition.

  20. [Laparoscopy findings of the yellow spot, a focal fatty liver infiltration].

    PubMed

    Koch, H; Henning, H; Friedrich, K; Lüders, C J

    1984-05-01

    From 1976 to 1982 in 279 patients amongst 3719 laparoscopies focal fatty liver infiltrates were found at the right and/or left liver edge next to the insertion point of the round ligament. These so-called "yellow spots" mainly could be recognized in case of normal liver tissue and in cases suffering from chronic hepatitis insofar as a cirrhotic transformation or a significant fibrosis had not taken place. The localization and the shape of these focal lesions indicate, that an abnormality in the portal blood supply of the corresponding area may play an etiologic role for the development of the fatty infiltration.

  1. Echocardiography and NAFLD (non-alcoholic fatty liver disease).

    PubMed

    Trovato, Francesca M; Martines, Giuseppe F; Catalano, Daniela; Musumeci, Giuseppe; Pirri, Clara; Trovato, Guglielmo M

    2016-10-15

    Non-alcoholic-fatty-liver-disease (NAFLD) is associated with atherosclerosis, increased cardiovascular risks and mortality. We investigated if, independently of insulin resistance, diet, physical activity and obesity, fatty liver involvement has any relationship with echocardiographic measurements in NAFLD. 660 NAFLD and 791 non-NAFLD subjects, referred to the same out-patients medical unit for lifestyle-nutritional prescription, were studied. Congestive heart failure, myocardial infarction, malignancies, diabetes mellitus, extreme obesity, underweight-bad-nourished subjects and renal insufficiency were exclusion criteria. Liver steatosis was assessed by Ultrasound-Bright-Liver-Score (BLS), left ventricular ejection fraction (LVEF), trans-mitral E/A doppler ratio (diastolic relaxation) and left ventricular myocardial mass (LVMM/m(2)) by echocardiography. Doppler Renal artery Resistive Index (RRI), insulin resistance (HOMA) and lifestyle profile were also included in the clinical assessment. LVMM/m(2) is significantly greater in NAFLD, 101.62±34.48 vs. 88.22±25.61, p<0.0001 both in men and in women. Ejection fraction is slightly smaller only in men with NAFLD; no significant difference was observed for the E/A ratio. BMI (30.42±5.49 vs. 24.87±3.81; p<0.0001) and HOMA (2.90±1.70 vs. 1.85±1.25; p: 0.0001) were significantly greater in NAFLD patients. By Multiple-Linear-Regression, NAFLD and unhealthy dietary profile are associated also in lean non-diabetic subjects with lower systolic function, independently of BMI, dietary profile, physical activity, RRI and insulin resistance. NAFLD may be a meaningful early clue suggestive of diminishing heart function, with similar determining factors. NAFLD is amenable to management and improvement by lifestyle change counseling, addressing a dual target: reducing fatty liver, which is easily monitored by ultrasound, and, independently, maintaining a normal heart function. Copyright © 2016 Elsevier Ireland Ltd. All rights

  2. Fatty liver index and hepatic steatosis index for prediction of non-alcoholic fatty liver disease in type 1 diabetes.

    PubMed

    Sviklāne, Laura; Olmane, Evija; Dzērve, Zane; Kupčs, Kārlis; Pīrāgs, Valdis; Sokolovska, Jeļizaveta

    2018-01-01

    Little is known about the diagnostic value of hepatic steatosis index (HSI) and fatty liver index (FLI), as well as their link to metabolic syndrome in type 1 diabetes mellitus. We have screened the effectiveness of FLI and HSI in an observational pilot study of 40 patients with type 1 diabetes. FLI and HSI were calculated for 201 patients with type 1 diabetes. Forty patients with FLI/HSI values corresponding to different risk of liver steatosis were invited for liver magnetic resonance study. In-phase/opposed-phase technique of magnetic resonance was used. Accuracy of indices was assessed from the area under the receiver operating characteristic curve. Twelve (30.0%) patients had liver steatosis. For FLI, sensitivity was 90%; specificity, 74%; positive likelihood ratio, 3.46; negative likelihood ratio, 0.14; positive predictive value, 0.64; and negative predictive value, 0.93. For HSI, sensitivity was 86%; specificity, 66%; positive likelihood ratio, 1.95; negative likelihood ratio, 0.21; positive predictive value, 0.50; and negative predictive value, 0.92. Area under the receiver operating characteristic curve for FLI was 0.86 (95% confidence interval [0.72; 0.99]); for HSI 0.75 [0.58; 0.91]. Liver fat correlated with liver enzymes, waist circumference, triglycerides, and C-reactive protein. FLI correlated with C-reactive protein, liver enzymes, and blood pressure. HSI correlated with waist circumference and C-reactive protein. FLI ≥ 60 and HSI ≥ 36 were significantly associated with metabolic syndrome and nephropathy. The tested indices, especially FLI, can serve as surrogate markers for liver fat content and metabolic syndrome in type 1 diabetes. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  3. Anti-fatty liver effects of oils from Zingiber officinale and Curcuma longa on ethanol-induced fatty liver in rats.

    PubMed

    Nwozo, Sarah Onyenibe; Osunmadewa, Damilola Adeola; Oyinloye, Babatunji Emmanuel

    2014-01-01

    The present study is aimed at evaluating the protective effects of oils from Zingiber officinale (ginger) and Curcuma longa (turmeric) on acute ethanol-induced fatty liver in male Wistar rats. Ferric reducing antioxidant power activity and oxygen radical absorbance capacity of the oils were evaluated ex vivo. Rats were pretreated for 28 d with standard drug (Livolin Forte) and oils from Z. officinale and C. longa before they were exposed to 45% ethanol (4.8 g/kg) to induce acute fatty liver. Histological changes were observed and the degree of protection was measured by using biochemical parameters such as alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities. Serum triglyceride (TG) level, total cholesterol (TC) level and the effects of both oils on reduced gluthatione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD) and hepatic malondialdehyde (MDA) levels were estimated. Oils from Z. officinale and C. longa at a dose of 200 mg/kg showed hepatoprotection by decreasing the activities of serum enzymes, serum TG, serum TC and hepatic MDA, while they significantly restored the level of GSH as well as GST and SOD activities. Histological examination of rats tissues was related to the obtained results. From the results it may be concluded that oils from Z. officinale and C. longa (200 mg/kg) exhibited hepatoprotective activity in acute ethanol-induced fatty liver and Z. officinale oil was identified to have better effects than C. longa oil.

  4. Tissue distribution comparison between healthy and fatty liver rats after oral administration of hawthorn leaf extract.

    PubMed

    Yin, Jingjing; Qu, Jianguo; Zhang, Wenjie; Lu, Dongrui; Gao, Yucong; Ying, Xixiang; Kang, Tingguo

    2014-05-01

    Hawthorn leaves, a well-known traditional Chinese medicine, have been widely used for treating cardiovascular and fatty liver diseases. The present study aimed to investigate the therapeutic basis treating fatty liver disease by comparing the tissue distribution of six compounds of hawthorn leaf extract (HLE) in fatty liver rats and healthy rats after oral administration at first day, half month and one month, separately. Therefore, a sensitive and specific HPLC method with internal standard was developed and validated to determine chlorogenic acid, vitexin-4''-O-glucoside, vitexin-2''-O-rhamnoside, vitexin, rutin and hyperoside in the tissues including heart, liver, spleen, kidney, stomach and intestine. The results indicated that the six compounds in HLE presented some bioactivity in treating rat fatty liver as the concentrations of the six compounds varied significantly in inter- and intragroup comparisons (healthy and/or fatty liver group). Copyright © 2013 John Wiley & Sons, Ltd.

  5. Effects of dietary polyunsaturated fatty acids and nucleotides on tissue fatty acid profiles of rats with carbon tetrachloride-induced liver damage.

    PubMed

    Fontana, L; Moreira, E; Torres, M I; Periago, J L; Sánchez de Medina, F; Gil, A

    1999-04-01

    The deficiency of polyunsaturated fatty acids (PUFA) that occurs in plasma of patients with liver cirrhosis has been assessed in rats with severe steatosis and mild liver necrosis induced by repeated administration of low doses of carbon tetrachloride (CCl(4)). The contribution of both dietary (n-3) long-chain PUFA and nucleotides to the recovery of the altered fatty acid profiles of tissue lipids of these rats has also been studied. Two groups of rats were used. The first was intraperitoneally injected 0.15 ml of a 10% (v/v) CCl(4)solution in paraffin per 100 g of body weight, three times a week for 9 weeks; the second received paraffin alone. After the treatment, six rats of each group were killed. Afterwards, the remaining controls were fed a semipurified diet (SPD) for 3 weeks, and the remaining rats in the CCl(4)group were divided into three new groups: the first was fed the SP diet; the second was fed the SP diet supplemented with 1% (n-3) polyunsaturated fatty acids (PUFA diet); and the third was fed the SP diet supplemented with 250 mg nucleotides per 100 g diet (NT diet). Fatty acids of plasma, erythrocyte membranes and liver microsomes were analyzed. Decreases in linoleic and arachidonic acids in both total plasma lipids and liver microsomal phospholipids were the main findings due to CCl(4)treatment. The rats that received CCl(4)and the PUFA diet showed the lowest levels of (n-6) PUFA and the highest levels of (n-3) PUFA in liver microsomal phospholipids, as well as a significant increase of (n-3) PUFAs in total plasma lipids. The animals that received the NT diet showed no signs of fatty infiltration and exhibited the highest levels of (n-6) PUFAs in liver microsomal phospholipids. These results show that CCl(4)affects fatty acid metabolism which is accordingly reflected in altered tissue fatty acid profiles, and that balanced diets containing PUFA and nucleotides are important for the recovery of the damaged liver in rats. Copyright 1999 Harcourt

  6. Background of the FIB-4 index in Japanese non-alcoholic fatty liver disease.

    PubMed

    Wada, Takashi; Zeniya, Mikio

    2015-01-01

    We investigated the distribution and characteristics of the FIB-4 index of liver fibrosis in 1,441 Japanese men (age 50.7±10.2 years) and 304 women (age 53.9±10.3 years) who underwent comprehensive general health checkups and were identified as having non-alcoholic fatty liver disease. With respect to the FIB-4 index, differences according to sex, metabolic indices, and ultrasonic findings were investigated. Among 9,255 individuals who underwent comprehensive general health checkups, 2,750 (29.8%) were found to have mild fatty liver or fatty liver based on ultrasound findings. After excluding patients who consumed ≥150 g alcohol/week (818 individuals), those testing positive for hepatitis B surface antigens or hepatitis C virus antibody (184 individuals), and those for whom data were insufficient (three individuals), we investigated the FIB-4 indices in the remaining 1,745 subjects. There were no sex differences in the FIB-4 index. A total of 1,370 patients (78.5%) exhibited a low cut-off index (COI) (<1.30), 357 (20.5%), exhibited an indeterminate COI (1.30-2.67), and 18 (1.0%) exhibited a high COI (>2.67). There were no associations between the FIB-4 index and the constituent factors of metabolic syndrome. In contrast, there was a significant difference in the ln FIB-4 index between the patients with and without mild fatty liver or fatty liver on ultrasound among men (0.006±0.43 and -0.092±0.39, p<0.001), but not women. The FIB-4 index was is significantly lower in men, but not women, with fatty liver. The FIB-4 index must be calculated separately during medical checkups and evaluated in conjunction with ultrasound findings.

  7. Dietary modification dampens liver inflammation and fibrosis in obesity-related fatty liver disease.

    PubMed

    Larter, Claire Z; Yeh, Matthew M; Haigh, W Geoffrey; Van Rooyen, Derrick M; Brooling, John; Heydet, Deborah; Nolan, Christopher J; Teoh, Narci C; Farrell, Geoffrey C

    2013-06-01

    Alms1 mutant (foz/foz) mice develop hyperphagic obesity, diabetes, metabolic syndrome, and fatty liver (steatosis). High-fat (HF) feeding converts pathology from bland steatosis to nonalcoholic steatohepatitis (NASH) with fibrosis, which leads to cirrhosis in humans. We sought to establish how dietary composition contributes to NASH pathogenesis. foz/foz mice were fed HF diet or chow 24 weeks, or switched HF to chow after 12 weeks. Serum ALT, NAFLD activity score (NAS), fibrosis severity, neutrophil, macrophage and apoptosis immunohistochemistry, uncoupling protein (UCP)2, ATP, NF-κB activation/expression of chemokines/adhesion molecules/fibrogenic pathways were determined. HF intake upregulated liver fatty acid and cholesterol transporter, CD36. Dietary switch expanded adipose tissue and decreased hepatomegaly by lowering triglyceride, cholesterol ester, free cholesterol and diacylglyceride content of liver. There was no change in lipogenesis or fatty acid oxidation pathways; instead, CD36 was suppressed. These diet-induced changes in hepatic lipids improved NAS, reduced neutrophil infiltration, normalized UCP2 and increased ATP; this facilitated apoptosis with a change in macrophage phenotype favoring M2 cells. Dietary switch also abrogated NF-κB activation and chemokine/adhesion molecule expression, and arrested fibrosis by dampening stellate cell activation. Reversion to a physiological dietary composition after HF feeding in foz/foz mice alters body weight distribution but not obesity. This attenuates NASH severity and fibrotic progression by suppressing NF-κB activation and reducing neutrophil and macrophage activation. However, adipose inflammation persists and is associated with continuing apoptosis in the residual fatty liver disease. Taken together, these findings indicate that other measures, such as weight reduction, may be required to fully reverse obesity-related NASH. Copyright © 2013 The Obesity Society.

  8. Studies on fatty acid-binding proteins. The detection and quantification of the protein from rat liver by using a fluorescent fatty acid analogue.

    PubMed Central

    Wilkinson, T C; Wilton, D C

    1986-01-01

    Fatty acid-binding protein from rat liver is shown to bind the fluorescent fatty acid probe dansyl undecanoic acid. Binding is accompanied by a shift in the fluorescence emission maximum from 550 nm to 500 nm and a 60-fold fluorescence enhancement at 500 nm. These spectral properties have allowed the use of this probe to detect and quantify microgram amounts of liver fatty acid-binding protein during purification procedures. In conjunction with h.p.l.c. the method allows the rapid estimation of liver fatty acid-binding protein in biological samples. The validity of the method is demonstrated by measuring the concentration of fatty acid-binding protein in livers from control and hypolipidaemic-drug-treated rats. The dramatic diurnal rhythm previously reported for this protein [Dempsey (1984) Curr. Top. Cell. Regul. 24, 63-86] was not observed with this method. Images Fig. 1. PMID:3800946

  9. Size mismatch in liver transplantation.

    PubMed

    Fukazawa, Kyota; Nishida, Seigo

    2016-08-01

    Size mismatch is an unique and inevitable but critical issue in live donor liver transplantation. Unmatched metabolic demand of recipient as well as physiologic mismatch aggravates the damage to liver graft, inevitably leading to graft failure on recipient. Also, an excessive resection of liver graft for better recipient outcome in live donor liver transplant may jeopardize the healthy donor well-being and even put donor life in danger. There is a fine balance between resected graft volume required to meet the recipient's metabolic demand and residual graft volume required for donor safety. The obvious clinical necessity of finding that balance has prompted a clinical need and promoted the improvement of knowledge and development of management strategies for size-mismatched transplants. The development of the size-matching methodology has significantly improved graft outcome and recipient survival in live donor liver transplants. On the other hand, the effect of size mismatch in cadaveric transplants has never been observed as being so pronounced. The importance of matching of the donor recipient size has been unrecognized in cadaveric liver transplant. In this review, we attempt to summarize the current most updated knowledge on the subject, particularly addressing the definition and complications of size-mismatched cadaveric liver transplant, as well as management strategies. © 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  10. Antioxidant dietary approach in treatment of fatty liver: New insights and updates

    PubMed Central

    Ferramosca, Alessandra; Di Giacomo, Mariangela; Zara, Vincenzo

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols (i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids (i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates (i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver. PMID:28694655

  11. Antioxidant dietary approach in treatment of fatty liver: New insights and updates.

    PubMed

    Ferramosca, Alessandra; Di Giacomo, Mariangela; Zara, Vincenzo

    2017-06-21

    Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols ( i.e ., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids ( i.e ., lycopene, astaxanthin and fucoxanthin) and glucosinolates ( i.e ., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.

  12. Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in Japanese patients with non-alcoholic fatty liver disease.

    PubMed

    Kato, Ken-Ichiro; Takeshita, Yumie; Misu, Hirofumi; Zen, Yoh; Kaneko, Shuichi; Takamura, Toshinari

    2015-03-01

    To examine the association between liver histological features and organ-specific insulin resistance indices calculated from 75-g oral glucose tolerance test data in patients with non-alcoholic fatty liver disease. Liver biopsy specimens were obtained from 72 patients with non-alcoholic fatty liver disease, and were scored for steatosis, grade and stage. Hepatic and skeletal muscle insulin resistance indices (hepatic insulin resistance index and Matsuda index, respectively) were calculated from 75-g oral glucose tolerance test data, and metabolic clearance rate was measured using the euglycemic hyperinsulinemic clamp method. The degree of hepatic steatosis, and grade and stage of non-alcoholic steatohepatitis were significantly correlated with Matsuda index (steatosis r = -0.45, P < 0.001; grade r = -0.54, P < 0.001; stage r = -0.37, P < 0.01), but not with hepatic insulin resistance index. Multiple regression analyses adjusted for age, sex, body mass index and each histological score showed that the degree of hepatic steatosis (coefficient = -0.22, P < 0.05) and grade (coefficient = -0.40, P < 0.01) were associated with Matsuda index, whereas the association between stage and Matsuda index (coefficient = -0.07, P = 0.593) was no longer significant. A similar trend was observed for the association between steatosis and metabolic clearance rate (coefficient = -0.62, P = 0.059). Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in patients with non-alcoholic fatty liver disease, suggesting a central role of fatty liver in the development of peripheral insulin resistance and the existence of a network between the liver and skeletal muscle.

  13. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease.

    PubMed

    Dumas, Marc-Emmanuel; Kinross, James; Nicholson, Jeremy K

    2014-01-01

    Metabolic syndrome, a cluster of risk factors for type 2 diabetes mellitus and cardiovascular disease, is becoming an increasing global health concern. Insulin resistance is often associated with metabolic syndrome and also typical hepatic manifestations such as nonalcoholic fatty liver disease. Profiling of metabolic products (metabolic phenotyping or metabotyping) has provided new insights into metabolic syndrome and nonalcoholic fatty liver disease. Data from nuclear magnetic resonance spectroscopy and mass spectrometry combined with statistical modeling and top-down systems biology have allowed us to analyze and interpret metabolic signatures in terms of metabolic pathways and protein interaction networks and to identify the genomic and metagenomic determinants of metabolism. For example, metabolic phenotyping has shown that relationships between host cells and the microbiome affect development of the metabolic syndrome and fatty liver disease. We review recent developments in metabolic phenotyping and systems biology technologies and how these methodologies have provided insights into the mechanisms of metabolic syndrome and nonalcoholic fatty liver disease. We discuss emerging areas of research in this field and outline our vision for how metabolic phenotyping could be used to study metabolic syndrome and fatty liver disease. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  14. From the liver to the heart: Cardiac dysfunction in obese children with non-alcoholic fatty liver disease

    PubMed Central

    Di Sessa, Anna; Umano, Giuseppina Rosaria; Miraglia del Giudice, Emanuele; Santoro, Nicola

    2017-01-01

    In the last decades the prevalence of non-alcoholic fatty liver disease (NAFLD) has increased as a consequence of the childhood obesity world epidemic. The liver damage occurring in NAFLD ranges from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Recent findings reported that fatty liver disease is related to early atherosclerosis and cardiac dysfunction even in the pediatric population. Moreover, some authors have shown an association between liver steatosis and cardiac abnormalities, including rise in left ventricular mass, systolic and diastolic dysfunction and epicardial adipose tissue thickness. In this editorial, we provide a brief overview of the current knowledge concerning the association between NAFLD and cardiac dysfunction. PMID:28144387

  15. From the liver to the heart: Cardiac dysfunction in obese children with non-alcoholic fatty liver disease.

    PubMed

    Di Sessa, Anna; Umano, Giuseppina Rosaria; Miraglia Del Giudice, Emanuele; Santoro, Nicola

    2017-01-18

    In the last decades the prevalence of non-alcoholic fatty liver disease (NAFLD) has increased as a consequence of the childhood obesity world epidemic. The liver damage occurring in NAFLD ranges from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Recent findings reported that fatty liver disease is related to early atherosclerosis and cardiac dysfunction even in the pediatric population. Moreover, some authors have shown an association between liver steatosis and cardiac abnormalities, including rise in left ventricular mass, systolic and diastolic dysfunction and epicardial adipose tissue thickness. In this editorial, we provide a brief overview of the current knowledge concerning the association between NAFLD and cardiac dysfunction.

  16. Human germline hedgehog pathway mutations predispose to fatty liver.

    PubMed

    Guillen-Sacoto, Maria J; Martinez, Ariel F; Abe, Yu; Kruszka, Paul; Weiss, Karin; Everson, Joshua L; Bataller, Ramon; Kleiner, David E; Ward, Jerrold M; Sulik, Kathleen K; Lipinski, Robert J; Solomon, Benjamin D; Muenke, Maximilian

    2017-10-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations that affect this pathway. Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2 +/- ) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2 +/- mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2 +/- mice exposed to a high-fat diet. Our results indicate that germline mutations disrupting Hh signaling promotes liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition in the liver predominantly due to high calorie intake and a sedentary lifestyle. NAFLD progression is usually accompanied by activation of the Sonic hedgehog (SHH) pathway leading to fibrous

  17. Sex impact on the quality of fatty liver and its genetic determinism in mule ducks.

    PubMed

    Marie-Etancelin, C; Retailleau, B; Alinier, A; Vitezica, Z G

    2015-09-01

    Recent changes to French regulations now allow farmers to produce "foie gras" from both male and female mule ducks. The aim of this study was to assess the quality of female fatty liver and to compare, from a phenotypic and genetic point of view, liver quality in males and females. A total of 914 mule ducks (591 males and 323 females), hatched in a single pedigree batch, were reared until 86 d of age and then force-fed for 12 d, before being slaughtered. Carcasses and livers were weighed and liver quality was assessed by grading the extent of liver veining and measuring the liver melting rate, either after sterilization of 60 g of liver or pasteurization of 180 g of liver. Sexual dimorphism was observed in favor of males, with a difference of approximately 10% in carcass and liver weights and up to 54% for the liver melting rate. Moreover, one-third of female livers showed moderate to high veining, whereas this was not the case for male livers. The fatty livers of female mule ducks are, therefore, of poorer quality and could not be transformed into a product with the appellation "100% fatty liver." According to sex and parental line, heritability values ranged from 0.12 ± 0.05 to 0.18 ± 0.07 for fatty liver weight and from 0.09 ± 0.05 to 0.18 ± 0.05 for the 2 melting rate traits. The genetic correlations between the fatty liver weight and both melting rates were high (greater than +0.80) in the Muscovy population, whereas in the Pekin population, the liver weight and melting rates were less strongly correlated (estimates ranging from +0.36 ± 0.30 to +0.45 ± 0.28). Selection for lower liver melting rates without reducing the liver weight would, therefore, be easier to achieve in the Pekin population. Finally, as the 2 melting rate measurements are highly correlated (0.91 and over 0.95 for phenotypic and genetic correlations, respectively), we suggest using the easiest method, that is, sterilization of 60 g of liver.

  18. Nonalcoholic Fatty Liver Disease: Noninvasive Methods of Diagnosing Hepatic Steatosis

    PubMed Central

    AlShaalan, Rasha; Aljiffry, Murad; Al-Busafi, Said; Metrakos, Peter; Hassanain, Mazen

    2015-01-01

    Hepatic steatosis is the buildup of lipids within hepatocytes. It is the simplest stage in nonalcoholic fatty liver disease (NAFLD). It occurs in approximately 30% of the general population and as much as 90% of the obese population in the United States. It may progress to nonalcoholic steatohepatitis, which is a state of hepatocellular inflammation and damage in response to the accumulated fat. Liver biopsy remains the gold standard tool to diagnose and stage NAFLD. However, it comes with the risk of complications ranging from simple pain to life-threatening bleeding. It is also associated with sampling error. For these reasons, a variety of noninvasive radiological markers, including ultrasound, computed tomography, magnetic resonance spectroscopy, and the controlled attenuation parameter using transient elastography and Xenon-133 scan have been proposed to increase our ability to diagnose NAFLD, hence avoiding liver biopsy. The aim of this review is to discuss the utility and accuracy of using available noninvasive diagnostic modalities for fatty liver in NAFLD. PMID:25843191

  19. Establishment of the Tree Shrew as an Alcohol-Induced Fatty Liver Model for the Study of Alcoholic Liver Diseases

    PubMed Central

    Xing, Huijie; Jia, Kun; He, Jun; Shi, Changzheng; Fang, Meixia; Song, Linliang; Zhang, Pu; Zhao, Yue; Fu, Jiangnan; Li, Shoujun

    2015-01-01

    Currently, the pathogenesis of alcoholic liver diseases (ALDs) is not clear. As a result, there is no effective treatment for ALDs. One limitation is the lack of a suitable animal model for use in studying ALDs. The tree shrew is a lower primate animal, characterized by a high-alcohol diet. This work aimed to establish a fatty liver model using tree shrews and to assess the animals’ suitability for the study of ALDs. Tree shrews were treated with alcohol solutions (10% and 20%) for two weeks. Hemophysiology, blood alcohol concentrations (BACs), oxidative stress factors, alcohol metabolic enzymes and hepatic pathology were checked and assayed with an automatic biochemical analyzer, enzyme-linked immunosorbent assay (ELISA), western blot, hematoxylin-eosin (HE) staining and oil red O staining, and magnetic resonance imaging (MRI). Compared with the normal group, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), total cholesterol (TC), triglyceride (TG), reactive oxygen species (ROS), and malondialdehyde (MDA) were significantly enhanced in alcohol-treated tree shrews. However, the activity of reduced glutathione hormone (GSH) and superoxide dismutase (SOD) declined. Notable changes in alcohol dehydrogenase(ADH1), aldehyde dehydrogenase(ALDH2), CYP2E1, UDP-glucuronosyl transferase 1A1 (UGT1A1) and nuclear factor erythroid-related factor 2 (Nrf2) were observed. HE and oil red O staining showed that hepatocyte swelling, hydropic degeneration, and adipohepatic syndrome occurred in the tree shrews. Alcohol can induce fatty liver-like pathological changes and result in alterations in liver function, oxidative stress factors, alcohol metabolism enzymes and Nrf2. Therefore, the established fatty liver model of tree shrews induced by alcohol should be a promising tool for the study of ALDs. PMID:26030870

  20. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.

    PubMed

    Dongiovanni, P; Stender, S; Pietrelli, A; Mancina, R M; Cespiati, A; Petta, S; Pelusi, S; Pingitore, P; Badiali, S; Maggioni, M; Mannisto, V; Grimaudo, S; Pipitone, R M; Pihlajamaki, J; Craxi, A; Taube, M; Carlsson, L M S; Fargion, S; Romeo, S; Kozlitina, J; Valenti, L

    2018-04-01

    Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease. © 2017 The Authors Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

  1. Evaluation of Potential Donors in Living Donor Liver Transplantation.

    PubMed

    Dirican, A; Baskiran, A; Dogan, M; Ates, M; Soyer, V; Sarici, B; Ozdemir, F; Polat, Y; Yilmaz, S

    2015-06-01

    Correct donor selection in living donor liver transplantation (LDLT) is essential not only to decrease the risks of complications for the donors but also to increase the survival of both the graft and the recipient. Knowing their most frequent reasons of donor elimination is so important for transplantation centers to gain time. In this study we evaluated the effectiveness of potential donors in LDLT and studied the reasons for nonmaturation of potential liver donors at our transplantation center. We studied the outcomes of 342 potential living donor candidates for 161 recipient candidates for liver transplantation between January 2013 and June 2014. Donor candidates' gender, age, body mass index (BMI), relationship with recipient, and causes of exclusion were recorded. Among 161 recipients, 96 had a LDLT and 7 had cadaveric liver transplantation. Twelve of the 342 potential donors did not complete their evaluation; 106 of the remaining 330 donor candidates were accepted as suitable for donation (32%) but 10 of these were excluded preoperatively. The main reasons for unsuitability for liver donation were small remnant liver size (43%) and fatty changes of the liver (38.4%). Other reasons were arterial anatomic variations, ABO incompatibility, and Gilbert syndrome. Only 96 of the candidates (29% of the 330 candidates who completed the evaluation) underwent donation. Effective donors were 29% of potential and 90.5% of suitable donors. In our center, 106 of 330 (32%) donor candidates were suitable for donation and the main reasons for unsuitability for liver donation were small remnant liver size and fatty changes of the liver. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Fatty liver and drugs: the two sides of the same coin.

    PubMed

    Miele, L; Liguori, A; Marrone, G; Biolato, M; Araneo, C; Vaccaro, F G; Gasbarrini, A; Grieco, A

    2017-03-01

    Drug-induced liver injury (DILI) is a common and underestimated cause of liver disease. Several drugs and other xenobiotics can be the cause of different clinicopathologic patterns of liver disease. Steatosis and steatohepatitis are rare but well-documented types of DILI. Over the past decades commonly used drugs like amiodarone, tamoxifen, irinotecan, methotrexate, valproic acid and glucocorticoids have been recognized to be associated with steatosis. Even though the pathophysiological pathways are still only partially understood, inhibition of mitochondrial beta-oxidation, reduced very low-density lipoprotein secretion, insulin resistance induction and increased de novo synthesis or increased liver uptake of fatty acids are considered the main pathogenic mechanisms through which drugs can lead to hepatic steatosis. On the other hand, fatty liver itself is a very common clinical condition, and there is a growing awareness of the potential risk factors for DILI due to the underlying metabolic condition itself.

  3. Non-invasive Diagnosis of Fibrosis in Non-alcoholic Fatty Liver Disease

    PubMed Central

    Arora, Anil; Sharma, Praveen

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed as well as in developing countries. Its prevalence continues to rise currently affecting approximately 20-30% of adults and 10% of children in the United States. Non-alcoholic fatty liver disease represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign non-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several non-invasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. There has been a substantial development of non-invasive risk scores, biomarker panels, and radiological modalities to identify at risk patients with NAFLD without recourse to liver biopsy on a routine basis. Examples include combination of serum markers like NAFLD fibrosis score (NFS), BARD score, fibrometer, FIB4, and non-invasive tools like fibroscan which assess fibrosis in patients with NAFLD. Other markers of fibrosis that have been evaluated include high-sensitivity C-reactive protein, plasma pentraxin 3, interleukin-6, and cytokeratin-18. This review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on the potential future markers under investigation. PMID:25755423

  4. Obstructive Sleep Apnea and Non-Alcoholic Fatty Liver Disease: Is the Liver Another Target?

    PubMed Central

    Mirrakhimov, Aibek E.; Polotsky, Vsevolod Y.

    2012-01-01

    Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done. PMID:23087670

  5. Association between soil heavy metals and fatty liver disease in men in Taiwan: a cross sectional study.

    PubMed

    Lin, Yen-Chih; Lian, Ie-Bin; Kor, Chew-Teng; Chang, Chia-Chu; Su, Pei-Yuan; Chang, Wan-Tzu; Liang, Yu-Fen; Su, Wei-Wen; Soon, Maw-Soan

    2017-01-23

    Metabolic factors are major risk factors for non-alcoholic fatty liver disease although other factors may also contribute to development of fatty liver disease. We explored the association between exposure to soil heavy metals and prevalence of fatty liver disease. We retrospectively analysed data from patients diagnosed with fatty liver disease in 2014 at the Health Evaluation Centre of Chang-Hua Christian Hospital (n=1137). We used residency data provided in the records of the Health Evaluation Centre and data for soil metal concentrations from a nationwide survey conducted by the Environmental Protection Administration of Taiwan. We studied the correlations between the severity of fatty liver disease and concentrations of soil heavy metals (arsenic, mercury, cadmium, chromium, copper, nickel, lead and zinc). The prevalence of moderate to severe fatty liver disease in our study was 26.5%. Using univariate and multivariate analysis, we demonstrated that the presence of soil heavy metals was a significant risk factor for fatty liver disease in men (OR 1.83, 95% CI 1.161 to 2.899, p=0.009). With stratification by body mass index (BMI) and gender, lean men with a BMI <24 kg/m 2 were the most susceptible to soil heavy metals (OR 5.059, 95% CI 1.628 to 15.728, p<0.05). Our study suggested a significant association between exposure to soil heavy metals and fatty liver disease in lean men. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  6. Fatty Acid–Regulated Transcription Factors in the Liver

    PubMed Central

    Jump, Donald B.; Tripathy, Sasmita; Depner, Christopher M.

    2014-01-01

    Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population. PMID:23528177

  7. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis

    PubMed Central

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K.; Mukherjee, Rathin; Reddy, Duvvur N.; Rao, Padaki N.

    2015-01-01

    Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed. PMID:26155043

  8. Fat content, fatty acid pattern and iron content in livers of turkeys with hepatic lipidosis.

    PubMed

    Visscher, Christian; Middendorf, Lea; Günther, Ronald; Engels, Alexandra; Leibfacher, Christof; Möhle, Henrik; Düngelhoef, Kristian; Weier, Stefan; Haider, Wolfram; Radko, Dimitri

    2017-05-30

    The so-called "hepatic lipidosis" in turkeys is an acute progressive disease associated with a high mortality rate in a very short time. Dead animals show a massive fatty degeneration of the liver. The cause is still unclear. Previous findings suggest that there may be parallels to human non-alcoholic fatty liver disease. The object of the study was to examine the changes in the fat contents, the fatty acid composition and the iron content in livers of animals, which have died from hepatic lipidosis. The conspicuous livers (n = 85) were collected from 20 flocks where the phenomenon of massive increased animal losses accompanied by marked macroscopically visible pathological liver steatosis suddenly occurred. For comparison and as a reference, livers (n = 16) of two healthy flocks were taken. Healthy and diseased flocks were fed identical diets concerning official nutrient recommendations and were operating under standardized, comparable conventional conditions. Compared to livers of healthy animals, in the livers of turkeys died from hepatic lipidosis there were found massively increased fat levels (130 ± 33.2 vs. 324 ± 101 g/kg dry matter-DM). In all fatty livers, different fatty acids concentrations were present in significantly increased concentrations compared to controls (palmitic acid: 104 g/kg DM, +345%; palmitoleic acid: 18.0 g/kg DM, + 570%; oleic acid: 115 g/kg DM, +437%). Fatty acids concentrations relevant for liver metabolism and inflammation were significantly reduced (arachidonic acid: 2.92 g/kg DM, -66.6%; eicosapentaenoic acid: 0.141 g/kg DM, -78.3%; docosahexaenoic acid: 0.227 g/kg DM, -90.4%). The ratio of certain fatty acids to one another between control and case livers changed analogously to liver diseases in humans (e.g.: C18:0/C16:0 - 0.913 against 0.311; C16:1n7/C16:0 - 0.090 against 0.165; C18:1/C18:0 - 0.938 against 4.03). The iron content in the liver tissue also increased massively (271 ± 51.5 vs 712 ± 214 mg/kg DM). The hepatic

  9. Lactobacillus rhamnosus GG Protects against Non-Alcoholic Fatty Liver Disease in Mice

    PubMed Central

    Ritze, Yvonne; Bárdos, Gyöngyi; Claus, Anke; Ehrmann, Veronika; Bergheim, Ina; Schwiertz, Andreas; Bischoff, Stephan C.

    2014-01-01

    Objective Experimental evidence revealed that obesity-associated non-alcoholic fatty liver disease (NAFLD) is linked to changes in intestinal permeability and translocation of bacterial products to the liver. Hitherto, no reliable therapy is available except for weight reduction. Within this study, we examined the possible effect of the probiotic bacterial strain Lactobacillus rhamnosus GG (LGG) as protective agent against experimental NAFLD in a mouse model. Methods Experimental NAFLD was induced by a high-fructose diet over eight weeks in C57BL/J6 mice. Fructose was administered via the drinking water containing 30% fructose with or without LGG at a concentration resulting in approximately 5×107 colony forming units/g body weight. Mice were examined for changes in small intestinal microbiota, gut barrier function, lipopolysaccharide (LPS) concentrations in the portal vein, liver inflammation and fat accumulation in the liver. Results LGG increased beneficial bacteria in the distal small intestine. Moreover, LGG reduced duodenal IκB protein levels and restored the duodenal tight junction protein concentration. Portal LPS (P≤0.05) was reduced and tended to attenuate TNF-α, IL-8R and IL-1β mRNA expression in the liver feeding a high-fructose diet supplemented with LGG. Furthermore liver fat accumulation and portal alanine-aminotransferase concentrations (P≤0.05) were attenuated in mice fed the high-fructose diet and LGG. Conclusions We show for the first time that LGG protects mice from NAFLD induced by a high-fructose diet. The underlying mechanisms of protection likely involve an increase of beneficial bacteria, restoration of gut barrier function and subsequent attenuation of liver inflammation and steatosis. PMID:24475018

  10. Nonalcoholic fatty liver disease and polycystic ovary syndrome.

    PubMed

    Vassilatou, Evangeline

    2014-07-14

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world comprising a spectrum of liver damage from fatty liver infiltration to end-stage liver disease, in patients without significant alcohol consumption. Increased prevalence of NAFLD has been reported in patients with polycystic ovary syndrome (PCOS), one of the most common endocrinopathies in premenopausal women, which has been redefined as a reproductive and metabolic disorder after the recognition of the important role of insulin resistance in the pathophysiology of the syndrome. Obesity, in particular central adiposity and insulin resistance are considered as the main factors related to NAFLD in PCOS. Moreover, existing data support that androgen excess, which is the main feature of PCOS and is interrelated to insulin resistance, may be an additional contributing factor to the development of NAFLD. Although the natural history of NAFLD remains unclear and hepatic steatosis seems to be a relatively benign condition in most patients, limited data imply that advanced stage of liver disease is possibly more frequent in obese PCOS patients with NAFLD. PCOS patients, particularly obese patients with features of the metabolic syndrome, should be submitted to screening for NAFLD comprising assessment of serum aminotransferase levels and of hepatic steatosis by abdominal ultrasound. Lifestyle modifications including diet, weight loss and exercise are the most appropriate initial therapeutic interventions for PCOS patients with NAFLD. When pharmacologic therapy is considered, metformin may be used, although currently there is no medical therapy of proven benefit for NAFLD. Long-term follow up studies are needed to clarify clinical implications and guide appropriate diagnostic evaluation, follow-up protocol and optimal treatment for PCOS patients with NAFLD.

  11. Nonalcoholic fatty liver disease and polycystic ovary syndrome

    PubMed Central

    Vassilatou, Evangeline

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world comprising a spectrum of liver damage from fatty liver infiltration to end-stage liver disease, in patients without significant alcohol consumption. Increased prevalence of NAFLD has been reported in patients with polycystic ovary syndrome (PCOS), one of the most common endocrinopathies in premenopausal women, which has been redefined as a reproductive and metabolic disorder after the recognition of the important role of insulin resistance in the pathophysiology of the syndrome. Obesity, in particular central adiposity and insulin resistance are considered as the main factors related to NAFLD in PCOS. Moreover, existing data support that androgen excess, which is the main feature of PCOS and is interrelated to insulin resistance, may be an additional contributing factor to the development of NAFLD. Although the natural history of NAFLD remains unclear and hepatic steatosis seems to be a relatively benign condition in most patients, limited data imply that advanced stage of liver disease is possibly more frequent in obese PCOS patients with NAFLD. PCOS patients, particularly obese patients with features of the metabolic syndrome, should be submitted to screening for NAFLD comprising assessment of serum aminotransferase levels and of hepatic steatosis by abdominal ultrasound. Lifestyle modifications including diet, weight loss and exercise are the most appropriate initial therapeutic interventions for PCOS patients with NAFLD. When pharmacologic therapy is considered, metformin may be used, although currently there is no medical therapy of proven benefit for NAFLD. Long-term follow up studies are needed to clarify clinical implications and guide appropriate diagnostic evaluation, follow-up protocol and optimal treatment for PCOS patients with NAFLD. PMID:25024594

  12. Creatine supplementation prevents fatty liver in rats fed choline-deficient diet: a burden of one-carbon and fatty acid metabolism.

    PubMed

    Deminice, Rafael; de Castro, Gabriela Salim Ferreira; Francisco, Lucas Vieira; da Silva, Lilian Eslaine Costa Mendes; Cardoso, João Felipe Rito; Frajacomo, Fernando Tadeu Trevisan; Teodoro, Bruno Gonzaga; Dos Reis Silveira, Leonardo; Jordao, Alceu Afonso

    2015-04-01

    To examine the effects of creatine (Cr) supplementation on liver fat accumulation in rats fed a choline-deficient diet. Twenty-four rats were divided into 3 groups of 8 based on 4 weeks of feeding an AIN-93 control diet (C), a choline-deficient diet (CDD) or a CDD supplemented with 2% Cr. The CDD diet was AIN-93 without choline. The CDD significantly increased plasma homocysteine and TNFα concentration, as well as ALT activity. In liver, the CDD enhanced concentrations of total fat (55%), cholesterol (25%), triglycerides (87%), MDA (30%), TNFα (241%) and decreased SAM concentrations (25%) and the SAM/SAH ratio (33%). Cr supplementation prevented all these metabolic changes, except for hepatic SAM and the SAM/SAH ratio. However, no changes in PEMT gene expression or liver phosphatidylcholine levels were observed among the three experimental groups, and there were no changes in hepatic triglyceride transfer protein (MTP) mRNA level. On the contrary, Cr supplementation normalized expression of the transcription factors PPARα and PPARγ that were altered by the CDD. Further, the downstream targets and fatty acids metabolism genes, UCP2, LCAD and CPT1a, were also normalized in the Cr group as compared to CDD-fed rats. Cr supplementation prevented fat liver accumulation and hepatic injures in rats fed with a CDD for 4 weeks. Our results demonstrated that one-carbon metabolism may have a small role in mitigating hepatic fat accumulation by Cr supplementation. The modulation of key genes related to fatty acid oxidation pathway suggests a new mechanism by which Cr prevents liver fat accumulation. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Dietary intake of ain-93 standard diet induces Fatty liver with altered hepatic fatty acid profile in Wistar rats.

    PubMed

    Farias Santos, Juliana; Suruagy Amaral, Monique; Lima Oliveira, Suzana; Porto Barbosa, Júnia; Rego Cabral, Cyro; Sofia Melo, Ingrid; Bezerra Bueno, Nassib; Duarte Freitas, Johnatan; Goulart Sant'ana, Antônio; Rocha Ataíde, Terezinha

    2015-05-01

    There are several standard diets for animals used in scientific research, usually conceived by scientific institutions. The AIN-93 diet is widely used, but there are some reports of fatty liver in Wistar rats fed this diet. We aimed to evaluate the hepatic repercussions of the AIN-93 diet intake in Wistar rats. Forty newly-weaned 21-day-old male Wistar rats were fed either the AIN-93 diet or a commercial diet for either 1 month or 4 months. Weight gain, serum biochemistry, hepatic histology, and hepatic fatty acid profile were analyzed. Hepatic steatosis was observed, especially in the group fed the AIN-93 diet. Serum blood glucose, absolute and relative liver weight and hepatic levels of oleic, palmitoleic, stearic, and palmitic fatty acids were related to the observed steatosis, while lipidogram and serum markers of liver function and injury were not. AIN-93 diet induced acute hepatic steatosis in Wistar rats, which may compromise its use as a standard diet for experimental studies with rodents. The hepatic fatty acid profile was associated with steatosis, with possible implications for disease prognosis. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  14. Statistical-techniques-based computer-aided diagnosis (CAD) using texture feature analysis: application in computed tomography (CT) imaging to fatty liver disease

    NASA Astrophysics Data System (ADS)

    Chung, Woon-Kwan; Park, Hyong-Hu; Im, In-Chul; Lee, Jae-Seung; Goo, Eun-Hoe; Dong, Kyung-Rae

    2012-09-01

    This paper proposes a computer-aided diagnosis (CAD) system based on texture feature analysis and statistical wavelet transformation technology to diagnose fatty liver disease with computed tomography (CT) imaging. In the target image, a wavelet transformation was performed for each lesion area to set the region of analysis (ROA, window size: 50 × 50 pixels) and define the texture feature of a pixel. Based on the extracted texture feature values, six parameters (average gray level, average contrast, relative smoothness, skewness, uniformity, and entropy) were determined to calculate the recognition rate for a fatty liver. In addition, a multivariate analysis of the variance (MANOVA) method was used to perform a discriminant analysis to verify the significance of the extracted texture feature values and the recognition rate for a fatty liver. According to the results, each texture feature value was significant for a comparison of the recognition rate for a fatty liver ( p < 0.05). Furthermore, the F-value, which was used as a scale for the difference in recognition rates, was highest in the average gray level, relatively high in the skewness and the entropy, and relatively low in the uniformity, the relative smoothness and the average contrast. The recognition rate for a fatty liver had the same scale as that for the F-value, showing 100% (average gray level) at the maximum and 80% (average contrast) at the minimum. Therefore, the recognition rate is believed to be a useful clinical value for the automatic detection and computer-aided diagnosis (CAD) using the texture feature value. Nevertheless, further study on various diseases and singular diseases will be needed in the future.

  15. Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease.

    PubMed

    Gariani, Karim; Ryu, Dongryeol; Menzies, Keir J; Yi, Hyon-Seung; Stein, Sokrates; Zhang, Hongbo; Perino, Alessia; Lemos, Vera; Katsyuba, Elena; Jha, Pooja; Vijgen, Sandrine; Rubbia-Brandt, Laura; Kim, Yong Kyung; Kim, Jung Tae; Kim, Koon Soon; Shong, Minho; Schoonjans, Kristina; Auwerx, Johan

    2017-01-01

    To date, no pharmacological therapy has been approved for non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the therapeutic potential of poly ADP-ribose polymerase (PARP) inhibitors in mouse models of NAFLD. As poly ADP-ribosylation (PARylation) of proteins by PARPs consumes nicotinamide adenine dinucleotide (NAD + ), we hypothesized that overactivation of PARPs drives NAD + depletion in NAFLD. Therefore, we assessed the effectiveness of PARP inhibition to replenish NAD + and activate NAD + -dependent sirtuins, hence improving hepatic fatty acid oxidation. To do this, we examined the preventive and therapeutic benefits of the PARP inhibitor (PARPi), olaparib, in different models of NAFLD. The induction of NAFLD in C57BL/6J mice using a high-fat high-sucrose (HFHS)-diet increased PARylation of proteins by PARPs. As such, increased PARylation was associated with reduced NAD + levels and mitochondrial function and content, which was concurrent with elevated hepatic lipid content. HFHS diet supplemented with PARPi reversed NAFLD through repletion of NAD + , increasing mitochondrial biogenesis and β-oxidation in liver. Furthermore, PARPi reduced reactive oxygen species, endoplasmic reticulum stress and fibrosis. The benefits of PARPi treatment were confirmed in mice fed with a methionine- and choline-deficient diet and in mice with lipopolysaccharide-induced hepatitis; PARP activation was attenuated and the development of hepatic injury was delayed in both models. Using Sirt1 hep-/- mice, the beneficial effects of a PARPi-supplemented HFHS diet were found to be Sirt1-dependent. Our study provides a novel and practical pharmacological approach for treating NAFLD, fueling optimism for potential clinical studies. Non-alcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the Western world and has no approved pharmacological therapy. PARP inhibitors given as a treatment in two different mouse

  16. The impact of weight changes on nonalcoholic Fatty liver disease in adult men with normal weight.

    PubMed

    Cho, Ji-Young; Chung, Tae-Heum; Lim, Kyoung-Mo; Park, Hee-Jin; Jang, Jung-Mi

    2014-09-01

    Although it is known that losing weight has an effect on the treatment of non-alcoholic fatty liver disease, the studies that show how losing weight affects the non-alcoholic fatty liver disease for the normal weight male adults are limited so far. In this study, we set body mass index as criteria and investigated how the weight changes for 4 years makes an impact on the risk of non-alcoholic fatty liver disease for the male adults who have the normal body mass index. From January to December of 2004, among the normal weight male adults who had general check-up at the Health Promotion Center of Ulsan University Hospital, 180 people (average age, 47.4 ± 4.61 years) who were diagnosed with fatty liver through abdominal ultrasonography were included in this study and were observed according to the variety of data and ultrasonography after 4 years (2008). People who had a history of drinking more than 140 g of alcohol per week or who had a past medical history were excluded from the analysis. The weight change of subjects was calculated using the formula 'weight change = weight of 2008 (kg) - weight of 2004 (kg)' and classified into three groups, loss group (≤-3.0 kg), stable group (-2.9 to 2.9 kg), and gain group (≥3.0 kg). The odds for disappearance of non-alcoholic fatty liver disease in those three different groups were compared. Among 180 subjects, compared with stable group (67.2%, 121 subjects), loss group (11.7%, 21 subjects) showed 18.37-fold increase in the odds of disappearance of non-alcoholic fatty liver disease (95% confidence interval [CI], 4.34 to 77.80) and gain group (21.1%, 38 subjects) showed 0.28-fold decrease in the odds of disappearance of non-alcoholic fatty liver disease (95% CI, 0.10 to 0.83). Even for the normal weight people, losing weight has an effect on the improvement of non-alcoholic fatty liver disease.

  17. Resolution of donor non-alcoholic fatty liver disease following liver transplantation.

    PubMed

    Posner, Andrew D; Sultan, Samuel T; Zaghloul, Norann A; Twaddell, William S; Bruno, David A; Hanish, Steven I; Hutson, William R; Hebert, Laci; Barth, Rolf N; LaMattina, John C

    2017-09-01

    Transplant surgeons conventionally select against livers displaying high degrees (>30%) of macrosteatosis (MaS), out of concern for primary non-function or severe graft dysfunction. As such, there is relatively limited experience with such livers, and the natural history remains incompletely characterized. We present our experience of transplanted livers with high degrees of MaS and microsteatosis (MiS), with a focus on the histopathologic and clinical outcomes. Twenty-nine cases were identified with liver biopsies available from both the donor and the corresponding liver transplant recipient. Donor liver biopsies displayed either MaS or MiS ≥15%, while all recipients received postoperative liver biopsies for cause. The mean donor MaS and MiS were 15.6% (range 0%-60%) and 41.3% (7.5%-97.5%), respectively. MaS decreased significantly from donor (M=15.6%) to recipient postoperative biopsies (M=0.86%), P<.001. Similarly, MiS decreased significantly from donor biopsies (M=41.3%) to recipient postoperative biopsies (M=1.8%), P<.001. At a median of 68 days postoperatively (range 4-384), full resolution of MaS and MiS was observed in 27 of 29 recipients. High degrees of MaS and MiS in donor livers resolve in recipients following liver transplantation. Further insight into the mechanisms responsible for treating fatty liver diseases could translate into therapeutic targets. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Liver X receptor alpha regulates fatty acid synthase expression in chicken.

    PubMed

    Demeure, O; Duby, C; Desert, C; Assaf, S; Hazard, D; Guillou, H; Lagarrigue, S

    2009-12-01

    Liver X receptor alpha (LXRalpha), also referred to as nuclear receptor subfamily 1, group H, member 3 is a member of the nuclear hormone receptor superfamily, and has recently been shown to act as a master transcription factor governing hepatic lipogenesis in mammals. Liver X receptor alpha directly regulates both the expression of other lipogenic transcription factors and the expression of lipogenic enzymes, thereby enhancing hepatic fatty acid synthesis (FASN). In birds, like in humans, fatty acid synthesis primarily occurs in the liver. Whether LXRalpha is involved in hepatic regulation of lipogenic genes remained to be investigated in this species. Here we show that fatty acid synthase and the expression of other lipogenic genes (sterol regulatory element binding protein 1 and steroyl coenzyme A desaturase 1) are induced in chicken hepatoma cells in response to a pharmacological liver X receptor agonist, T0901317. A detailed analysis of the chicken FASN promoter revealed a functional liver X response element. These data define the chicken FASN gene as a direct target of LXRalpha and further expand the role of LXRalpha as a regulator of lipid metabolism in this species.

  19. [Dietetary recommendation for non-alcoholic fatty liver disease].

    PubMed

    Jeznach-Steinhagen, Anna; Ostrowska, Joanna; Czerwonogrodzka-Senczyna, Aneta; Boniecka, Iwona; Gronostajska, Wioletta

    2017-12-22

    Non-alcoholic Fatty Liver Disease (NAFLD) is currently the most common chronic liver disease in the developed world. Nowadays, in the adult population of Europe it is estimated at 14% to 21%. Its most important risk factors are obesity and metabolic syndrome. Introducing lifestyle changes such as: dietary intervention and increased physical activity are the first-line treatment and are intended to support not only NAFLD but also associated diseases such as obesity, insulin resistance, diabetes and dyslipidemia. Dietary management focuses on weight reduction of overweight or obese people by decreasing energy in diet. It is recommended to limit the intake of saturated fats and trans fatty acids as well as cholesterol. Instead, it is important to increase the proportion of polyunsaturated fatty acid diets, mainly from the n-3 family, which exhibit anti-inflammatory activity. It is also beneficial to eat nuts, despite their high energy value, as a source of alpha linolenic acid, which lowers LDL cholesterol. It is important to increase the share of vegetable protein (eg. soya) and limit the intake of fat meat, milk and the dairy products. A key role in the treatment and prevention of NAFLD is also a reduction of simple sugars and total exclusion of added sugar in the diet. The rise of NAFLD in developed countries is analogous to the increase of fructose consumption, which high intake is directly indicated as the main cause of the disease. Choosing foods with high fiber content, low glycemic index and meals composed with low glycemic load, is conducive to weight reduction. An important role in supporting NAFLD treatment is also attributed to vitamin D, C and E supplementation and some probiotic bacteria, as well as cinnamon and turmeric, which improve insulin sensitivity. Daily physical activity is strongly recommended as the supplement of healthy lifestyle.

  20. Nonalcoholic fatty liver disease and liver transplantation - Where do we stand?

    PubMed Central

    Mikolasevic, Ivana; Filipec-Kanizaj, Tajana; Mijic, Maja; Jakopcic, Ivan; Milic, Sandra; Hrstic, Irena; Sobocan, Nikola; Stimac, Davor; Burra, Patrizia

    2018-01-01

    Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) is a challenging and multisystem disease that has a high socioeconomic impact. NAFLD/NASH is a main cause of macrovesicular steatosis and has multiple impacts on liver transplantation (LT), on patients on the waiting list for transplant, on post-transplant setting as well as on organ donors. Current data indicate new trends in the area of chronic liver disease. Due to the increased incidence of metabolic syndrome (MetS) and its components, NASH cirrhosis and hepatocellular carcinoma caused by NASH will soon become a major indication for LT. Furthermore, due to an increasing incidence of MetS and, consequently, NAFLD, there will be more steatotic donor livers and less high quality organs available for LT, in addition to a lack of available liver allografts. Patients who have NASH and are candidates for LT have multiple comorbidities and are unique LT candidates. Finally, we discuss long-term grafts and patient survival after LT, the recurrence of NASH and NASH appearing de novo after transplantation. In addition, we suggest topics and areas that require more research for improving the health care of this increasing patient population. PMID:29662288

  1. Audio-Visual Aid in Teaching "Fatty Liver"

    ERIC Educational Resources Information Center

    Dash, Sambit; Kamath, Ullas; Rao, Guruprasad; Prakash, Jay; Mishra, Snigdha

    2016-01-01

    Use of audio visual tools to aid in medical education is ever on a rise. Our study intends to find the efficacy of a video prepared on "fatty liver," a topic that is often a challenge for pre-clinical teachers, in enhancing cognitive processing and ultimately learning. We prepared a video presentation of 11:36 min, incorporating various…

  2. Performance of non-invasive models of fibrosis in predicting mild to moderate fibrosis in patients with non-alcoholic fatty liver disease.

    PubMed

    Siddiqui, Mohammad S; Patidar, Kavish R; Boyett, Sherry; Luketic, Velimir A; Puri, Puneet; Sanyal, Arun J

    2016-04-01

    In non-alcoholic fatty liver disease, presence of fibrosis is predictive of long-term liver-related complications. Currently, there are no reliable and non-invasive means of quantifying fibrosis in those with non-alcoholic fatty liver disease. Therefore, we aimed to evaluate the performance of a panel of non-invasive models in predicting fibrosis in non-alcoholic fatty liver disease. The accuracy of FibroMeter non-alcoholic fatty liver disease, fibrosis 4 and four other non-invasive models in predicting fibrosis in those with biopsy proven non-alcoholic fatty liver disease was compared. These models were constructed post hoc in patients who had necessary clinical information collected within 2 months of a liver biopsy. The areas under receiver operating characteristics curves were compared for each model using Delong analysis. Optimum cut-off for each model and fibrosis stage were calculated using the Youden index. The area under receiver operating characteristics curves for F ≥ 1 fibrosis for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease was 0.821 and 0.801 respectively. For F ≥ 3, the area under receiver operating characteristics curves was 0.866 for fibrosis 4 and 0.862 for FibroMeter non-alcoholic fatty liver disease. Delong analysis showed the area under receiver operating characteristics curves was statistically different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease compared with BARD, BAAT and aspartate aminotransferase:alanine aminotransferase ratio for F ≥ 1 and F ≥ 3. Area under receiver operating characteristics curves were significantly different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease for F ≥ 3 compared with non-alcoholic fatty liver disease fibrosis score. At a fixed sensitivity of 90%, FibroMeter non-alcoholic fatty liver disease had the highest specificity for F ≥ 1 (52.4%) and F ≥ 3 (63.8%). In contrast, at a fixed specificity of 90%, fibrosis 4 outperformed other models with a

  3. Original Research: Effect of various dietary fats on fatty acid profile in duck liver: Efficient conversion of short-chain to long-chain omega-3 fatty acids.

    PubMed

    Chen, Xi; Du, Xue; Shen, Jianliang; Lu, Lizhi; Wang, Weiqun

    2017-01-01

    Omega-3 fatty acids, especially long-chain omega-3 fatty acids, have been associated with potential health benefits for chronic disease prevention. Our previous studies found that dietary omega-3 fatty acids could accumulate in the meat and eggs in a duck model. This study was to reveal the effects of various dietary fats on fatty acid profile and conversion of omega-3 fatty acids in duck liver. Female Shan Partridge Ducks were randomly assigned to five dietary treatments, each consisting of 6 replicates of 30 birds. The experimental diets substituted the basal diet by 2% of flaxseed oil, rapeseed oil, beef tallow, or fish oil, respectively. In addition, a dose response study was further conducted for flaxseed and fish oil diets at 0.5%, 1%, and 2%, respectively. At the end of the five-week treatment, fatty acids were extracted from the liver samples and analyzed by GC-FID. As expected, the total omega-3 fatty acids and the ratio of total omega-3/omega-6 significantly increased in both flaxseed and fish oil groups when compared with the control diet. No significant change of total saturated fatty acids or omega-3 fatty acids was found in both rapeseed and beef tallow groups. The dose response study further indicated that 59-81% of the short-chain omega-3 ALA in flaxseed oil-fed group was efficiently converted to long-chain DHA in the duck liver, whereas 1% of dietary flaxseed oil could produce an equivalent level of DHA as 0.5% of dietary fish oil. The more omega-3 fatty acids, the less omega-6 fatty acids in the duck liver. Taken together, this study showed the fatty acid profiling in the duck liver after various dietary fat consumption, provided insight into a dose response change of omega-3 fatty acids, indicated an efficient conversion of short- to long-chain omega-3 fatty acid, and suggested alternative long-chain omega-3 fatty acid-enriched duck products for human health benefits. © 2016 by the Society for Experimental Biology and Medicine.

  4. Nonalcoholic fatty liver disease in spinal and bulbar muscular atrophy

    PubMed Central

    Guber, Robert D.; Takyar, Varun; Kokkinis, Angela; Fox, Derrick A.; Alao, Hawwa; Kats, Ilona; Bakar, Dara; Remaley, Alan T.; Hewitt, Stephen M.; Kleiner, David E.; Liu, Chia-Ying; Hadigan, Colleen; Fischbeck, Kenneth H.; Rotman, Yaron

    2017-01-01

    Objective: To determine the prevalence and features of fatty liver disease in spinal and bulbar muscular atrophy (SBMA). Methods: Two groups of participants with SBMA were evaluated. In the first group, 22 participants with SBMA underwent laboratory analysis and liver imaging. In the second group, 14 participants with SBMA were compared to 13 female carriers and 23 controls. Liver biopsies were done in 4 participants with SBMA. Results: Evidence of fatty liver disease was detected by magnetic resonance spectroscopy in all participants with SBMA in the first group, with an average dome intrahepatic triacylglycerol of 27% (range 6%–66%, ref ≤5.5%). Liver dome magnetic resonance spectroscopy measurements were significantly increased in participants with SBMA in the second group relative to age- and sex-matched controls, with average disease and male control measurements of 17% and 3%, respectively. Liver biopsies were consistent with simple steatosis in 2 participants and nonalcoholic steatohepatitis in 2 others. Conclusions: We observed evidence of nonalcoholic liver disease in nearly all of the participants with SBMA evaluated. These observations expand the phenotypic spectrum of the disease and provide a potential biomarker that can be monitored in future studies. PMID:29142082

  5. Effects of dietary fatty acids and cholesterol excess on liver injury: A lipidomic approach.

    PubMed

    Serviddio, Gaetano; Bellanti, Francesco; Villani, Rosanna; Tamborra, Rosanna; Zerbinati, Chiara; Blonda, Maria; Ciacciarelli, Marco; Poli, Giuseppe; Vendemiale, Gianluigi; Iuliano, Luigi

    2016-10-01

    Lipid accumulation is the hallmark of Non-alcoholic Fatty Liver Disease (NAFLD) and has been suggested to play a role in promoting fatty liver inflammation. Previous findings indicate that during oxidative stress conditions excess cholesterol autoxidizes to oxysterols. To date, the role of oxysterols and their potential interaction with fatty acids accumulation in NASH pathogenesis remains little investigated. We used the nutritional model of high fatty acids (HFA), high cholesterol (HCh) or high fat and high cholesterol (HFA+FCh) diets and explored by a lipidomic approach, the blood and liver distribution of fatty acids and oxysterols in response to dietary manipulation. We observed that HFA or HCh diets induced fatty liver without inflammation, which was otherwise observed only after supplementation of HFA+HCh. Very interestingly, the combination model was associated with a specific oxysterol fingerprint. The present work provides a complete analysis of the change in lipids and oxysterols profile induced by different lipid dietary model and their association with histological alteration of the liver. This study allows the generation of interesting hypotheses on the role of interaction of lipid and cholesterol metabolites in the liver injury during NAFLD development and progression. Moreover, the changes in the concentration and quality of oxysterols induced by a combination diet suggest a novel potential pathogenic mechanism in the progression from simple steatosis to steatohepatitis. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  6. The Relevance of the UPS in Fatty Liver Graft Preservation: A New Approach for IGL-1 and HTK Solutions

    PubMed Central

    Panisello-Roselló, Arnau; Verde, Eva; Amine Zaouali, Mohamed; Flores, Marta; Alva, Norma; Lopez, Alexandre; Folch-Puy, Emma; Hotter, Georgina; Adam, René; Roselló-Catafau, Joan

    2017-01-01

    The 26S proteasome is the central proteolytic machinery of the ubiquitin proteasome system (UPS), which is involved in the degradation of ubiquitinated protein substrates. Recently, UPS inhibition has been shown to be a key factor in fatty liver graft preservation during organ cold storage using University of Wisconsin solution (UW) and Institute Georges Lopez (IGL-1) solutions. However, the merits of IGL-1 and histidine-tryptophan-ketoglutarate (HTK) solutions for fatty liver preservation have not been compared. Fatty liver grafts from obese Zücker rats were preserved for 24 h at 4 °C. Aspartate aminotransferase and alanine aminotransferase (AST/ALT), glutamate dehydrogenase (GLDH), ATP, adenosine monophosphate protein kinase (AMPK), e-NOS, proteasome activity and liver polyubiquitinated proteins were determined. IGL-1 solution prevented ATP breakdown during cold-storage preservation of steatotic livers to a greater extent than HTK solution. There were concomitant increases in AMPK activation, e-NOS (endothelial NOS (NO synthase)) expression and UPS inhibition. UPS activity is closely related to the composition of the solution used to preserve the organ. IGL-1 solution provided significantly better protection against ischemia-reperfusion for cold-stored fatty liver grafts than HTK solution. The effect is exerted through the activation of the protective AMPK signaling pathway, an increase in e-NOS expression and a dysregulation of the UPS. PMID:29088097

  7. Nonalcoholic Fatty Liver Disease: Study of Demographic and Predictive Factors.

    PubMed

    Shil, Bimal Chandra; Saha, Madhusudan; Ahmed, Faruque; Dhar, Swapan Chandra

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver disease characterized by excess of fat in liver which ranges from simple steatosis to nonalcoholic steato-hepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC) in the absence of excessive alcohol consumption. The study was carried out in 216 with serologically defined fatty liver. They underwent detailed history evaluation, clinical examination and anthropometric measurements, biochemical and serological tests. The cut-off values for central obesity were waist hip ratio (WHR) > 0.85 in women and > 0.9 in men. The prevalence of NAFLD was highest in the age group of 31 to 60 years. It was more common in males than females. Twenty cases (11.7%) had discomfort at right upper abdomen. Hepatomegaly was found in 27 patients (13.2%), impaired glucose tolerance (IGT) in 29 (14.21%) and diabetes mellitus in 38 (18.63%) patients. Overweight or obesity was found in 110 (53.92%) cases and central obesity was seen in 129 (63.23%) patients. Hence, metabolic syndrome (according to International Diabetes Federation Criteria) was present in 62.25% cases of NAFLD. Alanine aminotransferase (ALT) more than upper limit of normal was found in 36.76% cases. Risk factors for NAFLD in Bangladesh are similar to reported from the rest of the world. Age more than 30 years, male sex, WHR > 0.9 in men and more than 0.85 in female, BMI more than 25, glucose intolerance are predictive factors for NAFLD. Shil BC, Saha M, Ahmed F, Dhar SC. Nonalcoholic Fatty Liver Disease: Study of Demographic and Predictive Factors. Euroasian J Hepato-Gastroenterol 2015;5(1):4-6.

  8. Original Research: Effect of various dietary fats on fatty acid profile in duck liver: Efficient conversion of short-chain to long-chain omega-3 fatty acids

    PubMed Central

    Chen, Xi; Du, Xue; Shen, Jianliang; Wang, Weiqun

    2016-01-01

    Omega-3 fatty acids, especially long-chain omega-3 fatty acids, have been associated with potential health benefits for chronic disease prevention. Our previous studies found that dietary omega-3 fatty acids could accumulate in the meat and eggs in a duck model. This study was to reveal the effects of various dietary fats on fatty acid profile and conversion of omega-3 fatty acids in duck liver. Female Shan Partridge Ducks were randomly assigned to five dietary treatments, each consisting of 6 replicates of 30 birds. The experimental diets substituted the basal diet by 2% of flaxseed oil, rapeseed oil, beef tallow, or fish oil, respectively. In addition, a dose response study was further conducted for flaxseed and fish oil diets at 0.5%, 1%, and 2%, respectively. At the end of the five-week treatment, fatty acids were extracted from the liver samples and analyzed by GC-FID. As expected, the total omega-3 fatty acids and the ratio of total omega-3/omega-6 significantly increased in both flaxseed and fish oil groups when compared with the control diet. No significant change of total saturated fatty acids or omega-3 fatty acids was found in both rapeseed and beef tallow groups. The dose response study further indicated that 59–81% of the short-chain omega-3 ALA in flaxseed oil-fed group was efficiently converted to long-chain DHA in the duck liver, whereas 1% of dietary flaxseed oil could produce an equivalent level of DHA as 0.5% of dietary fish oil. The more omega-3 fatty acids, the less omega-6 fatty acids in the duck liver. Taken together, this study showed the fatty acid profiling in the duck liver after various dietary fat consumption, provided insight into a dose response change of omega-3 fatty acids, indicated an efficient conversion of short- to long-chain omega-3 fatty acid, and suggested alternative long-chain omega-3 fatty acid-enriched duck products for human health benefits. PMID:27510581

  9. Genetics Home Reference: non-alcoholic fatty liver disease

    MedlinePlus

    ... different populations of microorganisms in the intestines (gut microbiota) on the breakdown and absorption of nutrients are ... Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background. Gastroenterol Res Pract. 2016;2016: ...

  10. Nonalcoholic fatty liver disease, association with cardiovascular disease and treatment (II). The treatment of nonalcoholic fatty liver disease.

    PubMed

    Brea, Ángel; Pintó, Xavier; Ascaso, Juan F; Blasco, Mariano; Díaz, Ángel; González-Santos, Pedro; Hernández-Mijares, Antonio; Mantilla, Teresa; Millán, Jesús; Pedro-Botet, Juan

    Disease nonalcoholic fatty liver disease (NAFLD) comprises a series of histologically similar to those induced by alcohol consumption in people with very little or no liver damage same. The importance of NAFLD is its high prevalence in our Western societies, from the point of view liver in its progressive evolution from steatosis to steatohepatitis, cirrhosis and liver cancer. During the last decade it has been observed that NAFLD leads to an increased cardiovascular risk with accelerated atherosclerosis and cardiovascular events, the leading cause of morbidity and mortality. This updated January 2016 revision consists of two parts. In this second part, the treatment of NAFLD and its influence on cardiovascular disease and drugs used in the control of cardiovascular risk factors showing a beneficial effect on the liver disease will be reviewed. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. Review article: Non-alcoholic fatty liver disease in morbidly obese patients and the effect of bariatric surgery.

    PubMed

    De Ridder, R J J; Schoon, E J; Smulders, J F; van Hout, G C M; Stockbrügger, R W; Koek, G H

    2007-12-01

    Morbid obesity is strongly associated with non-alcoholic fatty liver disease. The effects of bariatric surgery on liver tests an histological abnormalities after weight loss are controversial. To review the literature on the prevalence of non-alcoholic fatty liver disease in patients with morbid obesity with respect to laboratory and histopathological parameters and the effect of weight loss on these parameters after bariatric surgery. Standard liver tests do not seem to be a sensitive tool for the assessment and follow-up of non-alcoholic fatty liver disease in obesity. In nearly all patients with morbid obesity, histological abnormalities reflecting non-alcoholic fatty liver disease are present. Bariatric surgery in these patients will decrease the grade of steatosis. However, there are some concerns about the effect of bariatric surgery on hepatic inflammation and fibrosis. In particular, older follow-up studies reported negative results as opposed to more recent studies, which also showed improvement in hepatic inflammation and fibrosis. Unfortunately, most studies had limitations because of the selection of patients. Despite limitations in many studies, bariatric surgery seems to be a promising treatment in patients with obesity presenting with non-alcoholic fatty liver disease.

  12. Ethanol and liver: Recent insights into the mechanisms of ethanol-induced fatty liver

    PubMed Central

    Liu, Jinyao

    2014-01-01

    Alcoholic fatty liver disease (AFLD), a potentially pathologic condition, can progress to steatohepatitis, fibrosis, and cirrhosis, leading to an increased probability of hepatic failure and death. Alcohol induces fatty liver by increasing the ratio of reduced form of nicotinamide adenine dinucleotide to oxidized form of nicotinamide adenine dinucleotide in hepatocytes; increasing hepatic sterol regulatory element-binding protein (SREBP)-1, plasminogen activator inhibitor (PAI)-1, and early growth response-1 activity; and decreasing hepatic peroxisome proliferator-activated receptor-α activity. Alcohol activates the innate immune system and induces an imbalance of the immune response, which is followed by activated Kupffer cell-derived tumor necrosis factor (TNF)-α overproduction, which is in turn responsible for the changes in the hepatic SREBP-1 and PAI-1 activity. Alcohol abuse promotes the migration of bone marrow-derived cells (BMDCs) to the liver and then reprograms TNF-α expression from BMDCs. Chronic alcohol intake triggers the sympathetic hyperactivity-activated hepatic stellate cell (HSC) feedback loop that in turn activates the HSCs, resulting in HSC-derived TNF-α overproduction. Carvedilol may block this feedback loop by suppressing sympathetic activity, which attenuates the progression of AFLD. Clinical studies evaluating combination therapy of carvedilol with a TNF-α inhibitor to treat patients with AFLD are warranted to prevent the development of alcoholic liver disease. PMID:25356030

  13. Focus on emerging drugs for the treatment of patients with non-alcoholic fatty liver disease

    PubMed Central

    Federico, Alessandro; Zulli, Claudio; de Sio, Ilario; Del Prete, Anna; Dallio, Marcello; Masarone, Mario; Loguercio, Carmela

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder in Western countries and is increasingly being recognized in developing nations. Fatty liver disease encompasses a spectrum of hepatic pathology, ranging from simple steatosis to non-alcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma and end-stage liver disease. Moreover, NAFLD is often associated with other metabolic conditions, such as diabetes mellitus type 2, dyslipidemia and visceral obesity. The most recent guidelines suggest the management and treatment of patients with NAFLD considering both the liver disease and the associated metabolic co-morbidities. Diet and physical exercise are considered the first line of treatment for patients with NAFLD, but their results on therapeutic efficacy are often contrasting. Behavior therapy is necessary most of the time to achieve a sufficient result. Pharmacological therapy includes a wide variety of classes of molecules with different therapeutic targets and, often, little evidence supporting the real efficacy. Despite the abundance of clinical trials, NAFLD therapy remains a challenge for the scientific community, and there are no licensed therapies for NAFLD. Urgently, new pharmacological approaches are needed. Here, we will focus on the challenges facing actual therapeutic strategies and the most recent investigated molecules. PMID:25492998

  14. Alternation of plasma fatty acids composition and desaturase activities in children with liver steatosis

    PubMed Central

    Su, Hui-Min; Yao, Tsung-Chieh; Kuo, Ming-Ling; Lai, Ming-Wei; Tsai, Ming-Han; Huang, Jing-Long

    2017-01-01

    Objective The aim of this study was to investigate changes in plasma fatty acids proportions and estimated desaturase activities for variable grading of liver steatosis in children. Methods In total, 111 schoolchildren (aged 8–18 years) were included in the analysis from March 2015 to August 2016. Anthropometric evaluation, liver ultrasound examination and scoring for nonalcoholic fatty liver disease (NAFLD score = 0–6), and biochemical and plasma fatty acids analysis were performed. We compared the composition ratio of fatty acids between children with high-grade liver steatosis (NAFLD score = 4–6), low-grade liver steatosis (NAFLD score = 1–3), and healthy controls (NAFLD score = 0). In addition, correlation coefficients (r) between NAFLD score, metabolic variables, and estimated activity of desaturase indices (stearoyl-coenzyme A desaturase-1 (SCD1), delta-5 and delta-6 desaturase) were calculated. Results Compared with healthy controls, children with liver steatosis showed a higher proportion of monounsaturated fatty acids (21.16 ± 2.81% vs. 19.68 ± 2.71%, p = 0.024). In addition, children with high- grade liver steatosis exhibited higher proportions of palmitic acid (C16:0), palmitoleic acid (C16:1n-7), dihomo-γ-linolenic acid (C20:3n-6), adrenic acid (C22:4n-6), and docosapentaenoic acid (C22:5n-6); and lower proportions of eicosapentaenoic acid (C20:5n-3) (P< 0.05). In all subjects, the NAFLD score was positively correlated with body mass index (BMI) (kg/m2) (r = 0.696), homeostasis model of assessment ratio–index (HOMA-IR) (r = 0.510), SCD1(16) (r = 0.273), and the delta-6 index (r = 0.494); and inversely associated with the delta-5 index (r = -0.443). Conclusion Our current data suggested that children with liver steatosis was highly associated with obesity, and insulin resistance. In addition, increased endogenous lipogenesis through altered desaturase activity may contribute to the progression of liver steatosis in children. PMID:28759573

  15. [The Development of Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease].

    PubMed

    Kwon, Oh Sang; Kim, Joon Hwan; Kim, Ju Hyun

    2017-06-25

    Non-alcoholic fatty liver disease (NAFLD) may be one of the important causes of cryptogenic hepatocellular carcinoma (HCC). NAFLD-related HCCs (NAFLD-HCCs) have the following clinical features: high body mass index, deranged lipid profiles, diabetes mellitus, hypertension, and metabolic syndrome. Among them, obesity, diabetes mellitus, and high Fe contents in the liver are risk factors of developing HCC in patients with NAFLD. Inflammatory cytokines, adipokines, insulin like growth factor-I, and lipotoxicity are intermingled and may cross react with each other to develop HCC. Because there is no guideline for early detection of HCC in patients with NAFLD, NAFLD-HCCs tend to be greater in size and in advanced stages when detected compared with hepatitis virus-related HCCs. Therefore, there is an urgent need of a surveillance program for the early detection of HCC. Treatment of NAFLD-HCCs is not different from other causes-related HCCs. However, patients with NAFLD-HCCs have cardiovascular disease and other metabolic problems, which may complicate treatment.

  16. Nonalcoholic fatty liver disease in hispanic youth with dysglycemia: Risk for subclinical atherosclerosis?

    USDA-ARS?s Scientific Manuscript database

    Obese Hispanic adolescents (OHAs) with dysglycemia have increased cardiovascular disease risk burden. To investigate if nonalcoholic fatty liver disease (NAFLD) confers added risk for endothelial dysfunction in these youth. Cross-sectional study. Academic institution. Thirty-six OHAs (15.360.4 years...

  17. [Balneotherapeutics of non-alcoholic fatty liver disease with the use of the Essentuki-type drinking mineral waters].

    PubMed

    Fedorova, T E; Efimenko, N V; Kaĭsinova, A S

    2012-01-01

    The objective of the present work was to estimate the effectiveness of combined spa-and-resort treatment with the use of the Essentuki-type drinking mineral waters for the patients presenting with non-alcoholic fatty liver disease. A total of 40 patients presening with non-alcoholic fatty liver disease (NOFLD) were available for the examination. The study has demonstrated positive dynamics of clinical symptoms and results of liver functional tests, characteristics of intrahepatic dynamics, lipid metabolism, antioxidant hemostais, and the hormonal status of the patients with non-alcoholic fatty liver disease. The intake of the Essentuki-type drinking mineral waters promoted normalization of adiponectin and leptin levels in conjunction with the reduction in the degree of insulin resistance, i.e., the key pathogenetic factors responsible for hepatic steatosis and non-alcoholic steatohepatitis. It is concluded that the Essentuki-type drinking mineral waters may be recommended for the inclusion in the combined treatment and prevention of the progression of non-alcoholic fatty liver disease.

  18. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease

    PubMed Central

    Perumpail, Brandon J; Khan, Muhammad Ali; Yoo, Eric R; Cholankeril, George; Kim, Donghee; Ahmed, Aijaz

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic fat accumulation after the exclusion of other causes of hepatic steatosis, including other causes of liver disease, excessive alcohol consumption, and other conditions that may lead to hepatic steatosis. NAFLD encompasses a broad clinical spectrum ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC). NAFLD is the most common liver disease in the world and NASH may soon become the most common indication for liver transplantation. Ongoing persistence of obesity with increasing rate of diabetes will increase the prevalence of NAFLD, and as this population ages, many will develop cirrhosis and end-stage liver disease. There has been a general increase in the prevalence of NAFLD, with Asia leading the rise, yet the United States is following closely behind with a rising prevalence from 15% in 2005 to 25% within 5 years. NAFLD is commonly associated with metabolic comorbidities, including obesity, type II diabetes, dyslipidemia, and metabolic syndrome. Our understanding of the pathophysiology of NAFLD is constantly evolving. Based on NAFLD subtypes, it has the potential to progress into advanced fibrosis, end-stage liver disease and HCC. The increasing prevalence of NAFLD with advanced fibrosis, is concerning because patients appear to experience higher liver-related and non-liver-related mortality than the general population. The increased morbidity and mortality, healthcare costs and declining health related quality of life associated with NAFLD makes it a formidable disease, and one that requires more in-depth analysis. PMID:29307986

  19. NNMT activation can contribute to the development of fatty liver disease by modulating the NAD + metabolism.

    PubMed

    Komatsu, Motoaki; Kanda, Takeshi; Urai, Hidenori; Kurokochi, Arata; Kitahama, Rina; Shigaki, Shuhei; Ono, Takashi; Yukioka, Hideo; Hasegawa, Kazuhiro; Tokuyama, Hirobumi; Kawabe, Hiroshi; Wakino, Shu; Itoh, Hiroshi

    2018-06-05

    Nicotinamide N-methyltransferase (NNMT) catalyses the reaction between nicotinamide (NAM) and S-adenosylmethionine to produce 1-methylnicotinamide and S-adenosylhomocysteine. Recently, this enzyme has also been reported to modulate hepatic nutrient metabolism, but its role in the liver has not been fully elucidated. We developed transgenic mice overexpressing NNMT to elucidate its role in hepatic nutrient metabolism. When fed a high fat diet containing NAM, a precursor for nicotinamide adenine dinucleotide (NAD) + , these NNMT-overexpressing mice exhibit fatty liver deterioration following increased expression of the genes mediating fatty acid uptake and decreased very low-density lipoprotein secretion. NNMT overactivation decreased the NAD + content in the liver and also decreased gene activity related to fatty acid oxidation by inhibiting NAD + -dependent deacetylase Sirt3 function. Moreover, the transgenic mice showed liver fibrosis, with the induction of inflammatory and fibrosis genes. Induced NNMT expression decreased the tissue methylation capacity, thereby reducing methylation of the connective tissue growth factor (CTGF) gene promoter, resulting in increased CTGF expression. These data indicate that NNMT links the NAD + and methionine metabolic pathways and promotes liver steatosis and fibrosis. Therefore, targeting NNMT may serve as a therapeutic strategy for treating fatty liver and fibrosis.

  20. Accurate Identification of Fatty Liver Disease in Data Warehouse Utilizing Natural Language Processing.

    PubMed

    Redman, Joseph S; Natarajan, Yamini; Hou, Jason K; Wang, Jingqi; Hanif, Muzammil; Feng, Hua; Kramer, Jennifer R; Desiderio, Roxanne; Xu, Hua; El-Serag, Hashem B; Kanwal, Fasiha

    2017-10-01

    Natural language processing is a powerful technique of machine learning capable of maximizing data extraction from complex electronic medical records. We utilized this technique to develop algorithms capable of "reading" full-text radiology reports to accurately identify the presence of fatty liver disease. Abdominal ultrasound, computerized tomography, and magnetic resonance imaging reports were retrieved from the Veterans Affairs Corporate Data Warehouse from a random national sample of 652 patients. Radiographic fatty liver disease was determined by manual review by two physicians and verified with an expert radiologist. A split validation method was utilized for algorithm development. For all three imaging modalities, the algorithms could identify fatty liver disease with >90% recall and precision, with F-measures >90%. These algorithms could be used to rapidly screen patient records to establish a large cohort to facilitate epidemiological and clinical studies and examine the clinic course and outcomes of patients with radiographic hepatic steatosis.

  1. IL-17A, MCP-1, CCR-2, and ABCA1 polymorphisms in children with non-alcoholic fatty liver disease.

    PubMed

    Akbulut, Ulas Emre; Emeksiz, Hamdi Cihan; Citli, Senol; Cebi, Alper Han; Korkmaz, Hatice Ayca Ata; Baki, Gaye

    2018-05-05

    The prevalence of non-alcoholic fatty liver disease in children has risen significantly, owing to the worldwide childhood obesity epidemic in the last two decades. Non-alcoholic fatty liver disease is closely linked to sedentary lifestyle, increased body mass index, and visceral adiposity. In addition, individual genetic variations also have a role in the development and progression of non-alcoholic fatty liver disease. The aim of this study was to investigate the gene polymorphisms of MCP-1 (-2518 A/G) (rs1024611), CCR-2 (190 G/A) (rs1799864), ABCA1 (883 G/A) (rs4149313), and IL-17A (-197 G/A) (rs2275913) in obese Turkish children with non-alcoholic fatty liver disease. The study recruited 186 obese children aged 10-17 years, including 101 children with non-alcoholic fatty liver disease and 85 children without non-alcoholic fatty liver disease. Anthropometric measurements, insulin resistance, a liver panel, a lipid profile, liver ultrasound examination, and genotyping of the four variants were performed. No difference was found between the groups in respect to age and gender, body mass index, waist/hip ratio, or body fat ratio. In addition to the elevated ALT levels, AST and GGT levels were found significantly higher in the non-alcoholic fatty liver disease group compared to the non non-alcoholic fatty liver disease group (p<0.05). The A-allele of IL-17A (-197 G/A) (rs2275913) was associated with non-alcoholic fatty liver disease (odds ratio 2.05, 95% confidence interval: 1.12-3.77, p=0.02). The findings of this study suggest that there may be an association between IL-17A (-197 G/A) (rs2275913) polymorphism and non-alcoholic fatty liver disease development in obese Turkish children. Copyright © 2018 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  2. Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Anders, Lisanne C

    Background: Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. Methods: Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10 weeksmore » after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). Results: In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. Conclusions: Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH. - Highlights: • CE promotes inflammatory liver injury caused by dietary fatty acids. • This effect is stronger with saturated than with unsaturated fatty acids. • Damage caused by saturated

  3. Valproic acid and nonalcoholic fatty liver disease: A possible association?

    PubMed Central

    Farinelli, Edoardo; Giampaoli, David; Cenciarini, Anja; Cercado, Ephraim; Verrotti, Alberto

    2015-01-01

    Valproic acid (VPA) is one of the most prescribed drugs in children with newly diagnosed epilepsy. Weight gain and obesity have been observed as side effects of VPA. These are often linked with other metabolic disturbances such as development of insulin resistance, dyslipidemia, metabolic syndrome (MetS) and non-alcoholic fatty liver disease or nonalcoholic fatty liver disease (NAFLD). NAFLD refers to a group of liver disorders with marked hepatic steatosis. It is associated with an increased incidence of cardiovascular diseases and overall reduced life expectancy. NAFLD occurs in 20%-25% of the general population and it is known to be the most common cause of chronic liver disease. NAFLD therefore represents a major public health issue worldwide. This study reviews and summarizes relevant literature that supports the existence of an association between VPA therapy and the development of NAFLD in children. Long-term VPA-therapy appears to be associated with an increased risk of developing NAFLD. Further studies are needed to clarify the pathogenic mechanisms that lie behind this association and to standardize the options for the use of this drug in overweight patients and in those with risks for developing MetS and NAFLD. PMID:26019740

  4. The Relationship Between Fatty Liver Disease and Periodontal Disease

    DTIC Science & Technology

    2017-03-22

    Periodontitis is a highly prevalent and destructive chronic disease. Numerous studies support an association between periodontal disease and other...systemic diseases (diabetes, cardiovascular disease, chronic kidney disease, adverse pregnancy outcome, etc.). Non-alcoholic fatty liver disease is a... chronic inflammatory disease that is characterized by accumulation of triglycerides and fat in the liver which may lead to fibrosis and even cirrhosis

  5. Soft drink consumption linked with fatty liver in the absence of traditional risk factors

    PubMed Central

    Assy, Nimer; Nasser, Gattas; Kamayse, Iad; Nseir, William; Beniashvili, Zaza; Djibre, Agness; Grosovski, Maria

    2008-01-01

    BACKGROUND: Little is known about dietary habits and their relationships with liver disease in nonalcoholic fatty liver disease (NAFLD) patients, particularly in the absence of obesity, diabetes or hyperlipidemia. OBJECTIVE: To assess the association between soft drink consumption and the presence of fatty liver in NAFLD patients who do not have classic risk factors. METHODS: Three hundred ten patients with NAFLD diagnosed by ultrasound were assessed for 36 months in a cross-sectional manner. Thirty-one patients (10%) who had NAFLD without classic risk factors were compared with 30 healthy controls. Physical activity was assessed during the preceding week and year, and every six months for 36 months. Data on daily dietary intake of food and soft drink, and the source of added sugar were collected during two seven-day periods, at the beginning of the study, and within two weeks after the metabolic tests by using a validated food questionnaire given by a trained dietician. Insulin resistance and lipid peroxidation were assessed by homeostasis model assessment-insulin resistance index (HOMA-IRI) and malondialdehyde (MDA) levels, respectively. RESULTS: Eighty per cent of patients (25 of 31) consumed an excessive amount of soft drink beverages (more than 50 g/day of added sugar) for 36 months, compared with 20% in healthy controls (P<0.001). Twenty per cent of patients consumed one drink per day, 40% consumed two to three drinks per day, and 40% consumed more than four drinks per day for most days during 36 months. The most common soft drinks consumed were regular Coca-Cola (40% of patients), Diet Coke (40%) and flavoured fruit juices (20%). Ultrasound findings revealed mild fatty liver in 44% of cases (n=14), moderate fatty liver in 38% (n=12), and severe fatty liver in 18% (n=5). HOMA-IRI and MDA levels were significantly higher in patients with NAFLD than in healthy controls (HOMA-IRI, 3.7 versus 1.7, P<0.001; and MDA, 420±300 μmol/mL versus 200±100 μmol/mL; P<0

  6. Soft drink consumption linked with fatty liver in the absence of traditional risk factors.

    PubMed

    Assy, Nimer; Nasser, Gattas; Kamayse, Iad; Nseir, William; Beniashvili, Zaza; Djibre, Agness; Grosovski, Maria

    2008-10-01

    Little is known about dietary habits and their relationships with liver disease in nonalcoholic fatty liver disease (NAFLD) patients, particularly in the absence of obesity, diabetes or hyperlipidemia. To assess the association between soft drink consumption and the presence of fatty liver in NAFLD patients who do not have classic risk factors. Three hundred ten patients with NAFLD diagnosed by ultrasound were assessed for 36 months in a cross-sectional manner. Thirty-one patients (10%) who had NAFLD without classic risk factors were compared with 30 healthy controls. Physical activity was assessed during the preceding week and year, and every six months for 36 months. Data on daily dietary intake of food and soft drink, and the source of added sugar were collected during two seven-day periods, at the beginning of the study, and within two weeks after the metabolic tests by using a validated food questionnaire given by a trained dietician. Insulin resistance and lipid peroxidation were assessed by homeostasis model assessment-insulin resistance index (HOMA-IRI) and malondialdehyde (MDA) levels, respectively. Eighty per cent of patients (25 of 31) consumed an excessive amount of soft drink beverages (more than 50 g/day of added sugar) for 36 months, compared with 20% in healthy controls (P<0.001). Twenty per cent of patients consumed one drink per day, 40% consumed two to three drinks per day, and 40% consumed more than four drinks per day for most days during 36 months. The most common soft drinks consumed were regular Coca-Cola (40% of patients), Diet Coke (40%) and flavoured fruit juices (20%). Ultrasound findings revealed mild fatty liver in 44% of cases (n=14), moderate fatty liver in 38% (n=12), and severe fatty liver in 18% (n=5). HOMA-IRI and MDA levels were significantly higher in patients with NAFLD than in healthy controls (HOMA-IRI, 3.7 versus 1.7, P<0.001; and MDA, 420+/-300 micromol/mL versus 200+/-100 micromol/mL; P<0.001). When controlled for other

  7. Correlation of Body Mass Index and Serum Parameters With Ultrasonographic Grade of Fatty Change in Non-alcoholic Fatty Liver Disease

    PubMed Central

    Abangah, Ghobad; Yousefi, Atefeh; Asadollahi, Rouhangiz; Veisani, Yousef; Rahimifar, Paria; Alizadeh, Sajjad

    2014-01-01

    Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease in the western population and expanding disease in the world. Pathological changes in fatty liver are like alcohol liver damage, which can lead to end-stage liver disease. The prevalence of NAFLD in obese or overweight people is higher than general population, and it seems that people with high Body Mass Index (BMI) or abnormality in some laboratory tests are more susceptible for severe fatty liver and high grade of NAFLD in ultrasonography (U.S). Objectives: This study aimed to evaluate the correlation of BMI and laboratory tests with NAFLD in ultrasonography. Materials and Methods: During a multi-step process, we selected two-hundred and thirteen cases from four hundred and eighteen patients with NAFLD. Laboratory tests performed included: ALT, AST, FBS, Triglyceride and cholesterol levels, hepatitis B surface antigen, hepatitis C antibody, ceruloplasmin, serum iron, TIBC, transferrin saturation, ferritin, AMA, ANA, ANTI LKM1, serum protein electrophoresis, TSH, anti TTG (IgA). BMI and ultrasonography for 213 patients were performed, and then data was analyzed. These parameters and grades of ultrasonography were compared with the values obtained using one way ANOVA. An ordinal logistic regression model was used to estimate the probability of ultrasonography grade. The Statistical Package for the Social Science program (SPSS, version 16.0) was used for data analysis. Results: Two-hundred and thirteen cases including 140 male and 73 female, were studied. In general, 72.3% of patients were overweight and obese. Post-hoc tests showed that only BMI (P < 0.001) and TG (P < 0.011) among variables had statistically significant associations with ultrasonography grade (USG), and ordinal logistic regression model showed that BMI and AST were the best predictors. Discussion: Our results suggest that in patients with NAFLD, BMI and TG are most effective factors in severity of fatty liver disease

  8. Correlation of Body Mass Index and Serum Parameters With Ultrasonographic Grade of Fatty Change in Non-alcoholic Fatty Liver Disease.

    PubMed

    Abangah, Ghobad; Yousefi, Atefeh; Asadollahi, Rouhangiz; Veisani, Yousef; Rahimifar, Paria; Alizadeh, Sajjad

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common liver disease in the western population and expanding disease in the world. Pathological changes in fatty liver are like alcohol liver damage, which can lead to end-stage liver disease. The prevalence of NAFLD in obese or overweight people is higher than general population, and it seems that people with high Body Mass Index (BMI) or abnormality in some laboratory tests are more susceptible for severe fatty liver and high grade of NAFLD in ultrasonography (U.S). This study aimed to evaluate the correlation of BMI and laboratory tests with NAFLD in ultrasonography. During a multi-step process, we selected two-hundred and thirteen cases from four hundred and eighteen patients with NAFLD. Laboratory tests performed included: ALT, AST, FBS, Triglyceride and cholesterol levels, hepatitis B surface antigen, hepatitis C antibody, ceruloplasmin, serum iron, TIBC, transferrin saturation, ferritin, AMA, ANA, ANTI LKM1, serum protein electrophoresis, TSH, anti TTG (IgA). BMI and ultrasonography for 213 patients were performed, and then data was analyzed. These parameters and grades of ultrasonography were compared with the values obtained using one way ANOVA. An ordinal logistic regression model was used to estimate the probability of ultrasonography grade. The Statistical Package for the Social Science program (SPSS, version 16.0) was used for data analysis. Two-hundred and thirteen cases including 140 male and 73 female, were studied. In general, 72.3% of patients were overweight and obese. Post-hoc tests showed that only BMI (P < 0.001) and TG (P < 0.011) among variables had statistically significant associations with ultrasonography grade (USG), and ordinal logistic regression model showed that BMI and AST were the best predictors. Our results suggest that in patients with NAFLD, BMI and TG are most effective factors in severity of fatty liver disease and ultrasonography grade (USG). On the other hand, BMI as a

  9. Postnatal overfeeding promotes early onset and exaggeration of high-fat diet-induced nonalcoholic fatty liver disease through disordered hepatic lipid metabolism in rats.

    PubMed

    Ji, Chenlin; Dai, Yanyan; Jiang, Weiwei; Liu, Juan; Hou, Miao; Wang, Junle; Burén, Jonas; Li, Xiaonan

    2014-11-01

    Exposure to overnutrition in critical or sensitive developmental periods may increase the risk of developing obesity and metabolic syndrome in adults. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, but the relationship among postnatal nutrition, lipid metabolism, and NAFLD progression during development remains poorly understood. Here we investigated in a rat model whether postnatal overfeeding increases susceptibility to NAFLD in response to a high-fat diet. Litters from Sprague-Dawley dams were culled to three (small litters) or ten (normal litters) pups and then weaned onto a standard or high-fat diet at postnatal day 21 to generate normal-litter, small-litter, normal-litter/high-fat, and small-litter/high-fat groups. At age 16 weeks, the small-litter and both high-fat groups showed obesity, dyslipidemia, and insulin resistance. Hepatic disorders appeared earlier in the small-litter/high-fat rats with greater liver mass gain and higher hepatic triglycerides and steatosis score versus normal-litter/high-fat rats. Hepatic acetyl-CoA carboxylase activity and mRNA expression were increased in small-litter rats and aggravated in small-litter/high-fat rats but not in normal-litter/high-fat rats. The high expression in small-litter/high-fat rats coincided with high sterol regulatory element-binding protein-1c mRNA and protein expression. However, mRNA expression of enzymes involved in hepatic fatty acid oxidation (carnitine palmitoyltransferase 1) and output (microsomal triglyceride transfer protein) was decreased under a high-fat diet regardless of litter size. In conclusion, overfeeding related to small-litter rearing during lactation contributes to the NAFLD phenotype when combined with a high-fat diet, possibly through up-regulated hepatic lipogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. [Effects of three Wenyang Jianpi Tang on cell proliferation and apoptosis of nonalcoholic fatty liver cells].

    PubMed

    Yang, Jia-Yao; Tao, Dong-Qing; Liu, Song; Zhang, Shu; Ma, Wei; Shi, Zhao-Hong

    2017-04-01

    To investigate the effects of Sijunzi Tang, Lizhong Tang and Fuzi Lizhong Tang on the cell proliferation and apoptosis of nonalcoholic fatty liver cells through the nonalcoholic fatty liver cell model established by inducing L02 cells with oleic acid. Different concentrations of oleic acid were added into L02 cells to induce the nonalcoholic fatty liver cell model. Oil red O staining was used to observe fatty droplets of fatty liver cells. Automatic biochemical analyzer was used to detect the levels of aspartic transaminase(AST), alanine aminotransferase(ALT), total cholesterol(TC), and triglyceride(TG) in the cell supernatants. There were five groups, namely normal group, model group, model and Sijunzi Tang group, model and Lizhong Tang group, and model and Fuzi Lizhong Tang group. The cell proliferation and apoptosis of the five groups were detected by MTT colorimetry test and flow cytometer. The expressions of PCNA, cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, Bax and Bcl-2 proteins of the five groups were detected by Western blot. The oil red O staining results showed that the optimum concentration of oleic acid that was used to induce nonalcoholic fatty liver cell models was 80 mg•L-1. The levels of AST, ALT, TC and TG in the nonalcoholic fatty liver cell supernatants were higher than that in normal liver cell supernatants(P<0.01). MTT colorimetry test and flow cytometer results showed that all of Sijunzi Tang, Lizhong Tang and Fuzi Lizhong Tang could effectively promote the cell proliferation, and inhibit the cellular apoptosis of nonalcoholic fatty liver cells(P<0.01). And Fuzi Lizhong Tang showed the best effect. Western blot results showed that Sijunzi Tang, Lizhong Tang and Fuzi Lizhong Tang could down-regulate the expressions of cleaved caspase-3, cleaved caspase-8, cleaved caspase-9 and Bax proteins, and up-regulate the expressions of PCNA and Bcl-2 proteins of nonalcoholic fatty liver cells. And Fuzi Lizhong Tang showed the best effect

  11. Triglycerides to high-density lipoprotein cholesterol ratio is an independent predictor of incident fatty liver; a population-based cohort study.

    PubMed

    Fukuda, Yukiko; Hashimoto, Yoshitaka; Hamaguchi, Masahide; Fukuda, Takuya; Nakamura, Naoto; Ohbora, Akihiro; Kato, Takahiro; Kojima, Takao; Fukui, Michiaki

    2016-05-01

    Triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) has been recommended for surrogates of insulin resistance. However, it remains to be elucidated the association between TG/HDL-C and incident fatty liver. To investigate the association between TG/HDL-C and incident fatty liver. We performed population-based historical cohort study consisted with 4518 healthy Japanese who received yearly health-checkup programmes over decade. Fatty liver was diagnosed using ultrasonography. During the observation periods, 38.8% (case/N = 1023/2637) of men and 17.2% (case/N = 324/1881) of women developed fatty liver. Adjusting odds ratio of TG/HDL-C for incident fatty liver were 1.59 (95% confidence interval (CI) 1.42-1.79, P < 0.0001) in men and 2.50 (95% CI 1.80-3.51, P < 0.0001) in women. In addition, adjusting odds ratio of TG/HDL-C for incident non-alcoholic fatty liver disease were 1.55 (95% CI 1.35-1.77, P < 0.0001) in men and 2.72 (95% CI 1.88-3.95, P < 0.0001) in women. According to the receiver operator characteristic (ROC) analysis, the optimal cut-off point of TG/HDL-C for incident fatty liver was 0.88 (area under the ROC curve (AUC) 0.67 [95% CI 0.65-0.69], sensitivity = 0.64, specificity = 0.60, P < 0.0001) in men and 0.64 (AUC 0.69 [95% CI 0.66-0.72], sensitivity = 0.50, specificity = 0.78, P < 0.0001) in women. The TG/HDL-C could predict the incident fatty liver. Thus, it is important to check TG/HDL-C and lifestyles modification is needed for preventing future fatty liver disease in patients with high TG/HDL-C. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Non-alcoholic fatty liver disease: What the clinician needs to know

    PubMed Central

    Machado, Mariana Verdelho; Cortez-Pinto, Helena

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the Western world. Furthermore, it is increasing worldwide, paralleling the obesity pandemic. Though highly frequent, only about one fifth of affected subjects are at risk of developing the progressive form of the disease, non-alcoholic steatohepatitis with fibrosis. Even in the latter, liver disease is slowly progressive, though, since it is so prevalent, it is already the third cause of liver transplantation in the United States, and it is predicted to get to the top of the ranking in few years. Of relevance, fatty liver is also associated with increased overall mortality and particularly increased cardiovascular mortality. The literature and amount of published papers on NAFLD is increasing as fast as its prevalence, which makes it difficult to keep updated in this topic. This review aims to summarize the latest knowledge on NAFLD, in order to help clinicians understanding its pathogenesis and advances on diagnosis and treatment. PMID:25278691

  13. Gut Microbiota as a Driver of Inflammation in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Ianiro, Gianluca; Simonelli, Claudia; Newton, Estelle E.

    2018-01-01

    The prevalence of nonalcoholic fatty liver disease and the consequent burden of metabolic syndrome have increased in recent years. Although the pathogenesis of nonalcoholic fatty liver disease is not completely understood, it is thought to be the hepatic manifestation of the dysregulation of insulin-dependent pathways leading to insulin resistance and adipose tissue accumulation in the liver. Recently, the gut-liver axis has been proposed as a key player in the pathogenesis of NAFLD, as the passage of bacteria-derived products into the portal circulation could lead to a trigger of innate immunity, which in turn leads to liver inflammation. Additionally, higher prevalence of intestinal dysbiosis, larger production of endogenous ethanol, and higher prevalence of increased intestinal permeability and bacterial translocation were found in patients with liver injury. In this review, we describe the role of intestinal dysbiosis in the activation of the inflammatory cascade in NAFLD. PMID:29563854

  14. Ablation of systemic SIRT1 activity promotes nonalcoholic fatty liver disease by affecting liver-mesenteric adipose tissue fatty acid mobilization

    USDA-ARS?s Scientific Manuscript database

    The incidence of nonalcoholic fatty liver disease (NAFLD) is escalating paralleled with obesity rates in both adults and children. Mammalian sirtuin 1 (SIRT1), a highly conserved NAD+-dependent protein deacetylase, has been identified as a metabolic regulator of lipid homeostasis and a potential tar...

  15. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice.

    PubMed

    Lin, Chih-Wen; Zhang, Hao; Li, Min; Xiong, Xiwen; Chen, Xi; Chen, Xiaoyun; Dong, Xiaocheng C; Yin, Xiao-Ming

    2013-05-01

    Pharmacological approaches can potentially improve fatty liver condition in alcoholic and non-alcoholic fatty liver diseases. The salutary effects of reducing lipid synthesis or promoting lipid oxidation have been well reported, but the benefits of increasing lipid degradation have yet to be well explored. Macroautophagy is a cellular degradation process that can remove subcellular organelles including lipid droplets. We thus investigated whether pharmacological modulation of macroautophagy could be an effective approach to alleviate fatty liver condition and liver injury. C57BL/6 mice were given ethanol via intraperitoneal injection (acute) or by a 4-week oral feeding regime (chronic), or high fat diet for 12 weeks. An autophagy enhancer, carbamazepine or rapamycin, or an autophagy inhibitor, chloroquine, was given before sacrifice. Activation of autophagy, level of hepatic steatosis, and blood levels of triglycerides, liver enzyme, glucose and insulin were measured. In both acute and chronic ethanol condition, macroautophagy was activated. Carbamazepine, as well as rapamycin, enhanced ethanol-induced macroautophagy in hepatocytes in vitro and in vivo. Hepatic steatosis and liver injury were exacerbated by chloroquine, but alleviated by carbamazepine. The protective effects of carbamazepine and rapamycin in reducing steatosis and in improving insulin sensitivity were also demonstrated in high fat diet-induced non-alcoholic fatty liver condition. These findings indicate that pharmacological modulation of macroautophagy in the liver can be an effective strategy for reducing fatty liver condition and liver injury. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  16. Multicausality in fatty liver disease: Is there a rationale to distinguish between alcoholic and non-alcoholic origin?

    PubMed Central

    Völzke, Henry

    2012-01-01

    Apart from alcohol, there are other factors that may induce complications, which resemble alcohol-related liver disorders. In particular, obesity has been brought into focus as a risk factor for fatty liver disease. The term “non-alcoholic” fatty liver disease is commonly used to distinguish between obesity-related and alcohol-related hepatic steatosis. This review uses the epidemiological perspective to critically assess whether it is necessary and useful to differentiate between alcoholic and “non-alcoholic” fatty liver disease. The MEDLINE database was searched using the PubMed search engine, and a review of reference lists from original research and review articles was conducted. The concept to distinguish between alcoholic and “non-alcoholic” fatty liver disease is mainly based on specific pathomechanisms. This concept has, however, several limitations including the common overlap between alcohol misuse and obesity-related metabolic disorders and the non-consideration of additional causal factors. Both entities share similar histopathological patterns. Studies demonstrating differences in clinical presentation and outcome are often biased by selection. Risk factor reduction is the main principle of prevention and treatment of both disease forms. In conclusion, alcoholic and “non-alcoholic” fatty liver diseases are one and the same disease caused by different risk factors. A shift from artificial categories to a more general approach to fatty liver disease as a multicausal disorder may optimize preventive strategies and help clinicians more effectively treat patients at the individual level. PMID:22826613

  17. Identification of protective components that prevent the exacerbation of goose fatty liver: Characterization, expression and regulation of adiponectin receptors.

    PubMed

    Geng, Tuoyu; Yang, Biao; Li, Fuyuan; Xia, Lili; Wang, Qianqian; Zhao, Xing; Gong, Daoqing

    2016-01-01

    Fat accumulation in the liver is a natural process in goose, which prepares goose for long-distance migration. In contrast to mammalian fatty liver that usually progresses into an irreversible status, steatohepatitis, goose fatty liver can return to normal without obvious pathological damage, suggesting a protective system exists in goose liver. This study was to identify the components of this system. We first focused on goose adiponectin receptor 1 and 2 (Adipor1/2) as they have ceramidase activity, and can cleave ceramide, a group of proinflammatory signaling lipid species. Quantitative analysis indicated that tumor necrosis factor alpha (Tnfα), a key proinflammatory cytokine, was down-regulated in goose fatty liver by overfeeding. This inhibition of Tnfα was accompanied with reduced adiponectin and increased Adipor1/2 in the adipose tissues and in the livers of the overfed geese, respectively. To investigate the regulation of goose Adipor2 in the context of fatty liver, we treated goose primary hepatocytes with fatty liver associated factors. Data indicated that Adipor2 was upregulated by glucose and oleate but not palmitate. Its expression was even suppressed by high level of insulin. The regulation of Adipor1 by these factors was quite similar to that of Adipor2 except that glucose did not induce Adipor1. Together, these findings suggest the upregulation of Adipor1/2 may, at least partially, contribute to the inhibition of inflammation in goose fatty liver, and the expression of Adipor1/2 can be regulated by fatty liver-associated factors. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Interactions between fatty acid synthesis, oxidation, and esterification in the production of triglyceride-rich lipoproteins by the liver.

    PubMed

    Fukuda, N; Ontko, J A

    1984-08-01

    triglyceride produced from both de novo fatty acid synthesis and from infused free fatty acid substrate. These observations suggest the following chain of events in the liver following TOFA treatment: inhibition of fatty acid and cholesterol synthesis; increased fatty acid oxidation and ketogenesis; decreased triglyceride synthesis as a result of inhibition of fatty acid synthesis, stimulation of fatty acid oxidation, and altered partition of diglyceride between triglyceride and phospholipid synthesis; and decreased production of VLDL. These comparative rat liver perfusion experiments indicate that free fatty acids provide the major source of substrate for the hepatic production of triglyceri

  19. Nutritional Management of Insulin Resistance in Nonalcoholic Fatty Liver Disease (NAFLD)

    PubMed Central

    Conlon, Beth A.; Beasley, Jeannette M.; Aebersold, Karin; Jhangiani, Sunil S.; Wylie-Rosett, Judith

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an emerging global health concern. It is the most common form of chronic liver disease in Western countries, affecting both adults and children. NAFLD encompasses a broad spectrum of fatty liver disease, ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH), and is strongly associated with obesity, insulin resistance, and dyslipidemia. First-line therapy for NAFLD includes weight loss achieved through diet and physical activity. However, there is a lack of evidenced-based dietary recommendations. The American Diabetes Association’s (ADA) recommendations that aim to reduce the risk of diabetes and cardiovascular disease may also be applicable to the NAFLD population. The objectives of this review are to: (1) provide an overview of NAFLD in the context of insulin resistance, and (2) provide a rationale for applying relevant aspects of the ADA recommendations to the nutritional management of NAFLD. PMID:24152749

  20. Factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Tasneem, Abbas Ali; Luck, Nasir Hassan; Majid, Zain

    2018-04-01

    Introduction To determine the factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Methodology All patients aged >18 years and having a fatty liver on abdominal ultrasound (US), presenting from January 2011 to January 2017, were included. A liver biopsy was performed on all the patients. Results Of 96 patients undergoing liver biopsy for non-alcoholic fatty liver disease (NAFLD), 76 (79.2%) were men. On liver US, diffuse fatty liver (DFL) was noted in 68 (70.8%) patients. Liver biopsy showed non-alcoholic steatohepatitis (NASH) in 78 (81.3%) patients. Factors associated with NASH were male gender, body mass index (BMI) > 27 kg/m 2 , DFL and raised alanine aminotransferase (ALT). A GULAB score (based on gender, US liver findings, lipid (fasting) levels, ALT level and BMI) of ≥5 predicted NASH with 82.05% sensitivity. Factors associated with advanced fibrosis in NAFLD were age >40 years, diabetes mellitus, AST/ALT ratio > 1 and raised GGT. Conclusion NASH is common in patients with male gender, high BMI, DFL on liver US, raised ALT and GULAB score ≥5.

  1. Psoriasis and Nonalcoholic Fatty Liver Disease.

    PubMed

    Carrascosa, J M; Bonanad, C; Dauden, E; Botella, R; Olveira-Martín, A

    Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver condition in the West. The prevalence and severity of NAFLD is higher and the prognosis worse in patients with psoriasis. The pathogenic link between psoriasis and NAFLD is chronic inflammation and peripheral insulin resistance, a common finding in diseases associated with psoriasis. NAFLD should therefore be ruled out during the initial evaluation of patients with psoriasis, in particular if they show signs of metabolic syndrome and require systemic treatment. Concomitant psoriasis and NAFLD and the likelihood of synergy between them place limitations on general recommendations and treatment for these patients given the potential for liver toxicity. As hepatotoxic risk is associated with some of the conventional drugs used in this setting (e.g., acitretin, methotrexate, and ciclosporin), patients prescribed these treatments should be monitored as appropriate. Anti-tumor necrosis factor agents hold the promise of potential benefits based on their effects on the inflammatory process and improving peripheral insulin resistance. However, cases of liver toxicity have also been reported in relation to these biologics. No evidence has emerged to suggest that anti-p40 or anti-interleukin 17 agents provide benefits or have adverse effects. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. The benefits of exercise for patients with non-alcoholic fatty liver disease.

    PubMed

    Keating, Shelley E; George, Jacob; Johnson, Nathan A

    2015-01-01

    As exercise is now an established therapy for the management of non-alcoholic fatty liver disease (NAFLD), recent investigations have sought to identify the optimal dose (type, intensity and amount) of exercise for hepatic benefit. Here, the authors discuss the following: the role of aerobic exercise for the modulation of hepatic steatosis; the limited evidence for the role of resistance training in reducing liver fat; the lack of evidence from clinical trials on the role of exercise in non-alcoholic steatohepatitis; and the benefits of exercise for patients with NAFLD, beyond steatosis. Based on current evidence, the authors provide recommendations for exercise prescription for patients with NAFLD.

  3. NHE1 deficiency in liver: Implications for non-alcoholic fatty liver disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Prasad, Vikram, E-mail: prasadvm@ucmail.uc.edu; Chirra, Shivani; Kohli, Rohit

    Highlights: • FXR, PGC1α and PPARγ levels are upregulated in NHE1 deficient livers. • NHE1 deficiency downregulates expression of pro-lipogenic genes in liver. • Chronic exposure to high-fat diet upregulates hepatic NHE1 expression. • Loss of NHE1 better preserves hepatic insulin signaling in high-fat diet-fed mice. - Abstract: Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na{sup +}/H{sup +} exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in livermore » that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress, which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors.« less

  4. Successful treatment for a patient with hemophagocytic syndrome after a small-for-size graft liver transplantation.

    PubMed

    Yoshizumi, Tomoharu; Taketomi, Akinobu; Kayashima, Hiroto; Harada, Noboru; Uchiyama, Hideaki; Yamashita, Yo-ichi; Ikegami, Toru; Soejima, Yuji; Nishizaki, Takashi; Shimada, Mitsuo; Maehara, Yoshihiko

    2008-01-01

    Hemophagocytic syndrome (HPS) is a hematological disorder caused by activated T lymphocytes, which leads to the proliferation of stimulated macrophages that phagocytose and destroy circulating blood elements and their precursors within bone marrow, and lead to the further production of inflammatory cytokines. Living donor liver transplantation (LDLT) between adults has been performed to compensate for the shortage of available organs. There have been some reports concerning HPS after LDLT; however, its prognosis is disappointingly poor. In particular, there is no report of treated HPS developed after LDLT using small-for-size left lobe grafts. We herein report a case of HPS in a 63-year old woman who underwent LDLT using left lobe graft weighing only 330g. The HPS was diagnosed on postoperative day 13, and was successfully treated using a combination of intravenous immunoglobulin, granulocyte colony stimulating factor, conversion of calcineurin inhibitor and steroid pulse. The trigger of HPS may not only be systemic infection, but also hypercytokinemia caused by various factors. HPS is a fatal complication in immunologically compromised patients; however, early and accurate diagnosis could lead to an adequate treatment and improve the outcome.

  5. Evaluation of liver regeneration diet supplemented with omega-3 fatty acids: experimental study in rats.

    PubMed

    Silva, Rosilda Mendes da; Malafaia, Osvaldo; Torres, Orlando Jorge Martins; Czeczko, Nicolau Gregori; Marinho Junior, Carlos Hespanha; Kozlowski, Ronaldo Kiviatcoski

    2015-01-01

    to evaluate liver regeneration in rats after partial hepatectomy of 60% with and without action diet supplemented with fatty acids through the study of the regenerated liver weight, laboratory parameters of liver function and histological study. thirty-six Wistar rats, males, adults were used, weighing between 195 and 330 g assigned to control and groups. The supplementation group received the diet by gavage and were killed after 24h, 72h and seven days. Evaluation of regeneration occurred through analysis of weight gain liver, serum aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase, and mitosis of the liver stained with H&E. the diet supplemented group showed no statistical difference (p>0.05) on the evolution of weights. Administration of fatty acids post-hepatectomy had significant reduction in gamma glutamyltransferase levels and may reflect liver regeneration. Referring to mitotic index, it did not differ between period of times among the groups. supplementation with fatty acids in rats undergoing 60% hepatic resection showed no significant interference related to liver regeneration.

  6. Fimasartan Ameliorates Nonalcoholic Fatty Liver Disease through PPARδ Regulation in Hyperlipidemic and Hypertensive Conditions

    PubMed Central

    Jang, Yoo-Na; Han, Yoon-Mi; Kim, Hyun-Min; Jeong, Jong-Min

    2017-01-01

    To investigate the effects of fimasartan on nonalcoholic fatty liver disease in hyperlipidemic and hypertensive conditions, the levels of biomarkers related to fatty acid metabolism were determined in HepG2 and differentiated 3T3-L1 cells treated by high fatty acid and liver and visceral fat tissue samples of spontaneously hypertensive rats (SHRs) given high-fat diet. In HepG2 cells and liver tissues, fimasartan was shown to increase the protein levels of peroxisome proliferator-activated receptor delta (PPARδ), phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylated acetyl-CoA carboxylase (p-ACC), malonyl-CoA decarboxylase (MCD), medium chain acyl-CoA dehydrogenase (MCAD), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and it led to a decrease in the protein levels of 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSDH1), fatty acid synthase (FAS), and tumor necrosis factor-alpha (TNF-α). Fimasartan decreased lipid contents in HepG2 and differentiated 3T3-L1 cells and liver tissues. In addition, fimasartan increased the adiponectin level in visceral fat tissues. The antiadipogenic effects of fimasartan were offset by PPARδ antagonist (GSK0660). Consequently, fimasartan ameliorates nonalcoholic fatty liver disease mainly through the activation of oxidative metabolism represented by PPARδ-AMPK-PGC-1α pathway. PMID:28386270

  7. Kefir improves fatty liver syndrome by inhibiting the lipogenesis pathway in leptin-deficient ob/ob knockout mice.

    PubMed

    Chen, H-L; Tung, Y-T; Tsai, C-L; Lai, C-W; Lai, Z-L; Tsai, H-C; Lin, Y-L; Wang, C-H; Chen, C-M

    2014-09-01

    Fatty liver disease is commonly associated with obesity, insulin resistance and diabetes. Severe fatty liver is sometimes accompanied by steatohepatitis and may lead to the development of hepatocellular carcinoma. At present, there is no effective treatment for non-alcoholic fatty liver disease (NAFLD); thus, recent investigations have focused on developing effective therapeutics to treat this condition. This study aimed to evaluate the effects of kefir on the hepatic lipid metabolism of ob/ob mice, which are commonly used to model fatty liver disease. In this study, we used leptin receptor-deficient ob/ob mice as an animal disease model of NAFLD. Six-week-old ob/ob mice were orally administered the dairy product kefir (140 mg kg(-1) of body weight (BW) per day) for 4 weeks. The data demonstrated that kefir improved fatty liver syndrome on BW, energy expenditure and basal metabolic rate by inhibiting serum glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) activities (P<0.05) and by decreasing the triglyceride (TG) and total cholesterol (TC) contents of the liver (P<0.05). Oral kefir administration also significantly reduced the macrovesicular fat quantity in liver tissue. In addition, kefir markedly decreased the expression of the genes sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) (P<0.05) but not the expression of peroxisome proliferator-activated receptor α (PPARα) or hepatic carnitine palmitoyltransferase-1α (CPT1α) in the livers of ob/ob mice. On the basis of these results, we conclude that kefir improves NAFLD on BW, energy expenditure and basal metabolic rate by inhibiting the lipogenesis pathway and that kefir may have the potential for clinical application to the prevention or treatment of NAFLD.

  8. Association of nonalcoholic fatty liver disease and liver cancer

    PubMed Central

    Schulz, Perla Oliveira; Ferreira, Fabio Gonçalves; Nascimento, Maria de Fátima Araújo; Vieira, Andrea; Ribeiro, Mauricio Alves; David, André Ibrahim; Szutan, Luiz Arnaldo

    2015-01-01

    AIM: To investigate the association between nonalcoholic fatty liver disease (NAFLD) and liver cancer, and NAFLD prevalence in different liver tumors. METHODS: This is a retrospective study of the clinical, laboratory and histological data of 120 patients diagnosed with primary or secondary hepatic neoplasms and treated at a tertiary center where they underwent hepatic resection and/or liver transplantation, with subsequent evaluation of the explant or liver biopsy. The following criteria were used to exclude patients from the study: a history of alcohol abuse, hepatitis B or C infection, no tumor detected in the liver tissue examined by histological analysis, and the presence of chronic autoimmune hepatitis, hemochromatosis, Wilson’s disease, or hepatoblastoma. The occurrence of NAFLD and the association with its known risk factors were studied. The risk factors considered were diabetes mellitus, impaired glucose tolerance, impaired fasting glucose, body mass index, dyslipidemia, and arterial hypertension. Presence of reticulin fibers in the hepatic neoplasms was assessed by histological analysis using slide-mounted specimens stained with either hematoxylin and eosin or Masson’s trichrome and silver impregnation. Analysis of tumor-free liver parenchyma was carried out to determine the association between NAFLD and its histological grade. RESULTS: No difference was found in the association of NAFLD with the general population (34.2% and 30.0% respectively, 95%CI: 25.8-43.4). Evaluation by cancer type showed that NAFLD was more prevalent in patients with liver metastasis of colorectal cancer than in patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma (OR = 3.99, 95%CI: 1.78-8.94, P < 0.001 vs OR = 0.60, 95%CI: 0.18-2.01, P = 0.406 and OR = 0.70, 95%CI: 0.18-2.80, P = 0.613, respectively). There was a higher prevalence of liver fibrosis in patients with hepatocellular carcinoma (OR = 3.50, 95%CI: 1.06-11.57, P = 0.032). Evaluation of the

  9. Obstructive sleep apnea is associated with fatty liver and abnormal liver enzymes: a meta-analysis.

    PubMed

    Sookoian, Silvia; Pirola, Carlos J

    2013-11-01

    Obstructive sleep apnea (OSA) is associated with the cluster of clinical conditions that comprise the metabolic syndrome, including nonalcoholic fatty liver disease (NAFLD). Our primary purpose was to estimate the effect of OSA on serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Our secondary purpose was to investigate the potential influence of OSA on histological severity of NAFLD to explore whether chronic intermittent hypoxia is associated with inflammation and fibrosis. Our literature search identified 11 studies, from which we extracted information about numbers of control subjects and OSA patients, and ALT, AST, and NAFLD. From a total of 668 OSA patients and 404 controls, we found that the standardized difference in mean values of ALT and AST levels in patients with OSA was significantly different from that in the controls. Meta-regression showed that the association was independent of body mass index and type 2 diabetes. Fatty liver was associated with OSA in five studies with 400 subjects. OSA was significantly associated with liver fibrosis in 208 subjects, but not with lobular inflammation. Routine assessment of liver enzymes and liver damage should be implemented in OSA patients because they have an increase of 13.3% of ALT and 4.4% of AST levels, and a 2.6-fold higher risk of liver fibrosis when they have NAFLD, which is 2.6 times more frequent in OSA patients.

  10. Thyroid Hormones Concentrations during the Mid-Dry Period: An Early Indicator of Fatty Liver in Holstein-Friesian Dairy Cows

    PubMed Central

    Šamanc, Horea; Stojić, Velibor; Kirovski, Danijela; Jovanović, Milijan; Cernescu, Horia; Vujanac, Ivan

    2010-01-01

    Relationship between postpartal fatty liver and thyroid gland activity during the peripartal and mid dry periods was studied. Twenty one dry cows were chosen. Blood samples were obtained on days −30, −2, and +12 related to calving and analized for thyroxine (T4) and triiodothyronine (T3). A T3/T4 ratio was calculated. Liver tissue samples were taken 12 d after calving and tested for the lipid content. Cows were divided into three groups: mild (<20% fat), moderate (20 to 30%), or severe fatty liver (>30%). Cows, that were affected with severe fatty liver, were hypothyroid prior to development of the condition due to lower T4 concentrations, and had significantly lower concentration of T3 and higher T3/T4 ratios than cows with mild and moderate fatty liver. Thus, hypothyroid state during mid-dry period may be an early indicator of postpartal fatty liver and may provoke T3/T4 ratio increase in this group of cows. PMID:21048844

  11. Polyenylphosphatidylcholine attenuates alcohol-induced fatty liver and hyperlipemia in rats.

    PubMed

    Navder, K P; Baraona, E; Lieber, C S

    1997-09-01

    Chronic administration of a soybean-derived polyenylphosphatidylcholine (PPC) extract prevents the development of cirrhosis in alcohol-fed baboons. To assess whether this phospholipid also affects earlier changes induced by alcohol consumption (such as fatty liver and hyperlipemia), 28 male rat littermates were pair-fed liquid diets containing 36% of energy either as ethanol or as additional carbohydrate for 21 d, and killed 90 min after intragastric administration of the corresponding diets. Half of the rats were given PPC (3 g/l), whereas the other half received the same amount of linoleate (as safflower oil) and choline (as bitartrate salt). PPC did not affect diet or alcohol consumption [15.4 +/- 0.5 G/(kg.d)], but the ethanol-induced hepatomegaly and the hepatic accumulation of lipids (principally triglycerides and cholesterol esters) and proteins were about half those in rats not given PPC. The ethanol-induced postprandial hyperlipemia was lower with PPC than without, despite an enhanced fat absorption and no difference in the level of plasma free fatty acids. The attenuation of fatty liver and hyperlipemia was associated with correction of the ethanol-induced inhibition of mitochondrial oxidation of palmitoyl-1-carnitine and the depression of cytochrome oxidase activity, as well as the increases in activity of serum glutamate dehydrogenase and aminotransferases. Thus, PPC attenuates early manifestations of alcohol toxicity, at least in part, by improving mitochondrial injury. These beneficial effects of PPC at the initial stages of alcoholic liver injury may prevent or delay the progression to more advanced forms of alcoholic liver disease.

  12. Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in HIV.

    PubMed

    Rockstroh, Jürgen Kurt

    2017-04-01

    Abnormal liver enzymes (LE) are common in patients infected with the human immunodeficiency virus (HIV) even in the absence of viral hepatitis or alcohol abuse. With availability of antiretroviral combination therapy, life expectancy has improved dramatically and as a consequence the spectrum of liver disease is changing. Increased reports on the development of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) in HIV coinfected patients raise questions around prevalence, clinical manifestations, and clinical outcome of these liver diseases in HIV coinfection. Moreover, the potential impact of combination antiretroviral therapy as well as direct HIV effects on the emergence of non-alcoholic fatty liver disease needs to be explored. This review summarizes the recent literature on NAFLD and NASH in HIV.

  13. [Progress in research of the mechanisms related with the hepatic steatosis in the nonalcoholic fatty liver disease].

    PubMed

    Shi, Li-Juan; Song, Guang-Yao

    2013-12-01

    With the increased morbidity of Nonalcoholic fatty liver disease, the pathogenesis of which has become one of the focuses for researchers. Many details need to be clarified. The hepatic steatosis has been taken as the clinical pathological characters and the "golden standard of diagnosis" for the nonalcoholic fatty liver disease. More and more studies have shown that the hepatic steatosis (mainly as triglycerides) is the consequence of hepatic lipid metabolism disequilibrium. Generally, the related metabolism pathways including lipid input, lipid uptake, de novo lipogenesis, fatty acid oxidation, fatty acid reesterification, and lipid secretion etc. In this review, we focused on the progress of some key enzymes involved in these pathways in order to clarify the possible molecular mechanisms and the effective targets so that to broad our vision about the prevention and treatment of non-alcoholic fatty liver disease.

  14. Effect of severity of steatosis as assessed ultrasonographically on hepatic vascular indices in non-alcoholic fatty liver disease.

    PubMed

    Mohammadi, Afshin; Ghasemi-rad, Mohammad; Zahedi, Hengameh; Toldi, Gergely; Alinia, Tahereh

    2011-09-01

    Early monitoring of non-alcoholic fatty liver disease (NAFLD) progression in obese patients is important to avoid the development of complications associated with fatty infiltration. of this study was to investigate the relationship between the degrees of fatty infiltration and reduced vascular compliance in NAFLD patients in the three main hepatic vessels. Two hundred and fourty subjects were enrolled in the study. They were divided into 4 groups: 60 controls, 60 grade 1 NAFLD patients, 60 grade 2 NAFLD patients and 60 grade 3 NAFLD patients. After US confirmation of the presence and grade of NAFLD, the peak and mean portal vein velocity (PPVV and MPVV, respectively), the hepatic artery resistance index (HARI), and the phasicity of the hepatic vein were measured. The PPVV was 19.6 +/- 2.4 cm/sec in patients with grade 1 fatty liver, 17.6 +/- 1.2 cm/sec in grade 2 and 15.4 +/- 1.1 cm/sec in grade 3. The MPVV was 16.6 +/- 2.4 cm/sec in patients with grade 1 fatty liver, 16.6 +/- 2.9 cm/sec in grade 2 and 12.7 +/- 0.7 cm/sec in grade 3. The HARI was 0.75 in patients with grade 1 fatty liver, 0.68 in grade 2 and 0.64 in grade 3. There was an inverse relationship between PPVV, MPVV and HARI and different grades of fatty liver in patients (p = 0.001 for PPVV (Figure 7) and HARI, p = 0.006 for MPVV. The values of the investigated liver blood flow parameters were inversely correlated with the fatty infiltration grading. Fatty infiltration can severely influence hepatic blood flow, pointing attention to the importance of early diagnosis and the need for hepatic vessel flow abnormalities characterization in the NAFLD population.

  15. The fatty liver dystrophy (fld) mutation: Developmentally related alterations in hepatic triglyceride metabolism and protein expression

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Reue, K.; Rehnmark, S.; Cohen, R.D.

    1997-07-01

    Fatty liver dystrophy (fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and development of a fatty liver in the early neonatal period. Also associated with the fld phenotype is a tissue-specific deficiency in the expression of lipoprotein lipase and hepatic lipase, as well as elevations in hepatic apolipoprotein A-IV and apolipoprotein C-II mRNA levels. Although these lipid abnormalities resolve at the age of weaning, adult mutant mice exhibit a peripheral neuropathy associated with abnormal myelin formation. The fatty liver in fld/fld neonates is characterized by the accumulation of large triglyceride droplets within the parenchymal cells, and thesemore » droplets persist within isolated hepatocytes maintained in culture for several days. To identify the metabolic defect that leads to lipid accumulation, the authors investigated several aspects of cellular triglyceride metabolism. The mutant mice exhibited normal activity of acid triacylglycerol lipase, an enzyme thought to be responsible for hydrolysis of dietary triglycerides in the liver. Metabolic labeling studies performed with oleic acid revealed that free fatty acids accumulate in the liver of 3 day old fld/fld mice, but not in adults. This accumulation in liver was mirrored by elevated free fatty acid levels in plasma of fld/fld neonates, with levels highest in very young mice and returning to normal by the age of one month. Quantitation of fatty acid oxidation in cells isolated from fld/fld neonates revealed that oxidation rate is reduced 60% in hepatocytes and 40% in fibroblasts; hepatocytes from adult fld/fld mice exhibited an oxidation rate similar to those from wild-type mice.« less

  16. Non-alcoholic fatty liver disease: A poorly known pandemic.

    PubMed

    Augustin, Salvador; Graupera, Isabel; Caballeria, Juan

    2017-12-20

    Non-alcoholic fatty liver disease (NAFLD) consists of an excessive depositing of fat in the liver, which can end up by causing inflammation, fibrosis and also cirrhosis with the corresponding complications including liver cancer. NAFLD has become the most common liver disease worldwide. The incidence has increased in parallel with the obesity, diabetes and metabolic syndrome epidemic, thus resulting in becoming one of the main indications for liver transplant. The diagnosis has principally been through histology but with the development of non-invasive methods, these have helped in simplifying the management of these patients in clinical practice. The only therapeutic strategies currently available are focused on weight loss (lifestyle changes or bariatric surgery). There is still no approved pharmacological option for the treatment of NAFLD, however there are a number of molecular studies in advanced stages of development. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  17. The role of endoplasmic reticulum stress and insulin resistance in the occurrence of goose fatty liver.

    PubMed

    Geng, Tuoyu; Xia, Lili; Li, Fuyuan; Xia, Jing; Zhang, Yihui; Wang, Qianqian; Yang, Biao; Montgomery, Sean; Cui, Hengmi; Gong, Daoqing

    2015-09-11

    In mammals, insulin resistance (IR) is required for the occurrence of non-alcoholic fatty liver disease, and endoplasmic reticulum stress (ERS) contributes to IR. As geese have physiological and metabolic characteristics different from mammals, it is unclear whether these mechanisms also underlie the occurrence of goose fatty liver. To address this, 70-day-old geese were treated with an ERS inducer or overfed, and variables associated with ERS or IR were subsequently determined. The data indicated that the group of geese treated with the ERS inducer for 20d appeared to be more intolerant to blood glucose than the control group, and their livers showed features of hepatic steatosis, suggesting ERS can induce IR and hepatic steatosis in geese. In contrast, overfeeding did not induce ERS, probably due to the upregulated expression of fatty acid desaturases, but induced higher fasting/postprandial blood glucose as well as glucose intolerance in geese, which was accompanied by a dramatic increase of liver weight. Taken together, these findings delineated the role of ERS and IR in the occurrence of goose fatty liver. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. High coffee intake is associated with lower grade nonalcoholic fatty liver disease: the role of peripheral antioxidant activity.

    PubMed

    Gutiérrez-Grobe, Ylse; Chávez-Tapia, Norberto; Sánchez-Valle, Vicente; Gavilanes-Espinar, Juan Gabriel; Ponciano-Rodríguez, Guadalupe; Uribe, Misael; Méndez-Sánchez, Nahum

    2012-01-01

    Some phytochemicals present in coffee have a potential antioxidant role which seems to protect the human body against cardiovascular diseases, liver disease and malignancies. Nonalcoholic fatty liver disease is a common disease with limited therapeutic options. This study investigated the antioxidant effect of coffee by measuring antioxidant enzymes and lipid peroxidation markers in patients with nonalcoholic fatty liver disease. We performed a case-control study at the University Hospital, Mexico City. Anthropometric, metabolic, dietary and biochemical variables of all patients were determined and compared. The presence of nonalcoholic fatty liver disease was established by ultrasonography. All patients completed a dietary questionnaire in order to determine their of coffee consumption. Catalase, superoxide dismutase and thiobarbituric acid reactive substances were measured in all of the patients. Seventy-three subjects with and 57 without nonalcoholic fatty liver disease were included. Patients with nonalcoholic fatty liver disease had significantly higher body mass index, blood glucose, homeostasis model of assessment-insulin resistance and insulin values in comparison to patients without nonalcoholic fatty liver disease. On the one hand, there was a significant difference in coffee intake between the groups (p < 0.05, for all comparisons). There was no significant difference between groups in catalase (0.39 ± 0.74 vs. 0.28 ± 0.69 nM/min/mL), superoxide dismutase (5.4 ± 3.45 vs. 4.7 ± 2.1 U/mL) or thiobarbituric acid-reactive substances (4.05 ± 1.87 vs. 3.94 ± 1.59 µM/mL). A high intake of coffee has a protective effect against nonalcoholic fatty liver disease however there was no significant difference in the antioxidant variables analyzed.

  19. Genome-Wide Associations Related to Hepatic Histology in Nonalcoholic Fatty Liver Disease in Hispanic Boys.

    PubMed

    Wattacheril, Julia; Lavine, Joel E; Chalasani, Naga P; Guo, Xiuqing; Kwon, Soonil; Schwimmer, Jeffrey; Molleston, Jean P; Loomba, Rohit; Brunt, Elizabeth M; Chen, Yii-Der Ida; Goodarzi, Mark O; Taylor, Kent D; Yates, Katherine P; Tonascia, James; Rotter, Jerome I

    2017-11-01

    To identify genetic loci associated with features of histologic severity of nonalcoholic fatty liver disease in a cohort of Hispanic boys. There were 234 eligible Hispanic boys age 2-17 years with clinical, laboratory, and histologic data enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network included in the analysis of 624 297 single nucleotide polymorphisms (SNPs). After the elimination of 4 outliers and 22 boys with cryptic relatedness, association analyses were performed on 208 DNA samples with corresponding liver histology. Logistic regression analyses were carried out for qualitative traits and linear regression analyses were applied for quantitative traits. The median age and body mass index z-score were 12.0 years (IQR, 11.0-14.0) and 2.4 (IQR, 2.1-2.6), respectively. The nonalcoholic fatty liver disease activity score (scores 1-4 vs 5-8) was associated with SNP rs11166927 on chromosome 8 in the TRAPPC9 region (P = 8.7 -07 ). Fibrosis stage was associated with SNP rs6128907 on chromosome 20, near actin related protein 5 homolog (p = 9.9 -07 ). In comparing our results in Hispanic boys with those of previously reported SNPs in adult nonalcoholic steatohepatitis, 2 of 26 susceptibility loci were associated with nonalcoholic fatty liver disease activity score and 2 were associated with fibrosis stage. In this discovery genome-wide association study, we found significant novel gene effects on histologic traits associated with nonalcoholic fatty liver disease activity score and fibrosis that are distinct from those previously recognized by adult nonalcoholic fatty liver disease genome-wide association studies. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Secondhand tobacco exposure is associated with nonalcoholic fatty liver disease in children

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lin, Connie; Rountree, Carl B.; Department of Pediatrics, Bon Secour St. Mary's Hospital, 5801 Bremo Rd, Richmond, VA 23226

    Background: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in children in the United States, and prevalence rates are rising. Smoking is associated with NAFLD, but the association of secondhand smoke exposure with NAFLD is unknown. Aims: To investigate the association of secondhand tobacco exposure with NAFLD in children. Methods: We surveyed parents/guardians of 304 children aged 3–12 years who had received an abdominal ultrasound at Penn State Hershey Medical Center. The survey addressed demographics, medical history, secondhand tobacco exposure, activity level, screen viewing time and other environmental exposures. A pediatric radiologist and sonographer reviewed themore » ultrasounds to grade the presence of bight liver compatible with NAFLD. We conducted logistic regression analysis to assess the association of secondhand tobacco exposure and NAFLD. Results: 54% of eligible potential participants responded to the survey. Fatty liver was present in 3% of the children. Increasing child age was associated with increased odds of NAFLD (OR 1.63 95% CI 1.1, 2.4). Reported child obesity was associated with increased odds of NAFLD (OR 44.5 95% CI 5.3, 371.7). The rate of NAFLD was higher in the smoke exposed group (6.7% vs. 1.7%). For every extra pack per day smoked at home, the odds of a child having NAFLD increased 1.8 times (AOR 1.8, 95% CI 1.2, 2.8), and any exposure increased a child's odds of NAFLD four-fold (AOR 4.0, 95% CI 1.02, 15.8). Conclusion: We found an association of secondhand smoke exposure and NAFLD in children. This may represent an area for future prevention efforts. - Highlights: • We evaluated the relation of tobacco exposure with nonalcoholic fatty liver disease. • Tobacco smoke exposure was associated with nonalcoholic fatty liver disease. • Tobacco smoke exposure may be an addressable risk factor.« less

  1. Solution Structure and Backbone Dynamics of Human Liver Fatty Acid Binding Protein: Fatty Acid Binding Revisited

    PubMed Central

    Cai, Jun; Lücke, Christian; Chen, Zhongjing; Qiao, Ye; Klimtchuk, Elena; Hamilton, James A.

    2012-01-01

    Liver fatty acid binding protein (L-FABP), a cytosolic protein most abundant in liver, is associated with intracellular transport of fatty acids, nuclear signaling, and regulation of intracellular lipolysis. Among the members of the intracellular lipid binding protein family, L-FABP is of particular interest as it can i), bind two fatty acid molecules simultaneously and ii), accommodate a variety of bulkier physiological ligands such as bilirubin and fatty acyl CoA. To better understand the promiscuous binding and transport properties of L-FABP, we investigated structure and dynamics of human L-FABP with and without bound ligands by means of heteronuclear NMR. The overall conformation of human L-FABP shows the typical β-clam motif. Binding of two oleic acid (OA) molecules does not alter the protein conformation substantially, but perturbs the chemical shift of certain backbone and side-chain protons that are involved in OA binding according to the structure of the human L-FABP/OA complex. Comparison of the human apo and holo L-FABP structures revealed no evidence for an “open-cap” conformation or a “swivel-back” mechanism of the K90 side chain upon ligand binding, as proposed for rat L-FABP. Instead, we postulate that the lipid binding process in L-FABP is associated with backbone dynamics. PMID:22713574

  2. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver

    PubMed Central

    Satapati, Santhosh; Kucejova, Blanka; Duarte, Joao A.G.; Fletcher, Justin A.; Reynolds, Lacy; Sunny, Nishanth E.; He, Tianteng; Nair, L. Arya; Livingston, Kenneth; Fu, Xiaorong; Merritt, Matthew E.; Sherry, A. Dean; Malloy, Craig R.; Shelton, John M.; Lambert, Jennifer; Parks, Elizabeth J.; Corbin, Ian; Magnuson, Mark A.; Browning, Jeffrey D.; Burgess, Shawn C.

    2015-01-01

    Mitochondria are critical for respiration in all tissues; however, in liver, these organelles also accommodate high-capacity anaplerotic/cataplerotic pathways that are essential to gluconeogenesis and other biosynthetic activities. During nonalcoholic fatty liver disease (NAFLD), mitochondria also produce ROS that damage hepatocytes, trigger inflammation, and contribute to insulin resistance. Here, we provide several lines of evidence indicating that induction of biosynthesis through hepatic anaplerotic/cataplerotic pathways is energetically backed by elevated oxidative metabolism and hence contributes to oxidative stress and inflammation during NAFLD. First, in murine livers, elevation of fatty acid delivery not only induced oxidative metabolism, but also amplified anaplerosis/cataplerosis and caused a proportional rise in oxidative stress and inflammation. Second, loss of anaplerosis/cataplerosis via genetic knockdown of phosphoenolpyruvate carboxykinase 1 (Pck1) prevented fatty acid–induced rise in oxidative flux, oxidative stress, and inflammation. Flux appeared to be regulated by redox state, energy charge, and metabolite concentration, which may also amplify antioxidant pathways. Third, preventing elevated oxidative metabolism with metformin also normalized hepatic anaplerosis/cataplerosis and reduced markers of inflammation. Finally, independent histological grades in human NAFLD biopsies were proportional to oxidative flux. Thus, hepatic oxidative stress and inflammation are associated with elevated oxidative metabolism during an obesogenic diet, and this link may be provoked by increased work through anabolic pathways. PMID:26571396

  3. Radiologic evaluation of nonalcoholic fatty liver disease

    PubMed Central

    Lee, Seung Soo; Park, Seong Ho

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a frequent cause of chronic liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH)-related liver cirrhosis. Although liver biopsy is still the gold standard for the diagnosis of NAFLD, especially for the diagnosis of NASH, imaging methods have been increasingly accepted as noninvasive alternatives to liver biopsy. Ultrasonography is a well-established and cost-effective imaging technique for the diagnosis of hepatic steatosis, especially for screening a large population at risk of NAFLD. Ultrasonography has a reasonable accuracy in detecting moderate-to-severe hepatic steatosis although it is less accurate for detecting mild hepatic steatosis, operator-dependent, and rather qualitative. Computed tomography is not appropriate for general population assessment of hepatic steatosis given its inaccuracy in detecting mild hepatic steatosis and potential radiation hazard. However, computed tomography may be effective in specific clinical situations, such as evaluation of donor candidates for hepatic transplantation. Magnetic resonance spectroscopy and magnetic resonance imaging are now regarded as the most accurate practical methods of measuring liver fat in clinical practice, especially for longitudinal follow-up of patients with NAFLD. Ultrasound elastography and magnetic resonance elastography are increasingly used to evaluate the degree of liver fibrosis in patients with NAFLD and to differentiate NASH from simple steatosis. This article will review current imaging methods used to evaluate hepatic steatosis, including the diagnostic accuracy, limitations, and practical applicability of each method. It will also briefly describe the potential role of elastography techniques in the evaluation of patients with NAFLD. PMID:24966609

  4. Effect of baicalin on toll-like receptor 4-mediated ischemia/reperfusion inflammatory responses in alcoholic fatty liver condition

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kim, Seok-Joo; Lee, Sun-Mee, E-mail: sunmee@skku.edu

    Alcoholic fatty liver is susceptible to secondary stresses such as ischemia/reperfusion (I/R). Baicalin is an active component extracted from Scutellaria baicalensis, which is widely used in herbal preparations for treatment of hepatic diseases and inflammatory disorders. This study evaluated the potential beneficial effect of baicalin on I/R injury in alcoholic fatty liver. Rats were fed an alcohol liquid diet or a control isocaloric diet for 5 weeks, and then subjected to 60 min of hepatic ischemia and 5 h of reperfusion. Baicalin (200 mg/kg) was intraperitoneally administered 24 and 1 h before ischemia. After reperfusion, baicalin attenuated the increases inmore » serum alanine aminotransferase activity, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels in alcoholic fatty liver. The increased levels of TNF-α and IL-6 mRNA expression and inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expressions increased after reperfusion, which were higher in ethanol-fed animals, were attenuated by baicalin. In ethanol-fed animals, baicalin attenuated the increases in toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 protein expressions and the nuclear translocation of NF-κB after reperfusion. In conclusion, our findings suggest that baicalin ameliorates I/R-induced hepatocellular damage by suppressing TLR4-mediated inflammatory responses in alcoholic fatty liver. -- Highlights: ► Baicalin attenuates hepatic I/R-induced inflammation in alcoholic fatty liver. ► Baicalin downregulates TLR4, MyD88 expression during I/R in alcoholic fatty liver. ► Baicalin attenuates NF-κB nuclear translocation during I/R in alcoholic fatty liver.« less

  5. Elevated fasting plasma C-peptide occurs in non-diabetic individuals with fatty liver, irrespective of insulin resistance.

    PubMed

    Perseghin, G; Caumo, A; Lattuada, G; De Cobelli, F; Ntali, G; Esposito, A; Belloni, E; Canu, T; Ragogna, F; Scifo, P; Del Maschio, A; Luzi, L

    2009-09-01

    Studies have pointed to insulin resistance as a pathogenic factor in fatty liver. Although pancreatic B-cell function is believed to be involved, its role is unclear. This study was undertaken to test whether fasting C-peptide, an index of fasting B-cell function, was related to intra-hepatic fat (IHF) content in non-diabetic humans. We assessed, retrospectively, fasting plasma C-peptide concentration in 31 patients with fatty liver and 62 individuals without fatty liver. The IHF content was measured by proton magnetic resonance spectroscopy ((1)H-MRS), while insulin sensitivity was estimated based on fasting plasma glucose and insulin with the homestasis model assessment (HOMA) 2 method. Age, sex and body mass index (BMI) were not different between groups. Patients with fatty liver had higher fasting insulin (P < 0.01), C-peptide (P < 0.005) and lower insulin sensitivity (HOMA2-%S). Fasting insulin alone explained 14% of the IHF content variability (P < 0.001); inclusion of fasting C-peptide in multivariate regression explained up to 32% (P < 0.001). A subgroup analysis was performed by matching 1 : 1 for HOMA2-%S. These data were analysed by conditional logistic regression which showed that, when HOMA2-%S was matched between groups, fasting C-peptide remained the only significant predictor of fatty liver. Non-diabetic individuals with fatty liver are characterized by increased fasting plasma C-peptide concentration, irrespective of their insulin resistant state.

  6. Diagnosis of non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Yki-Järvinen, Hannele

    2016-06-01

    Non-alcoholic fatty liver disease (NAFLD) increases risk of mortality from liver and cardiovascular disease (CVD) and is the major cause of hepatocellular carcinoma (HCC), which may develop without cirrhosis. NAFLD predicts type 2 diabetes, even independently of obesity. Globally, the prevalence of NAFLD averages 25% and is as common as the metabolic syndrome. The majority of patients with type 2 diabetes have NAFLD. The challenge for the diabetologist is to identify patients at risk of advanced liver disease and HCC. At a minimum, liver function tests (LFTs), despite being neither specific nor sensitive, should be performed in all patients with the metabolic syndrome or type 2 diabetes. Increases in LFTs, for which the updated reference values are lower (serum ALT ≈30 U/l in men and ≈20 U/l in women) than those hitherto used in many laboratories, should prompt assessment of fibrosis biomarkers and referral of individuals at risk to a NAFLD/hepatology clinic. Preferably, evaluation of NAFLD should be based on measurement of steatosis biomarkers or ultrasound if easily available. A large number of individuals carry the patatin-like phospholipase domain containing 3 (PNPLA3) I148M variant (30-50%) or the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant (11-15%). These variants increase the risk of advanced liver disease and HCC but not of diabetes or CVD. Genotyping of selected patients for these variants is recommended. Many patients have 'double trouble', i.e. carry both a genetic risk factor and have the metabolic syndrome. Excess use of alcohol could be a cause of 'triple trouble', but such patients would be classified as having alcoholic fatty liver disease. This review summarises a presentation given at the symposium 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1 , and by John Jones, DOI: 10.1007/s00125

  7. Omega-3 fatty acid deficiency selectively up-regulates delta6-desaturase expression and activity indices in rat liver: prevention by normalization of omega-3 fatty acid status.

    PubMed

    Hofacer, Rylon; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Magrisso, I Jack; Benoit, Stephen C; McNamara, Robert K

    2011-09-01

    This study investigated the effects of perinatal dietary omega-3 (n-3) fatty acid depletion and subsequent repletion on the expression of genes that regulate long-chain (LC) polyunsaturated fatty acid biosynthesis in rat liver and brain. It was hypothesized that chronic n-3 fatty acid deficiency would increase liver Fads1 and Fads2 messenger RNA (mRNA) expression/activity and that n-3 fatty acid repletion would normalize this response. Adult rats fed the n-3-free diet during perinatal development exhibited significantly lower erythrocyte, liver, and frontal cortex LCn-3 fatty acid composition and reciprocal elevations in LC omega-6 (n-6) fatty acid composition compared with controls (CONs) and repleted rats. Liver Fads2, but not Fads1, Elovl2, or Elovl5, mRNA expression was significantly greater in n-3-deficient (DEF) rats compared with CONs and was partially normalized in repleted rats. The liver 18:3n-6/18:2n-6 ratio, an index of delta6-desturase activity, was significantly greater in DEF rats compared with CON and repleted rats and was positively correlated with Fads2 mRNA expression among all rats. The liver 18:3n-6/18:2n-6 ratio, but not Fads2 mRNA expression, was also positively correlated with erythrocyte and frontal cortex LCn-6 fatty acid compositions. Neither Fads1 or Fads2 mRNA expression was altered in brain cortex of DEF rats. These results confirm previous findings that liver, but not brain, delta6-desaturase expression and activity indices are negatively regulated by dietary n-3 fatty acids. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Supplementing dietary sugar promotes endoplasmic reticulum stress-independent insulin resistance and fatty liver in goose.

    PubMed

    Geng, Tuoyu; Zhao, Xing; Xia, Lili; Liu, Long; Li, Fuyuan; Yang, Biao; Wang, Qianqian; Montgomery, Sean; Cui, Hengmi; Gong, Daoqing

    2016-08-05

    It is known that endoplasmic reticulum stress (ERS) contributes to insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) in mammals. However, we recently demonstrated that overfeeding with a traditional diet (mainly consisting of cooked maize) does not induce ERS in goose. As cellular studies show that high glucose and palmitate can trigger ERS in mammalian cells, we hypothesized that supplementing sugar to the traditional diet could induce ERS, thus promoting insulin resistance and fatty liver. To test the hypothesis, we first treated goose primary hepatocytes with high glucose (25 mM and 50 mM) and palmitate (0.5 mM) supplemented with or without 0.25 mM oleate. Data indicated that, as in mammalian cells, high glucose and palmitate indeed induced ERS in goose primary hepatocytes, and palmitate-induced ERS was suppressed by supplemental 0.25 mM oleate. We then tested the hypothesis with an in vivo study, in which Landes geese overfed with traditional or novel diets (i.e., the traditional diet supplemented with sugar) were compared with control geese (normally fed with cooked maize) for ERS, IR and fatty liver. The differences in glucose tolerance, insulin tolerance and postprandial blood glucose between the geese overfed with traditional and novel diets suggested that supplementing dietary sugar promoted IR. This promotion was accompanied with an increasing trend of liver weight and abdominal fat weight relative to body weight. Surprisingly, compared to overfeeding with the traditional diet, overfeeding with the novel diet did not induce ERS, even further suppressed ERS in goose fatty liver. Together, our findings suggest that supplementing dietary sugar promotes ERS-independent IR and fatty liver in goose. It is intriguing to discover the factor(s) protecting goose liver from ERS as well as the non-ERS mechanism underlying IR. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine

    PubMed Central

    Kathirvel, Elango; Morgan, Kengathevy; Nandgiri, Ganesh; Sandoval, Brian C.; Caudill, Marie A.; Bottiglieri, Teodoro; French, Samuel W.

    2010-01-01

    Nonalcoholic fatty liver (NAFL) is a common liver disease, associated with insulin resistance. Betaine has been tested as a treatment for NAFL in animal models and in small clinical trials, with mixed results. The present study aims to determine whether betaine treatment would prevent or treat NAFL in mice and to understand how betaine reverses hepatic insulin resistance. Male mice were fed a moderate high-fat diet (mHF) containing 20% of calories from fat for 7 (mHF) or 8 (mHF8) mo without betaine, with betaine (mHFB), or with betaine for the last 6 wk (mHF8B). Control mice were fed standard chow containing 9% of calories from fat for 7 mo (SF) or 8 mo (SF8). HepG2 cells were made insulin resistant and then studied with or without betaine. mHF mice had higher body weight, fasting glucose, insulin, and triglycerides and greater hepatic fat than SF mice. Betaine reduced fasting glucose, insulin, triglycerides, and hepatic fat. In the mHF8B group, betaine treatment significantly improved insulin resistance and hepatic steatosis. Hepatic betaine content significantly decreased in mHF and increased significantly in mHFB. Betaine treatment reversed the inhibition of hepatic insulin signaling in mHF and in insulin-resistant HepG2 cells, including normalization of insulin receptor substrate 1 (IRS1) phosphorylation and of downstream signaling pathways for gluconeogenesis and glycogen synthesis. Betaine treatment prevents and treats fatty liver in a moderate high-dietary-fat model of NAFL in mice. Betaine also reverses hepatic insulin resistance in part by increasing the activation of IRS1, with resultant improvement in downstream signaling pathways. PMID:20724529

  10. Neglected features of lifestyle: Their relevance in non-alcoholic fatty liver disease

    PubMed Central

    Trovato, Francesca M; Martines, Giuseppe Fabio; Brischetto, Daniela; Trovato, Guglielmo; Catalano, Daniela

    2016-01-01

    AIM To investigated in non-alcoholic-fatty-liver-disease (NAFLD), with ultrasound (US)-detected fatty liver, and in a group of non-alcoholic and otherwise healthy subjects, relationship of neglected features of lifestyle with NAFLD and obesity. METHODS Five hundred and thirty-two NAFLD and 667 non-NAFLD healthy subjects, age 21-60 years were studied. Severity of liver steatosis was assessed by US bright liver score. The adherence to mediterranean diet score (AMDS) was assessed on the basis of a 1-wk recall computerized questionnaire which included a detailed physical activity reports (Baecke questionnaire). The western dietary profile score, as a simplified paradigm of unhealthy diet, a questionnaire quantifying sun exposure score and a sleep habits questionnaires provided a further comprehensive lifestyle assessment. RESULTS Body mass index (BMI), insulin resistance (HOMA), and triglycerides, poorer adherence to a mediterranean diet profile, sedentary habits, minor sun exposure and use of “western diet” foods are greater in NAFLD. Multiple linear regression analysis, weighted by years of age, displays BMI, HOMA and AMDS as the most powerful independent predictors of fatty liver severity; however, also the physical activity score, the western diet habit and the sun exposure score are acting inside the model with significant independent effects. CONCLUSION Articulated clinical intervention, according to our results, are justified in NAFLD and can be pursued addressing by focused intervention nutritional profile, physical exercise mainly in open-air subsets for enhancing sun exposure and healthier sleep duration and rhythm. PMID:27957244

  11. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children

    PubMed Central

    Vos, Miriam B.; Abrams, Stephanie H.; Barlow, Sarah E.; Caprio, Sonia; Daniels, Stephen R.; Kohli, Rohit; Mouzaki, Marialena; Sathya, Pushpa; Schwimmer, Jeffrey B.; Sundaram, Shikha S.; Xanthakos, Stavra A.

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that occurs in the setting of insulin resistance and increased adiposity. It has rapidly evolved into the most common liver disease seen in the pediatric population and is a management challenge for general pediatric practitioners, subspecialists and for health systems. In this guideline, the expert committee on NAFLD (ECON) reviewed and summarized the available literature, formulating recommendations to guide screening and clinical care of children with NAFLD. PMID:28107283

  12. [Insulin-like growth factor-binding protein-1: a new biochemical marker of nonalcoholic fatty liver disease?].

    PubMed

    Graffigna, Mabel Nora; Belli, Susana H; de Larrañaga, Gabriela; Fainboim, Hugo; Estepo, Claudio; Peres, Silvia; García, Natalia; Levalle, Oscar

    2009-03-01

    to assess the presence of nonalcoholic fatty liver disease in patients with risk factors for this pathology (obesity, dyslipidemia, metabolic syndrome and diabetes type 2) and to determine the role of insulin, HOMA index, insulin-like growth factor-binding protein-1, sex hormone-binding globulin and plasminogen activator inhibitor type 1, as biochemical markers. Ninety-one patients with risk factors for nonalcoholic fatty liver disease were evaluated. Serum transaminases, insulin, sex hormone-binding globulin, insulin-like growth factor-binding protein-1 and plasminogen activator inhibitor type 1 were measured. The diagnosis of fatty liver was performed by ultrasonography and liver biopsies were performed to 31 subjects who had steatosis by ultrasonography and high alanine aminotransferase. Nonalcoholic fatty liver disease was present in 65 out of 91 patients (71,4%). Liver biopsy performed to 31 subjects confirmed nonalcoholic steatohepatitis. Twenty-five patients had different degrees of fibrosis. Those individuals with fatty liver had higher waist circumference, serum levels of triglycerides, insulin and HOMA index, and lower serum insulin-like growth factor-binding protein-1 concentration. The degree ofhepatic steatosis by ultrasonography was positively correlated to waist circumference, triglycerides, insulin and HOMA index (p<0,003; p<0,003; p<0,002 and p<0,001, respectively), and was negatively correlated to HDL-cholesterol and insulin-like growth factor-binding protein-1 (p<0,025 and p<0,018, respectively). We found a high prevalence of NAFLD in patients with risk factors, most of them overweight or obese. Although SHBG and PAI-1 have a closely relationship to insulin resistance, they did not show to be markers of NAFLD. Regardless of low IGFBP-1 levels associated with NAFLD, serum IGFBP-1 measure is less accessible than insulin and triglycerides levels, HOMA index and waist circumference. Moreover, it is not a better marker for NAFLD than the above

  13. Researchers discover promising new targets for treatment of fatty liver disease | Center for Cancer Research

    Cancer.gov

    Researchers have identified potential new drug targets for the prevention and treatment of non-alcoholic fatty liver disease (NAFLD). The new study, which was a collaborative effort between scientists in the Laboratory of Metabolism at CCR and Peking University, was published October 9, 2017, in Nature Medicine. Read more…

  14. Induction of CYP2E1 in non-alcoholic fatty liver diseases

    PubMed Central

    Aljomah, Ghanim; Baker, Susan S.; Liu, Wensheng; Kozielski, Rafal; Oluwole, Janet; Lupu, Benita; Baker, Robert D.; Zhu, Lixin

    2015-01-01

    Mounting evidence supports a contribution of endogenous alcohol metabolism in the pathogenesis of non-alcoholic steatohepatitis (NASH). However, it is not known whether the expression of alcohol metabolism genes is altered in the livers of simple steatosis. There is also a current debate on whether fatty acids induce CYP2E1 in fatty livers. In this study, expression of alcohol metabolizing genes in the liver biopsies of simple steatosis patients was examined by quantitative real-time PCR (qRT-PCR), in comparison to biopsies of NASH livers and normal controls. Induction of alcohol metabolizing genes was also examined in cultured HepG2 cells treated with ethanol or oleic acid, by qRT-PCR and Western blots. We found that the mRNA expression of alcohol metabolizing genes including ADH1C, ADH4, ADH6, catalase and CYP2E1 were elevated in the livers of simple steatosis, to similar levels found in NASH livers. In cultured HepG2 cells, ethanol induced the expression of CYP2E1 mRNA and protein, but not ADH4 or ADH6; oleic acid did not induce any of these genes. These results suggest that elevated alcohol metabolism may contribute to the pathogenesis of NAFLD at the stage of simple steatosis as well as more severe stages. Our in vitro data support that CYP2E1 is induced by endogenous alcohol but not by fatty acids. PMID:26551085

  15. Circulating lipocalin 2 is neither related to liver steatosis in patients with non-alcoholic fatty liver disease nor to residual liver function in cirrhosis.

    PubMed

    Meier, Elisabeth M; Pohl, Rebekka; Rein-Fischboeck, Lisa; Schacherer, Doris; Eisinger, Kristina; Wiest, Reiner; Krautbauer, Sabrina; Buechler, Christa

    2016-09-01

    Lipocalin 2 (LCN2) is induced in the injured liver and associated with inflammation. Aim of the present study was to evaluate whether serum LCN2 is a non-invasive marker to assess hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD) or residual liver function in patients with liver cirrhosis. Therefore, LCN2 was measured by ELISA in serum of 32 randomly selected patients without fatty liver (controls), 24 patients with ultrasound diagnosed NAFLD and 42 patients with liver cirrhosis mainly due to alcohol. Systemic LCN2 was comparable in patients with liver steatosis, those with liver cirrhosis and controls. LCN2 negatively correlated with bilirubin in both cohorts. In cirrhosis, LCN2 was not associated with more advanced liver injury defined by the CHILD-PUGH score and model for end-stage liver disease score. Resistin but not C-reactive protein or chemerin positively correlated with LCN2. LCN2 levels were not increased in patients with ascites or patients with esophageal varices. Consequently, reduction of portal pressure by transjugular intrahepatic portosystemic shunt did not affect LCN2 levels. Hepatic venous blood (HVS), portal venous blood and systemic venous blood levels of LCN2 were similar. HVS LCN2 was unchanged in patients with end-stage liver cirrhosis compared to those with well-compensated disease arguing against increased hepatic release. Current data exclude that serum LCN2 is of any value as steatosis marker in patients with NAFLD and indicator of liver function in patients with alcoholic liver cirrhosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Obesity, fatty liver disease and intestinal microbiota

    PubMed Central

    Arslan, Nur

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder that is increasing in prevalence with the worldwide epidemic of obesity. NAFLD is the hepatic manifestation of the metabolic syndrome. The term NAFLD describes a spectrum of liver pathology ranges from simple steatosis to steatosis with inflammation nonalcoholic steatohepatitis and even cirrhosis. Metabolic syndrome and NAFLD also predict hepatocellular carcinoma. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms are not known. Intestinal ecosystem contains trillions of microorganisms including bacteria, Archaea, yeasts and viruses. Several studies support the relationship between the intestinal microbial changes and obesity and also its complications, including insulin resistance and NAFLD. Given that the gut and liver are connected by the portal venous system, it makes the liver more vulnerable to translocation of bacteria, bacterial products, endotoxins or secreted cytokines. Altered intestinal microbiota (dysbiosis) may stimulate hepatic fat deposition through several mechanisms: regulation of gut permeability, increasing low-grade inflammation, modulation of dietary choline metabolism, regulation of bile acid metabolism and producing endogenous ethanol. Regulation of intestinal microbial ecosystem by diet modifications or by using probiotics and prebiotics as a treatment for obesity and its complications might be the issue of further investigations. PMID:25469013

  17. Polyunsaturated fatty acids balance affects platelet NOX2 activity in patients with liver cirrhosis.

    PubMed

    Basili, Stefania; Raparelli, Valeria; Napoleone, Laura; Del Ben, Maria; Merli, Manuela; Riggio, Oliviero; Nocella, Cristina; Carnevale, Roberto; Pignatelli, Pasquale; Violi, Francesco

    2014-07-01

    NADPH-oxidase-2 up-regulation has been suggested in liver damage perpetuation via an oxidative stress-mediated mechanism. n-6/n-3 polyunsaturated fatty acids ratio derangement has been reported in liver disease. To explore polyunsaturated fatty acids balance and its interplay with platelet oxidative stress in liver cirrhosis. A cross-sectional study in 51 cirrhotic patients and sex- and age-matched controls was performed. Serum polyunsaturated fatty acids and oxidative stress markers (urinary isoprostanes and serum soluble NADPH-oxidase-2-derived peptide) were measured. The effect on platelet oxidative stress of n-6/n-3 polyunsaturated fatty acids ratio in vitro and in vivo (1-week supplementation with 3g/daily n-3-polyunsaturated fatty acids) was tested. Compared to controls, cirrhotic patients had significantly higher n-6/n-3 polyunsaturated fatty acids ratio. n-6/n-3 polyunsaturated fatty acids ratio correlated significantly with disease severity and oxidative stress markers. In vitro experiments showed that in Child-Pugh C patients' platelets incubation with low n-6/n-3 polyunsaturated fatty acids ratio resulted in dose-dependent decrease of radical oxigen species (-39%), isoprostanes (-25%) and NADPH-oxidase-2 regulation (-51%). n-3 polyunsaturated fatty acids supplemented patients showed significant oxidative stress indexes reduction. In cirrhosis, n-6/n-3 polyunsaturated fatty acids imbalance up-regulates platelet NADPH-oxidase-2 with ensuing oxidative stress. Further study to evaluate if n-3 supplementation may reduce disease progression is warranted. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  18. Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance.

    PubMed

    Stål, Per

    2015-10-21

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis (stage F3) and cirrhosis (stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers (e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques (transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD.

  19. Pathogenesis of hepatic steatosis: the link between hypercortisolism and non-alcoholic fatty liver disease.

    PubMed

    Tarantino, Giovanni; Finelli, Carmine

    2013-10-28

    Based on the available literature, non alcoholic fatty liver disease or generally speaking, hepatic steatosis, is more frequent among people with diabetes and obesity, and is almost universally present amongst morbidly obese diabetic patients. Non alcoholic fatty liver disease is being increasingly recognized as a common liver condition in the developed world, with non alcoholic steatohepatitis projected to be the leading cause of liver transplantation. Previous data report that only 20% of patients with Cushing's syndrome have hepatic steatosis. Aiming at clarifying the reasons whereby patients suffering from Cushing's syndrome - a condition characterized by profound metabolic changes - present low prevalence of hepatic steatosis, the Authors reviewed the current concepts on the link between hypercortisolism and obesity/metabolic syndrome. They hypothesize that this low prevalence of fat accumulation in the liver of patients with Cushing's syndrome could result from the inhibition of the so-called low-grade chronic-inflammation, mainly mediated by Interleukin 6, due to an excess of cortisol, a hormone characterized by an anti-inflammatory effect. The Cushing's syndrome, speculatively considered as an in vivo model of the hepatic steatosis, could also help clarify the mechanisms of non alcoholic fatty liver disease.

  20. In ovo injection of betaine alleviates corticosterone-induced fatty liver in chickens through epigenetic modifications

    PubMed Central

    Hu, Yun; Sun, Qinwei; Liu, Jie; Jia, Yimin; Cai, Demin; Idriss, Abdulrahman A.; Omer, Nagmeldin A.; Zhao, Ruqian

    2017-01-01

    Betaine alleviates high-fat diet-induced fatty liver and prenatal betaine programs offspring hepatic lipid metabolism. Excessive corticosterone (CORT) exposure causes fatty liver in chickens, yet it remains unknown whether and how prenatal betaine modulates the susceptibility of CORT-induced fatty liver later in life. In this study, fertilized eggs were injected with saline or betaine before incubation, and the hatchlings were raised at 8 weeks of age followed by 7 days of subcutaneous CORT injection. CORT-induced fatty liver was less severe in betaine-treated chickens, with significantly reduced oil-red staining and hepatic triglyceride content (P < 0.05). The protective effect of prenatal betaine was associated with significantly up-regulated expression of PPARα and CPT1α, as well as mitochondrial DNA (mtDNA)-encoded genes (P < 0.05). Moreover, betaine rescued CORT-induced alterations in methionine cycle genes, which coincided with modifications of CpG methylation on CPT1α gene promoter and mtDNA D-loop regions. Furthermore, the elevation of hepatic GR protein content after CORT treatment was significantly reduced (P < 0.05), while the reduction of GR binding to the control region of affected genes was significantly increased (P < 0.05), in betaine-treated chickens. These results indicate that in ovo betaine injection protects the juvenile chickens from CORT-induced fatty liver. PMID:28059170

  1. Modeling the relationships between quality and biochemical composition of fatty liver in mule ducks.

    PubMed

    Theron, L; Cullere, M; Bouillier-Oudot, M; Manse, H; Dalle Zotte, A; Molette, C; Fernandez, X; Vitezica, Z G

    2012-09-01

    The fatty liver of mule ducks (i.e., French "foie gras") is the most valuable product in duck production systems. Its quality is measured by the technological yield, which is the opposite of the fat loss during cooking. The purpose of this study was to determine whether biochemical measures of fatty liver could be used to accurately predict the technological yield (TY). Ninety-one male mule ducks were bred, overfed, and slaughtered under commercial conditions. Fatty liver weight (FLW) and biochemical variables, such as DM, lipid (LIP), and protein content (PROT), were collected. To evaluate evidence for nonlinear fat loss during cooking, we compared regression models describing linear and nonlinear relations between biochemical measures and TY. We detected significantly greater (P = 0.02) linear relation between DM and TY. Our results indicate that LIP and PROT follow a different pattern (linear) than DM and showed that LIP and PROT are nonexclusive contributing factors to TY. Other components, such as carbohydrates, other than those measured in this study, could contribute to DM. Stepwise regression for TY was performed. The traditional model with FLW was tested. The results showed that the weight of the liver is of limited value in the determination of fat loss during cooking (R(2) = 0.14). The most accurate TY prediction equation included DM (in linear and quadratic terms), FLW, and PROT (R(2) = 0.43). Biochemical measures in the fatty liver were more accurate predictors of TY than FLW. The model is useful in commercial conditions because DM, PROT, and FLW are noninvasive measures.

  2. Gut-Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease.

    PubMed

    Poeta, Marco; Pierri, Luca; Vajro, Pietro

    2017-08-02

    Non-alcoholic fatty liver disease (NAFLD) is the most frequent type of chronic liver disease in the pediatric age group, paralleling an obesity pandemic. A "multiple-hit" hypothesis has been invoked to explain its pathogenesis. The "first hit" is liver lipid accumulation in obese children with insulin resistance. In the absence of significant lifestyle modifications leading to weight loss and increased physical activity, other factors may act as "second hits" implicated in liver damage progression leading to more severe forms of inflammation and hepatic fibrosis. In this regard, the gut-liver axis (GLA) seems to play a central role. Principal players are the gut microbiota, its bacterial products, and the intestinal barrier. A derangement of GLA (namely, dysbiosis and altered intestinal permeability) may promote bacteria/bacterial product translocation into portal circulation, activation of inflammation via toll-like receptors signaling in hepatocytes, and progression from simple steatosis to non-alcoholic steato-hepatitis (NASH). Among other factors a relevant role has been attributed to the farnesoid X receptor, a nuclear transcriptional factor activated from bile acids chemically modified by gut microbiota (GM) enzymes. The individuation and elucidation of GLA derangement in NAFLD pathomechanisms is of interest at all ages and especially in pediatrics to identify new therapeutic approaches in patients recalcitrant to lifestyle changes. Specific targeting of gut microbiota via pre-/probiotic supplementation, feces transplantation, and farnesoid X receptor modulation appear promising.

  3. Cytoprotective Mechanisms in Fatty Liver Preservation against Cold Ischemia Injury: A Comparison between IGL-1 and HTK

    PubMed Central

    Panisello-Roselló, Arnau; Verde, Eva; Flores, Marta; Folch-Puy, Emma; Rolo, Anabela; Palmeira, Carlos; Hotter, Georgina; Adam, René; Roselló-Catafau, Joan

    2018-01-01

    Institute Goeorges Lopez 1 (IGL-1) and Histidine-Tryptophan-Ketoglutarate (HTK) preservation solutions are regularly used in clinical for liver transplantation besides University of Wisconsin (UW) solution and Celsior. Several clinical trials and experimental works have been carried out comparing all the solutions, however the comparative IGL-1 and HTK appraisals are poor; especially when they deal with the underlying protection mechanisms of the fatty liver graft during cold storage. Fatty livers from male obese Zücker rats were conserved for 24 h at 4 °C in IGL-1 or HTK preservation solutions. After organ recovery and rinsing of fatty liver grafts with Ringer Lactate solution, we measured the changes in mechanistic target of rapamycin (mTOR) signaling activation, liver autophagy markers (Beclin-1, Beclin-2, LC3B and ATG7) and apoptotic markers (caspase 3, caspase 9 and TUNEL). These determinations were correlated with the prevention of liver injury (aspartate and alanine aminostransferase (AST/ALT), histology) and mitochondrial damage (glutamate dehydrogenase (GLDH) and confocal microscopy findings). Liver grafts preserved in IGL-1 solution showed a marked reduction on p-TOR/mTOR ratio when compared to HTK. This was concomitant with significant increased cyto-protective autophagy and prevention of liver apoptosis, including inflammatory cytokines such as HMGB1. Together, our results revealed that IGL-1 preservation solution better protected fatty liver grafts against cold ischemia damage than HTK solution. IGL-1 protection was associated with a reduced liver damage, higher induced autophagy and decreased apoptosis. All these effects would contribute to limit the subsequent extension of reperfusion injury after graft revascularization in liver transplantation procedures. PMID:29364854

  4. Inhibition of Dexamethasone-induced Fatty Liver Development by Reducing miR-17-5p Levels

    PubMed Central

    Du, William W; Liu, Fengqiong; Shan, Sze Wan; Ma, Xindi Cindy; Gupta, Shaan; Jin, Tianru; Spaner, David; Krylov, Sergey N; Zhang, Yaou; Ling, Wenhua; Yang, Burton B

    2015-01-01

    Steatosis is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD) which can be driven by peroxisome proliferator-activated receptor-α (PPAR-α) dysregulation. Through examining the effect of PPAR-α on fatty liver development, we found that PPAR-α is a target of miR-17-5p. Transgenic mice expressing miR-17 developed fatty liver and produced higher levels of triglyceride and cholesterol but lower levels of PPAR-α. Ectopic expression of miR-17 enhanced cellular steatosis. Gain-of-function and loss-of-function experiments confirmed PPAR-α as a target of miR-17-5p. On the other hand, PPAR-α bound to the promoter of miR-17 and promoted its expression. The feed-back loop between miR-17-5p and PPAR-α played a key role in the induction of steatosis and fatty liver development. Mice with high levels of miR-17-5p were sensitive to Dexamethasone-induced fatty liver formation. Inhibition of miR-17-5p suppressed this process and enhanced PPAR-α expression in mice treated with Dexamethasone. Clofibrate, Ciprofibrate, and WY-14643: three agents used for treatment of metabolic disorders, were found to promote PPAR-α expression while decreasing miR-17-5p levels and inhibiting steatosis. Our studies show that miR-17-5p inhibitor and agents used in metabolic disorders may be applied in combination with Dexamethasone in the treatment of anti-inflammation, immunosuppression, and cancer patients. PMID:25896250

  5. Non-alcoholic fatty liver disease is associated with high prevalence of gastro-oesophageal reflux symptoms.

    PubMed

    Miele, Luca; Cammarota, Giovanni; Vero, Vittoria; Racco, Simona; Cefalo, Consuelo; Marrone, Giuseppe; Pompili, Maurizio; Rapaccini, Gianlodovico; Bianco, Alessandro; Landolfi, Raffaele; Gasbarrini, Antonio; Grieco, Antonio

    2012-12-01

    Gastro-oesophageal reflux symptoms are usually reported by patients with obesity and metabolic syndrome. Aim of this study was to assess the prevalence and clinical characteristics of gastro-oesophageal reflux symptoms in subjects with non-alcoholic fatty liver disease. Cross-sectional, case-control study of 185 consecutive patients with non-alcoholic fatty liver disease and an age- and sex-matched control group of 112 healthy volunteers. Participants were interviewed with the aid of a previously validated questionnaire to assess lifestyle and reflux symptoms in the 3 months preceding enrolment. Odds ratios were determined before and after adjustment for body mass index, increased waist circumference, physical activity, metabolic syndrome and proton pump inhibitors and/or antiacid medication. The prevalence of heartburn and/or regurgitation and of at least one of gastro-oesophageal reflux symptoms was significantly higher in the non-alcoholic fatty liver disease group. Non-alcoholic fatty liver disease subjects were associated to higher prevalence of heartburn (adjusted odds ratios: 2.17, 95% confidence intervals: 1.16-4.04), regurgitation (adjusted odds ratios: 2.61, 95% confidence intervals: 1.24-5.48) and belching (adjusted odds ratios: 2.01, 95% confidence intervals: 1.12-3.59) and had higher prevalence of at least one GER symptom (adjusted odds ratios: 3.34, 95% confidence intervals: 1.76-6.36). Non-alcoholic fatty liver disease is associated with a higher prevalence of gastro-oesophageal reflux symptoms. Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  6. Ischemic Preconditioning Increases the Tolerance of Fatty Liver to Hepatic Ischemia-Reperfusion Injury in the Rat

    PubMed Central

    Serafín, Anna; Roselló-Catafau, Joan; Prats, Neus; Xaus, Carme; Gelpí, Emilio; Peralta, Carmen

    2002-01-01

    Hepatic steatosis is a major risk factor in ischemia-reperfusion. The present study evaluates whether preconditioning, demonstrated to be effective in normal livers, could also confer protection in the presence of steatosis and investigates the potential underlying protective mechanisms. Fatty rats had increased hepatic injury and decreased survival after 60 minutes of ischemia compared with lean rats. Fatty livers showed a degree of neutrophil accumulation and microcirculatory alterations similar to that of normal livers. However, in presence of steatosis, an increased lipid peroxidation that could be reduced with glutathione-ester pretreatment was observed after hepatic reperfusion. Ischemic preconditioning reduced hepatic injury and increased animal survival. Both in normal and fatty livers, this endogenous protective mechanism was found to control lipid peroxidation, hepatic microcirculation failure, and neutrophil accumulation, reducing the subsequent hepatic injury. These beneficial effects could be mediated by nitric oxide, because the inhibition of nitric oxide synthesis and nitric oxide donor pretreatment abolished and simulated, respectively, the benefits of preconditioning. Thus, ischemic preconditioning could be an effective surgical strategy to reduce the hepatic ischemia-reperfusion injury in normal and fatty livers under normothermic conditions, including hepatic resections, and liver transplantation. PMID:12163383

  7. Mediterranean diet and nonalcoholic fatty liver disease.

    PubMed

    Anania, Caterina; Perla, Francesco Massimo; Olivero, Francesca; Pacifico, Lucia; Chiesa, Claudio

    2018-05-21

    Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease, and is characterized by a wide spectrum of fat-liver disorders that can result in severe liver disease and cirrhosis. Inflammation and oxidative stress are the major risk factors involved in the pathogenesis of NAFLD. Currently, there is no consensus concerning the pharmacological treatment of NAFLD. However, lifestyle interventions based on exercise and a balanced diet for quality and quantity, are considered the cornerstone of NAFLD management. Mediterranean diet (MD), rich in polyunsaturated fats, polyphenols, vitamins and carotenoids, with their anti-inflammatory and anti-oxidant effects, has been suggested to be effective in preventing cardiovascular risk factors. In adults, MD has also been demonstrated to be efficacious in reducing the risk of metabolic syndrome. However, few studies are available on the effects of the MD in both adult and pediatric subjects with NAFLD. Thus, the aims of the present narrative review are to analyze the current clinical evidence on the impact of MD in patients with NAFLD, and to summarize the main mechanisms of action of MD components on this condition.

  8. Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease.

    PubMed

    Derdak, Zoltan; Villegas, Kristine A; Harb, Ragheb; Wu, Annie M; Sousa, Aryanna; Wands, Jack R

    2013-04-01

    p53 and its transcriptional target miRNA34a have been implicated in the pathogenesis of fatty liver. We tested the efficacy of a p53 inhibitor, pifithrin-α p-nitro (PFT) in attenuating steatosis, associated oxidative stress and apoptosis in a murine model of non-alcoholic fatty liver disease (NAFLD). C57BL/6 mice were fed a high-fat (HFD) or control diet for 8 weeks; PFT or DMSO (vehicle) was administered three times per week. Markers of oxidative stress and apoptosis as well as mediators of hepatic fatty acid metabolism were assessed by immunohistochemistry, Western blot, real-time PCR, and biochemical assays. PFT administration suppressed HFD-induced weight gain, ALT elevation, steatosis, oxidative stress, and apoptosis. PFT treatment blunted the HFD-induced upregulation of miRNA34a and increased SIRT1 expression. In the livers of HFD-fed, PFT-treated mice, activation of the SIRT1/PGC1α/PPARα axis increased the expression of malonyl-CoA decarboxylase (MLYCD), an enzyme responsible for malonyl-CoA (mCoA) degradation. Additionally, the SIRT1/LKB1/AMPK pathway (upstream activator of MLYCD) was promoted by PFT. Thus, induction of these two pathways by PFT diminished the hepatic mCoA content by enhancing MLYCD expression and function. Since mCoA inhibits carnitine palmitoyltransferase 1 (CPT1), the decrease of hepatic mCoA in the PFT-treated, HFD-fed mice increased CPT1 activity, favored fatty acid oxidation, and decreased steatosis. Additionally, we demonstrated that PFT abrogated steatosis and promoted MLYCD expression in palmitoleic acid-treated human HepaRG cells. The p53 inhibitor PFT diminished hepatic triglyceride accumulation and lipotoxicity in mice fed a HFD, by depleting mCoA and favoring the β-oxidation of fatty acids. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  9. A comprehensive review of noninvasive liver fibrosis tests in pediatric nonalcoholic Fatty liver disease.

    PubMed

    Mansoor, Sana; Collyer, Elizabeth; Alkhouri, Naim

    2015-06-01

    Nonalcoholic fatty liver disease (NAFLD) and its spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis have been increasing in the pediatric population. The presence and severity of fibrosis in patients with NAFLD are important prognostic factors for the risk of disease progression to cirrhosis. The gold standard for staging liver fibrosis is a liver biopsy. However, given the risks of this procedure, especially in the pediatric population, the development of noninvasive markers to diagnose and monitor progression of NAFLD is desirable. This paper will review recently developed noninvasive methods for diagnosing liver fibrosis in children with NAFLD. These include simple fibrosis scores, advanced biochemical markers, and radiologic imaging studies. Simple fibrosis scores use readily available laboratory tests; available one include AST/ALT ratio, AST to platelet ratio index (APRI), fibrosis (FIB)-4 index, NAFLD fibrosis score (NFS), pediatric NAFLD fibrosis index (PNFI), and pediatric NALFD fibrosis score (PNFS). Advanced biochemical markers include biomarkers of hepatocyte cell death such as cytokeratin 18 fragment levels, and markers of extracellular matrix turnover such as the Enhanced Liver Fibrosis (ELF) test and hyaluronic acid. Radiologic imaging studies estimate liver stiffness as a surrogate for liver fibrosis; these include transient elastography (TE), magnetic resonance elastography (MRE), and acoustic radiation force impulse imaging (ARFI).

  10. Nonalcoholic fatty liver disease, association with cardiovascular disease and treatment. (I). Nonalcoholic fatty liver disease and its association with cardiovascular disease.

    PubMed

    Brea, Ángel; Pintó, Xavier; Ascaso, Juan F; Blasco, Mariano; Díaz, Ángel; González-Santos, Pedro; Hernández Mijares, Antonio; Mantilla, Teresa; Millán, Jesús; Pedro-Botet, Juan

    Non-alcoholic fatty liver disease (NAFLD) comprises a series of histologically lesions similar to those induced by alcohol consumption in people with very little or no liver damage. The importance of NAFLD is its high prevalence in the Western world and, from the point of view of the liver, in its gradual progression from steatosis to steatohepatitis, cirrhosis, and liver cancer. During the last decade it has been observed that NAFLD leads to an increased cardiovascular risk with acceleration of arteriosclerosis and events related to it, being the main cause of its morbidity and mortality. This review, updated to January 2016, consists of two parts, with the first part analysing the association of NAFLD with cardiovascular disease. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. Th17 involvement in nonalcoholic fatty liver disease progression to non-alcoholic steatohepatitis.

    PubMed

    Chackelevicius, Carla Melisa; Gambaro, Sabrina Eliana; Tiribelli, Claudio; Rosso, Natalia

    2016-11-07

    The nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a wide histological spectrum ranging from benign simple steatosis to non-alcoholic steatohepatitis (NASH). Sustained inflammation in the liver is critical in this process. Hepatic macrophages, including liver resident macropaghes (Kupffer cells), monocytes infiltrating the injured liver, as well as specific lymphocytes subsets play a pivotal role in the initiation and perpetuation of the inflammatory response, with a major deleterious impact on the progression of fatty liver to fibrosis. During the last years, Th17 cells have been involved in the development of inflammation not only in liver but also in other organs, such as adipose tissue or lung. Differentiation of a naïve T cell into a Th17 cell leads to pro-inflammatory cytokine and chemokine production with subsequent myeloid cell recruitment to the inflamed tissue. Th17 response can be mitigated by T regulatory cells that secrete anti-inflammatory cytokines. Both T cell subsets need TGF-β for their differentiation and a characteristic plasticity in their phenotype may render them new therapeutic targets. In this review, we discuss the role of the Th17 pathway in NAFLD progression to NASH and to liver fibrosis analyzing different animal models of liver injury and human studies.

  12. Relationship between hepatocellular carcinoma, metabolic syndrome and non-alcoholic fatty liver disease: which clinical arguments?

    PubMed

    Rosmorduc, Olivier

    2013-05-01

    Obesity and the metabolic syndrome are growing epidemics associated with an increased risk for many types of cancer. In the liver, inflammatory and angiogenic changes due to insulin resistance and fatty liver disease are associated with an increased incidence of liver cancer. Regardless of underlying liver disease, cirrhosis remains the most important risk factor for hepatocellular carcinoma (HCC) although are cases of HCC arising without cirrhosis raise the possibility of a direct carcinogenesis secondary to Non-alcoholic Fatty Liver Disease (NAFLD). Moreover, metabolic syndrome and its different features may also increase the risk of HCC in the setting of chronic liver diseases of other causes such as viral hepatitis or alcohol abuse. Taking into account all these data, it is necessary to better determine the risk of developing HCC in patients with metabolic syndrome to improve the screening guidelines and develop prophylactic treatments in this setting. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  13. Liver Fatty Acid Composition and Inflammation in Mice Fed with High-Carbohydrate Diet or High-Fat Diet.

    PubMed

    da Silva-Santi, Lorena Gimenez; Antunes, Marina Masetto; Caparroz-Assef, Silvana Martins; Carbonera, Fabiana; Masi, Laureane Nunes; Curi, Rui; Visentainer, Jesuí Vergílio; Bazotte, Roberto Barbosa

    2016-10-29

    Both high-carbohydrate diet (HCD) and high-fat diet (HFD) modulate liver fat accumulation and inflammation, however, there is a lack of data on the potential contribution of carbohydrates and lipids separately. For this reason, the changes in liver fatty acid (FA) composition in male Swiss mice fed with HCD or HFD were compared, at the time points 0 (before starting the diets), and after 7, 14, 28 or 56 days. Activities of stearoyl-CoA desaturase-1 (SCD-1), ∆-6 desaturase (D6D), elongases and de novo lipogenesis (DNL) were estimated. Liver mRNA expression of acetyl-CoA carboxylase 1 (ACC1) was evaluated as an additional indicator of the de novo lipogenesis. Myeloperoxidase activity, nitric oxide (NO) production, and mRNA expressions of F4/80, type I collagen, interleukin (IL)-6, IL-1β, IL-10, and tumor necrosis factor-α (TNF-α) were measured as indication of the liver inflammatory state. The HCD group had more intense lipid deposition, particularly of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). This group also showed higher DNL, SCD-1, and D6D activities associated with increased NO concentration, as well as myeloperoxidase activity. Livers from the HFD group showed higher elongase activity, stored more polyunsaturated fatty acids (PUFAs) and had a lower omega-6/omega-3 fatty acid ( n -6/ n -3) ratio. In conclusion, liver lipid accumulation, fatty acids (FA) composition and inflammation were modulated by the dietary composition of lipids and carbohydrates. The HCD group had more potent lipogenic and inflammatory effects in comparison with HFD.

  14. Circulating Extracellular Vesicles with Specific Proteome and Liver MicroRNAs Are Potential Biomarkers for Liver Injury in Experimental Fatty Liver Disease

    PubMed Central

    Povero, Davide; Eguchi, Akiko; Li, Hongying; Johnson, Casey D.; Papouchado, Bettina G.; Wree, Alexander; Messer, Karen; Feldstein, Ariel E.

    2014-01-01

    Background & Aim Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in both adult and children. Currently there are no reliable methods to determine disease severity, monitor disease progression, or efficacy of therapy, other than an invasive liver biopsy. Design Choline Deficient L-Amino Acid (CDAA) and high fat diets were used as physiologically relevant mouse models of NAFLD. Circulating extracellular vesicles were isolated, fully characterized by proteomics and molecular analyses and compared to control groups. Liver-related microRNAs were isolated from purified extracellular vesicles and liver specimens. Results We observed statistically significant differences in the level of extracellular vesicles (EVs) in liver and blood between two control groups and NAFLD animals. Time-course studies showed that EV levels increase early during disease development and reflect changes in liver histolopathology. EV levels correlated with hepatocyte cell death (r2 = 0.64, p<0.05), fibrosis (r2 = 0.66, p<0.05) and pathological angiogenesis (r2 = 0.71, p<0.05). Extensive characterization of blood EVs identified both microparticles (MPs) and exosomes (EXO) present in blood of NAFLD animals. Proteomic analysis of blood EVs detected various differentially expressed proteins in NAFLD versus control animals. Moreover, unsupervised hierarchical clustering identified a signature that allowed for discrimination between NAFLD and controls. Finally, the liver appears to be an important source of circulating EVs in NAFLD animals as evidenced by the enrichment in blood with miR-122 and 192 - two microRNAs previously described in chronic liver diseases, coupled with a corresponding decrease in expression of these microRNAs in the liver. Conclusions These findings suggest a potential for using specific circulating EVs as sensitive and specific biomarkers for the noninvasive diagnosis and monitoring of NAFLD. PMID:25470250

  15. Mechanism of impaired regeneration of fatty liver in mouse partial hepatectomy model.

    PubMed

    Murata, Hiroshi; Yagi, Takahito; Iwagaki, Hiromi; Ogino, Tetsuya; Sadamori, Hiroshi; Matsukawa, Hiroyoshi; Umeda, Yuzoh; Haga, Sanae; Takaka, Noriaki; Ozaki, Michitaka

    2007-12-01

    The mechanism of injury in steatotic liver under pathological conditions been extensively examined. However, the mechanism of an impaired regeneration is still not well understood. The aim of this study was to analyze the mechanism of impaired regeneration of steatotic liver after partial hepatectomy (PH). db/db fatty mice and lean littermates were used for the experiments. Following 70% PH, the survival rate and recovery of liver mass were examined. Liver tissue was histologically examined and analyzed by western blotting and RT-PCR. Of 35 db/db mice, 25 died within 48 h of PH, while all of the control mice survived. Liver regeneration of surviving db/db mice was largely impaired. In db/db mice, mitosis of hepatocytes after PH was disturbed, even though proliferating cell nuclear antigen (PCNA) expression (G1 to S phase marker) in hepatocytes was equally observed in both mice groups. Interestingly, phosphorylation of Cdc2 in db/db mice was suppressed by reduced expression of Wee1 and Myt1, which phosphorylate Cdc2 in S to G2 phase. In steatotic liver, cell-cycle-related proliferative disorders occurred at mid-S phase after PCNA expression. Reduced expression of Wee1 and Myt1 kinases may therefore maintain Cdc2 in an unphosphorylated state and block cell cycle progression in mid-S phase. These kinases may be critical factors involved in the impaired liver regeneration in fatty liver.

  16. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

    PubMed Central

    Gentric, Géraldine; Maillet, Vanessa; Paradis, Valérie; Couton, Dominique; L’Hermitte, Antoine; Panasyuk, Ganna; Fromenty, Bernard; Celton-Morizur, Séverine; Desdouets, Chantal

    2015-01-01

    Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development. PMID:25621497

  17. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease.

    PubMed

    Gentric, Géraldine; Maillet, Vanessa; Paradis, Valérie; Couton, Dominique; L'Hermitte, Antoine; Panasyuk, Ganna; Fromenty, Bernard; Celton-Morizur, Séverine; Desdouets, Chantal

    2015-03-02

    Polyploidization is one of the most dramatic changes that can occur in the genome. In the liver, physiological polyploidization events occur during both liver development and throughout adult life. Here, we determined that a pathological polyploidization takes place in nonalcoholic fatty liver disease (NAFLD), a widespread hepatic metabolic disorder that is believed to be a risk factor for hepatocellular carcinoma (HCC). In murine models of NAFLD, the parenchyma of fatty livers displayed alterations of the polyploidization process, including the presence of a large proportion of highly polyploid mononuclear cells, which are rarely observed in normal hepatic parenchyma. Biopsies from patients with nonalcoholic steatohepatitis (NASH) revealed the presence of alterations in hepatocyte ploidy compared with tissue from control individuals. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient. This alteration was associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. Furthermore, we determined that oxidative stress promotes the appearance of highly polyploid cells, and antioxidant-treated NAFLD hepatocytes resumed normal cell division and returned to a physiological state of polyploidy. Collectively, these findings indicate that oxidative stress promotes pathological polyploidization and suggest that this is an early event in NAFLD that may contribute to HCC development.

  18. Liver fibrosis in non-alcoholic fatty liver disease - diagnostic challenge with prognostic significance

    PubMed Central

    Stål, Per

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, with a prevalence of 20%. In a subgroup of patients, inflammation, ballooning degeneration of hepatocytes and a varying degree of fibrosis may develop, a condition named non-alcoholic steatohepatitis. Advanced liver fibrosis (stage F3) and cirrhosis (stage F4) are histologic features that most accurately predict increased mortality in both liver-related and cardiovascular diseases. Patients with advanced fibrosis or cirrhosis are at risk for complications such as hepatocellular carcinoma and esophageal varices and should therefore be included in surveillance programs. However, liver disease and fibrosis are often unrecognized in patients with NAFLD, possibly leading to a delayed diagnosis of complications. The early diagnosis of advanced fibrosis in NAFLD is therefore crucial, and it can be accomplished using serum biomarkers (e.g., the NAFLD Fibrosis Score, Fib-4 Index or BARD) or non-invasive imaging techniques (transient elastography or acoustic radiation force impulse imaging). The screening of risk groups, such as patients with obesity and/or type 2 diabetes mellitus, for NAFLD development with these non-invasive methods may detect advanced fibrosis at an early stage. Additionally, patients with a low risk for advanced fibrosis can be identified, and the need for liver biopsies can be minimized. This review focuses on the diagnostic challenge and prognostic impact of advanced liver fibrosis in NAFLD. PMID:26494963

  19. Fructose consumption as a risk factor for non-alcoholic fatty liver disease.

    PubMed

    Ouyang, Xiaosen; Cirillo, Pietro; Sautin, Yuri; McCall, Shannon; Bruchette, James L; Diehl, Anna Mae; Johnson, Richard J; Abdelmalek, Manal F

    2008-06-01

    While the rise in non-alcoholic fatty liver disease (NAFLD) parallels the increase in obesity and diabetes, a significant increase in dietary fructose consumption in industrialized countries has also occurred. The increased consumption of high fructose corn syrup, primarily in the form of soft drinks, is linked with complications of the insulin resistance syndrome. Furthermore, the hepatic metabolism of fructose favors de novo lipogenesis and ATP depletion. We hypothesize that increased fructose consumption contributes to the development of NAFLD. A dietary history and paired serum and liver tissue were obtained from patients with evidence of biopsy-proven NAFLD (n=49) without cirrhosis and controls (n=24) matched for gender, age (+/-5 years), and body mass index (+/-3 points). Consumption of fructose in patients with NAFLD was nearly 2- to 3-fold higher than controls [365 kcal vs 170 kcal (p<0.05)]. In patients with NAFLD (n=6), hepatic mRNA expression of fructokinase (KHK), an important enzyme for fructose metabolism, and fatty acid synthase, an important enzyme for lipogenesis were increased (p=0.04 and p=0.02, respectively). In an AML hepatocyte cell line, fructose resulted in dose-dependent increase in KHK protein and activity. The pathogenic mechanism underlying the development of NAFLD may be associated with excessive dietary fructose consumption.

  20. Effect of orlistat on periostin, adiponectin, inflammatory markers and ultrasound grades of fatty liver in obese NAFLD patients.

    PubMed

    Ali Khan, Rashid; Kapur, Prem; Jain, Abhinav; Farah, Farrukh; Bhandari, Uma

    2017-01-01

    Orlistat is recommended in the treatment of obesity, which is an independent risk factor for nonalcoholic fatty liver disease (NAFLD). The reported findings of orlistat in NAFLD are divisive. Recently, periostin is identified as an important regulatory molecule in the pathogenesis of obesity-induced fatty liver. Therefore, this study aimed to evaluate the potential effects of orlistat in the treatment of NAFLD. A 16-week prospective observational study was conducted, with obese NAFLD patient (n=77) receiving orlistat (120 mg capsules, three times a day) with hypocaloric diet or hypocaloric diet only. Grades of fatty liver were determined using ultrasound (US) echogenicity of liver; serum levels of periostin, adiponectin, tumor necrosis factor (TNF)-α and interleukin-6 were determined using ELISA kits at 0 and 16 weeks. Correlations of US grades of fatty liver with these biomarkers were also determined. Orlistat significantly reversed the US grades of fatty liver ( P =0.016), decreased serum levels of periostin ( P =0.030) and TNF-α ( P =0.040), and increased serum adiponectin levels ( P <0.001) when compared with hypocaloric diet only. Serum interleukin-6 levels were not found to be significantly different in both groups after the treatment. In the orlistat group, the degree of reduction in grades of fatty liver was found to be positively correlated with the changes in serum levels of periostin (r s =0.306, P =0.041) and adiponectin (r s =0.314, P =0.036), whereas the associations were insignificant with the change in serum levels of TNF-α (r s =0.053, P =0.729). Mild gastrointestinal side effects (20%) were reported in the orlistat group. In conclusion, orlistat is effective in the treatment of NAFLD patients without fibrosis. This study demonstrated a positive association between the reduction of fatty infiltration in the liver and the changes in serum levels of periostin and adiponectin in obese NAFLD patients.

  1. Effect of orlistat on periostin, adiponectin, inflammatory markers and ultrasound grades of fatty liver in obese NAFLD patients

    PubMed Central

    Ali Khan, Rashid; Kapur, Prem; Jain, Abhinav; Farah, Farrukh; Bhandari, Uma

    2017-01-01

    Orlistat is recommended in the treatment of obesity, which is an independent risk factor for nonalcoholic fatty liver disease (NAFLD). The reported findings of orlistat in NAFLD are divisive. Recently, periostin is identified as an important regulatory molecule in the pathogenesis of obesity-induced fatty liver. Therefore, this study aimed to evaluate the potential effects of orlistat in the treatment of NAFLD. A 16-week prospective observational study was conducted, with obese NAFLD patient (n=77) receiving orlistat (120 mg capsules, three times a day) with hypocaloric diet or hypocaloric diet only. Grades of fatty liver were determined using ultrasound (US) echogenicity of liver; serum levels of periostin, adiponectin, tumor necrosis factor (TNF)-α and interleukin-6 were determined using ELISA kits at 0 and 16 weeks. Correlations of US grades of fatty liver with these biomarkers were also determined. Orlistat significantly reversed the US grades of fatty liver (P=0.016), decreased serum levels of periostin (P=0.030) and TNF-α (P=0.040), and increased serum adiponectin levels (P<0.001) when compared with hypocaloric diet only. Serum interleukin-6 levels were not found to be significantly different in both groups after the treatment. In the orlistat group, the degree of reduction in grades of fatty liver was found to be positively correlated with the changes in serum levels of periostin (rs=0.306, P=0.041) and adiponectin (rs=0.314, P=0.036), whereas the associations were insignificant with the change in serum levels of TNF-α (rs=0.053, P=0.729). Mild gastrointestinal side effects (20%) were reported in the orlistat group. In conclusion, orlistat is effective in the treatment of NAFLD patients without fibrosis. This study demonstrated a positive association between the reduction of fatty infiltration in the liver and the changes in serum levels of periostin and adiponectin in obese NAFLD patients. PMID:28260907

  2. Nonalcoholic fatty liver disease: diagnosis, pathogenesis, and management.

    PubMed

    Başaranoğlu, Metin; Örmeci, Necati

    2014-04-01

    Nonalcoholic fatty liver disease (NAFLD) is an umbrella term that covers both a relatively benign condition, which is simple steatosis, and nonalcoholic steatohepatitis (NASH). NASH is characterized by a chronic and progressive liver pathology that may progress to cirrhosis, end-stage liver disease, hepatocellular carcinoma, and liver transplantation. Despite the growing body of evidence, one of the important and unresolved problems is the pathogenesis of NASH. It might be a metabolic disturbance as a primary abnormality in NAFLD. Insulin resistance is at the center of these metabolic abnormalities. Then, hepatocyte injury might be induced by oxidative stress. This ongoing process progresses to NASH, even to cirrhosis in some patients. In addition to oxidative stress, possibilities for the next hit are lipid peroxidation, reactive metabolites, adipose tissue products, transforming growth factor-β₁, Fas ligand, mitochondrial dysfunction, respiratory chain deficiency, and intestinal microbiota. Currently, there is no well-established and approved therapy. Recommendations are to improve existing co-morbidities, such as obesity, hyperlipidemia, or type 2 diabetes, and lifestyle modification with weight loss and exercise.

  3. Dietary fructose in nonalcoholic fatty liver disease.

    PubMed

    Vos, Miriam B; Lavine, Joel E

    2013-06-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in adults and children. A number of genetic and environmental factors are known to predispose individuals to NAFLD. Certain dietary sugars, particularly fructose, are suspected to contribute to the development of NAFLD and its progression. The increasing quantity of fructose in the diet comes from sugar additives (most commonly sucrose and high fructose corn syrup) in beverages and processed foods. Substantial links have been demonstrated between increased fructose consumption and obesity, dyslipidemia, and insulin resistance. Growing evidence suggests that fructose contributes to the development and severity of NAFLD. In human studies, fructose is associated with increasing hepatic fat, inflammation, and possibly fibrosis. Whether fructose alone can cause NAFLD or if it serves only as a contributor when consumed excessively in the setting of insulin resistance, positive energy balance, and sedentary lifestyle is unknown. Sufficient evidence exists to support clinical recommendations that fructose intake be limited through decreasing foods and drinks high in added (fructose-containing) sugars. Copyright © 2013 American Association for the Study of Liver Diseases.

  4. Fenofibrate, but not ezetimibe, prevents fatty liver disease in mice lacking phosphatidylethanolamine N-methyltransferase.

    PubMed

    van der Veen, Jelske N; Lingrell, Susanne; Gao, Xia; Takawale, Abhijit; Kassiri, Zamaneh; Vance, Dennis E; Jacobs, René L

    2017-04-01

    Mice lacking phosphatidylethanolamine N -methyltransferase (PEMT) are protected from high-fat diet (HFD)-induced obesity and insulin resistance. However, these mice develop severe nonalcoholic fatty liver disease (NAFLD) when fed the HFD, which is mainly due to inadequate secretion of VLDL particles. Our aim was to prevent NAFLD development in mice lacking PEMT. We treated Pemt -/- mice with either ezetimibe or fenofibrate to see if either could ameliorate liver disease in these mice. Ezetimibe treatment did not reduce fat accumulation in Pemt -/- livers, nor did it reduce markers for hepatic inflammation or fibrosis. Fenofibrate, conversely, completely prevented the development of NAFLD in Pemt -/- mice: hepatic lipid levels, as well as markers of endoplasmic reticulum stress, inflammation, and fibrosis, in fenofibrate-treated Pemt -/- mice were similar to those in Pemt +/+ mice. Importantly, Pemt -/- mice were still protected against HFD-induced obesity and insulin resistance. Moreover, fenofibrate partially reversed hepatic steatosis and fibrosis in Pemt -/- mice when treatment was initiated after NAFLD had already been established. Increasing hepatic fatty acid oxidation can compensate for the lower VLDL-triacylglycerol secretion rate and prevent/reverse fatty liver disease in mice lacking PEMT. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  5. Nonalcoholic fatty liver in patients with Laron syndrome and GH gene deletion - preliminary report.

    PubMed

    Laron, Zvi; Ginsberg, Shira; Webb, Muriel

    2008-10-01

    There is little information on the relationship between growth hormone/insulin-like growth factor-I (GH/IGF-I) deficiency or IGF-I treatment on nonalcoholic fatty liver disease (NAFLD) a disorder linked to obesity and insulin resistance. To find out whether the markedly obese patients with Laron syndrome (LS) and GH gene deletion have fatty livers. We studied 11 untreated adult patients with LS (5M, 6F), five girls with LS treated by IGF-I and five adult patients with GH gene deletion (3M, 3F), four previously treated by hGH in childhood. Fatty liver was quantitatively evaluated by ultrasonography using a phase array US system (HITACHI 6500, Japan). Body adiposity was determined by DEXA, and insulin resistance was estimated by HOMA-IR using the fasting serum glucose and insulin values. Six out of 11 adult patients with LS, two out of the five IGF-I treated girls with LS and three out of five adult hGH gene deletion patients were found to have NAFLD (nonalcoholic fatty liver disease). NAFLD is a frequent complication in untreated and treated congenital IGF-I deficiency. No correlation between NAFLD and age, sex, degree of obesity, blood lipids, or degree of insulin resistance was observed.

  6. Structural and functional interaction of fatty acids with human liver fatty acid-binding protein (L-FABP) T94A variant.

    PubMed

    Huang, Huan; McIntosh, Avery L; Martin, Gregory G; Landrock, Kerstin K; Landrock, Danilo; Gupta, Shipra; Atshaves, Barbara P; Kier, Ann B; Schroeder, Friedhelm

    2014-05-01

    The human liver fatty acid-binding protein (L-FABP) T94A variant, the most common in the FABP family, has been associated with elevated liver triglyceride levels. How this amino acid substitution elicits these effects is not known. This issue was addressed using human recombinant wild-type (WT) and T94A variant L-FABP proteins as well as cultured primary human hepatocytes expressing the respective proteins (genotyped as TT, TC and CC). The T94A substitution did not alter or only slightly altered L-FABP binding affinities for saturated, monounsaturated or polyunsaturated long chain fatty acids, nor did it change the affinity for intermediates of triglyceride synthesis. Nevertheless, the T94A substitution markedly altered the secondary structural response of L-FABP induced by binding long chain fatty acids or intermediates of triglyceride synthesis. Finally, the T94A substitution markedly decreased the levels of induction of peroxisome proliferator-activated receptor α-regulated proteins such as L-FABP, fatty acid transport protein 5 and peroxisome proliferator-activated receptor α itself meditated by the polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid in cultured primary human hepatocytes. Thus, although the T94A substitution did not alter the affinity of human L-FABP for long chain fatty acids, it significantly altered human L-FABP structure and stability, as well as the conformational and functional response to these ligands. © 2014 FEBS.

  7. Interactions between Human Liver Fatty Acid Binding Protein and Peroxisome Proliferator Activated Receptor Selective Drugs

    PubMed Central

    Velkov, Tony

    2013-01-01

    Fatty acid binding proteins (FABPs) act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors (PPARs). PPAR mediated gene activation is ultimately involved in maintenance of cellular homeostasis through the transcriptional regulation of metabolic enzymes and transporters that target the activating ligand. Here we show that liver- (L-) FABP displays a high binding affinity for PPAR subtype selective drugs. NMR chemical shift perturbation mapping and proteolytic protection experiments show that the binding of the PPAR subtype selective drugs produces conformational changes that stabilize the portal region of L-FABP. NMR chemical shift perturbation studies also revealed that L-FABP can form a complex with the PPAR ligand binding domain (LBD) of PPARα. This protein-protein interaction may represent a mechanism for facilitating the activation of PPAR transcriptional activity via the direct channeling of ligands between the binding pocket of L-FABP and the PPARαLBD. The role of L-FABP in the delivery of ligands directly to PPARα via this channeling mechanism has important implications for regulatory pathways that mediate xenobiotic responses and host protection in tissues such as the small intestine and the liver where L-FABP is highly expressed. PMID:23476633

  8. Fatty acid composition and development of hepatic lipidosis during food deprivation--mustelids as a potential animal model for liver steatosis.

    PubMed

    Nieminen, Petteri; Mustonen, Anne-Mari; Kärjä, Vesa; Asikainen, Juha; Rouvinen-Watt, Kirsti

    2009-03-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome characterized by asymptomatic hepatic steatosis. It is present in most cases of human obesity but also caused e.g., by rapid weight loss. The patients have decreased n-3 polyunsaturated fatty acid (PUFA) proportions with decreased percentages of 18:3(n-3), 20:5(n-3) and 22:6(n-3) and an increased n-6/n-3 PUFA ratio in liver and/or white adipose tissue (WAT). The present study examined a new experimental model to study liver steatosis with possible future applications to NAFLD. Ten European polecats (Mustela putorius), the wild form of the domestic ferret, were food-deprived for 5 days with 10 fed animals as controls. The food-deprived animals showed micro- and macrovesicular hepatic steatosis, decreased proportions of 20:5(n-3), 22:6(n-3) and total n-3 PUFA and increased n-6/n-3 PUFA ratios in liver and WAT. At the same time, the product/precursor ratios decreased in liver. The observed effects can be due to selective fatty acid mobilization preferring n-3 PUFA over n-6 PUFA, decreased Delta5 and Delta6 desaturase activities, oxidative stress, decreased arginine availability and activation of the endocannabinoid system. Hepatic lipidosis induced by food deprivation was manifested in the fatty acid composition of the polecat with similarities to human NAFLD despite the different principal etiologies.

  9. 4Ps medicine of the fatty liver: the research model of predictive, preventive, personalized and participatory medicine-recommendations for facing obesity, fatty liver and fibrosis epidemics.

    PubMed

    Trovato, Francesca Maria; Catalano, Daniela; Musumeci, Giuseppe; Trovato, Guglielmo M

    2014-01-01

    Relationship between adipose tissue and fatty liver, and its possible evolution in fibrosis, is supported by clinical and research experience. Given the multifactorial pathogenesis of non-alcoholic fatty liver disease (NAFLD), treatments for various contributory risk factors have been proposed; however, there is no single validated therapy or drug association recommended for all cases which can stand alone. Mechanisms, diagnostics, prevention and treatment of obesity, fatty liver and insulin resistance are displayed along with recommendations and position points. Evidences and practice can get sustainable and cost-benefit valuable outcomes by participatory interventions. These recommendations can be enhanced by comprehensive research projects, addressed to societal issues and innovation, market appeal and industry development, cultural acceptance and sustainability. The basis of participatory medicine is a greater widespread awareness of a condition which is both a disease and an easy documented and inclusive clue for associated diseases and unhealthy lifestyle. This model is suitable for addressing prevention and useful for monitoring improvement, worsening and adherence with non-invasive imaging tools which allow targeted approaches. The latter include health psychology and nutritional and physical exercise prescription expertise disseminated by continuous medical education but, more important, by concrete curricula for training undergraduate and postgraduate students. It is possible and recommended to do it by early formal teaching of ultrasound imaging procedures and of practical lifestyle intervention strategies, including approaches aimed to healthier fashion suggestions. Guidelines and requirements of research project funding calls should be addressed also to NAFLD and allied conditions and should encompass the goal of training by research and the inclusion of participatory medicine topics. A deeper awareness of ethics of competences in health professionals

  10. Non-alcoholic Fatty Liver Disease: East Versus West

    PubMed Central

    Agrawal, Swastik; Duseja, Ajay K

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease worldwide with prevalence ranging from 10% to 30% in various countries. It has become an important cause of unexplained rise in transaminases, cryptogenic cirrhosis, and cryptogenic hepatocellular carcinoma. Pathogenesis is related to obesity, insulin resistance, oxidative stress, lipotoxicity, and resultant inflammation in the liver progressing to fibrosis. Pharmacological treatment in patients with NAFLD is still evolving and the treatment of these patients rests upon lifestyle modification with diet and exercise being the cornerstones of therapy. While there are many similarities between patients with NAFLD from Asia and the West, there are certain features which make the patients with NAFLD from Asia stand apart. This review highlights the data on NAFLD from Asia comparing it with the data from the West. PMID:25755421

  11. Impact of diesel exhaust exposure on the liver of mice fed on omega-3 polyunsaturated fatty acids-deficient diet.

    PubMed

    Umezawa, Masakazu; Nakamura, Masayuki; El-Ghoneimy, Ashraf A; Onoda, Atsuto; Shaheen, Hazem M; Hori, Hiroshi; Shinkai, Yusuke; El-Sayed, Yasser S; El-Far, Ali H; Takeda, Ken

    2018-01-01

    Exposure to diesel exhaust (DE) exacerbates non-alcoholic fatty liver disease, and may systemically affect lipid metabolism. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have anti-inflammatory activity and suppresses hepatic triacylglycerol accumulation, but many daily diets are deficient in this nutrient. Therefore, the effect of DE exposure in mice fed n-3 PUFA-deficient diet was investigated. Mice were fed control chow or n-3 PUFA-deficient diet for 4 weeks, then exposed to clean air or DE by inhalation for further 4 weeks. Liver histology, plasma parameters, and expression of fatty acid synthesis-related genes were evaluated. N-3 PUFA-deficient diet increased hepatic lipid droplets accumulation and expression of genes promoting fatty acid synthesis: Acaca, Acacb, and Scd1. DE further increased the plasma leptin and the expression of fatty acid synthesis-related genes: Acacb, Fasn, and Scd1. N-3 PUFA-deficient diet and DE exposure potentially enhanced hepatic fatty acid synthesis and subsequently accumulation of lipid droplets. The combination of low-dose DE exposure and intake of n-3 PUFA-deficient diet may be an additional risk factor for the incidence of non-alcoholic fatty liver disease. The present study suggests an important mechanism for preventing toxicity of DE on the liver through the incorporation of n-3 PUFAs in the diet. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Role of folate in nonalcoholic fatty liver disease.

    PubMed

    Sid, Victoria; Siow, Yaw L; O, Karmin

    2017-10-01

    Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver conditions that are characterized by steatosis, inflammation, fibrosis, and liver injury. The global prevalence of NAFLD is rapidly increasing in proportion to the rising incidence of obesity and type 2 diabetes. Because NAFLD is a multifaceted disorder with many underlying metabolic abnormalities, currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folate is a water-soluble B vitamin that plays an essential role in one-carbon transfer reactions involved in nucleic acid biosynthesis, methylation reactions, and sulfur-containing amino acid metabolism. The liver is the primary organ responsible for storage and metabolism of folates. Low serum folate levels have been observed in patients with obesity and diabetes. It has been reported that a low level of endogenous folates in rodents perturbs folate-dependent one-carbon metabolism, and may be associated with development of metabolic diseases such as NAFLD. This review highlights the biological role of folate in the progression of NAFLD and its associated metabolic complications including obesity and type 2 diabetes. Understanding the role of folate in metabolic disease may position this vitamin as a potential therapeutic for NAFLD.

  13. Endocrine causes of nonalcoholic fatty liver disease

    PubMed Central

    Marino, Laura; Jornayvaz, François R

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed. PMID:26494962

  14. Primary non-function is frequently associated with fatty liver allografts and high mortality after re-transplantation.

    PubMed

    Kulik, Ulf; Lehner, Frank; Klempnauer, Jürgen; Borlak, Jürgen

    2017-08-01

    The shortage of liver donations demands the use of suboptimal grafts with steatosis being a frequent finding. Although ≤30% macrovesicular steatosis is considered to be safe the risk for primary non-function (PNF) and outcome after re-transplantation (re-OLT) is unknown. Among 1205 orthotopic liver transplantations performed at our institution the frequency, survival and reason of re-OLT were evaluated. PNF (group A) cases and those with initial transplant function but subsequent need for re-OLT (group B) were analysed. Histopathology and clinical judgement determined the cause of PNF and included an assessment of hepatic steatosis. Additionally, survival of fatty liver allografts (group C) not requiring re-OLT was considered in Kaplan-Meier and multivariate regression analysis. A total of 77 high urgency re-OLTs were identified and included 39 PNF cases. Nearly 70% of PNF cases were due to primary fatty liver allografts. The 3-month in-hospital mortality for PNF cases after re-OLT was 46% and the mean survival after re-OLT was 0.5 years as compared to 5.2 and 5.1 years for group B, C, respectively, (P<.008). In multivariate Cox regression analysis only hepatic steatosis was associated with an inferior survival (HR 4.272, P=.002). The MELD score, donor BMI, age, cold ischaemic time, ICU stay, serum sodium and transaminases did not influence overall survival. Our study highlights fatty liver allografts to be a major cause for PNF with excessive mortality after re-transplantation. The findings demand the development of new methods to predict risk for PNF of fatty liver allografts. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Similarities and differences between pediatric and adult nonalcoholic fatty liver disease.

    PubMed

    Crespo, Maricruz; Lappe, Sara; Feldstein, Ariel E; Alkhouri, Naim

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is highly common and potentially serious in children and adolescents. The term NAFLD refers to a spectrum of diseases ranging from accumulation of fat in the liver (simple steatosis or nonalcoholic fatty liver "NAFL") to the potentially progressive form of nonalcoholic steatohepatitis (NASH) characterized by hepatocyte ballooning, inflammation, and often associated with fibrosis. While large prospective longitudinal studies in pediatric NAFLD are still lacking, growing evidence suggests that children with NAFL are at increased risk for cardiometabolic complications, while those with NASH and advance fibrosis are also at risk for significant liver-related morbidity including cirrhosis and its complications. Pediatric NAFLD shares features of adult NAFLD but also shows many different characteristics in terms of prevalence, histology, diagnosis and management. Translational studies suggest that NAFLD is a highly heritable disease in which genetic variations and environment closely interact to determine the disease phenotype and the progression to the more advanced forms of the disease. Changes in lifestyle, targeting gradual weight reduction, and physical exercise continue to be the mainstay of treatment for NAFLD in children. Recent advances in development of noninvasive diagnostic modalities and the potential for identifying effective pharmacological interventions may result in significant progress in the management of NAFLD in the pediatric population. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Regulation of mitochondrial trifunctional protein modulates nonalcoholic fatty liver disease in mice

    PubMed Central

    Nassir, Fatiha; Arndt, Justin J.; Johnson, Sarah A.

    2018-01-01

    Mitochondrial trifunctional protein (MTP) plays a critical role in the oxidation of long-chain fatty acids. We previously reported that aging mice (>9 months old) heterozygous for an MTP defect (MTP+/−) develop nonalcoholic fatty liver disease (NAFLD). We tested whether a high-fat diet (HFD) accelerates NAFLD in young MTP+/−mice, and whether overexpression of the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuin 3 (SIRT3) deacetylates MTP and improves mitochondrial function and NAFLD. Three-month-old WT and MTP+/− mice were fed HFD (60% cal fat) for 16 weeks and livers were assessed for fatty acid oxidation (FAO) and NAFLD. Compared with WT, MTP+/− mice displayed reduced hepatic SIRT3 levels and reduced FAO, with increased hepatic steatosis and the inflammatory marker CD68. Hepatic overexpression of SIRT3 in HFD-fed MTP+/− mice increased hepatic MTP protein levels at the posttranscriptional level. Immunoprecipitation of MTP from liver mitochondria followed by Western blot with acetyl-lysine antibody showed higher acetylation of MTP in MTP+/− compared with WT mice. Overexpression of SIRT3 in MTP+/− mice significantly reduced the acetylation of MTP compared with β-galactosidase controls, increased mitochondrial FAO, and reduced hepatic steatosis, CD68, and serum ALT levels. Taken together, our data indicate that deacetylation of MTP by SIRT3 improves mitochondrial function and rescues NAFLD in MTP+/− mice. PMID:29581157

  17. The Role of Intestinal Bacteria Overgrowth in Obesity-Related Nonalcoholic Fatty Liver Disease

    PubMed Central

    Ferolla, Silvia M.; Armiliato, Geyza N. A.; Couto, Cláudia A.; Ferrari, Teresa C. A.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. It is a progressive disorder involving a spectrum of conditions that include pure steatosis without inflammation, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. The key factor in the pathophysiology of NAFLD is insulin resistance that determines lipid accumulation in the hepatocytes, which may be followed by lipid peroxidation, production of reactive oxygen species and consequent inflammation. Recent studies suggest that the characteristics of the gut microbiota are altered in NAFLD, and also, that small intestinal bacterial overgrowth (SIBO) contributes to the pathogenesis of this condition. This review presents the chief findings from all the controlled studies that evaluated SIBO, gut permeability and endotoxemia in human NAFLD. We also discuss the possible mechanisms involving SIBO, lipid accumulation and development of NASH. The understanding of these mechanisms may allow the development of new targets for NASH treatment in the future. PMID:25479248

  18. [Therapeutic effect of saxagliptin in rat models of nonalcoholic fatty liver and type 2 diabetes].

    PubMed

    Liu, Yan; Zhang, Zhen; Chen, Rongping; Sun, Jia; Chen, Hong

    2014-06-01

    To observe the therapeutic effect of saxagliptin in a rat model of nonalcoholic fatty liver and type 2 diabetes and investigate the possible mechanism. Rats models of nonalcoholic fatty liver and type 2 diabetes established by feeding on a high glucose and fat diet and streptozotocin injection were treated with saxagliptin (daily dose of 10 mg/kg) gavage for 8 weeks, using saline as the control. After the treatment, fasting blood glucose, serum insulin, blood lipids, liver function, liver oxidative indices, and hepatic pathologies were evaluated in all the rats, and the expressions of Bcl-2 and Bax in the liver tissue were detected with immunohistochemistry and Western blotting. Compared with the model group, saxagliptin intervention significantly reduced blood glucose and HOMA-IR, improved the liver function and SOD activity (P<0.01), lowered the liver weight, liver index (P<0.01) and MDA level (P<0.05), and slightly lowered the body weight and blood lipids (P>0.05); AST level was similar between the normal control group and saxagliptin intervention group (P>0.05). HE and oil red staining showed obvious hepatic pathologies in the model group, and saxagliptin intervention significantly reduced lipid droplets in the hepatocytes and improved the structural damage of the liver. Hepatic Bax expression significantly increased and Bcl-2 expression decreased in the model group, and these changes were reversed by saxagliptin. Saxagliptin shows good therapeutic effect in rat models of nonalcoholic fatty liver and type 2 diabetes possibly by controlling blood glucose, lowering insulin resistance, alleviating hepatic oxidative stress and hepatocyte damage, and regulating the expression of apoptosis-related proteins.

  19. Neutrophil depletion improves diet-induced non-alcoholic fatty liver disease in mice.

    PubMed

    Ou, Rongying; Liu, Jia; Lv, Mingfen; Wang, Jingying; Wang, Jinmeng; Zhu, Li; Zhao, Liang; Xu, Yunsheng

    2017-07-01

    Non-alcoholic fatty liver disease is highly associated with morbidity and mortality in population. Although studies have already demonstrated that the immune response plays a pivotal role in the development of non-alcoholic fatty liver disease, the comprehensive regulation is unclear. Therefore, present study was carried out to investigate the non-alcoholic fatty liver disease development under neutrophil depletion. To achieve the aim of the study, C57BL/6 J mice were fed with high fat diet for 6 weeks before treated with neutrophil deplete antibody 1A8 or isotype control (200 μg/ mouse every week) for another 4 weeks. Treated with 1A8 antibody, obese mice exhibited better whole body metabolic parameters, including reduction of body weight gain and fasting blood glucose levels. Neutrophil depletion also effectively reduced hepatic structural disorders, dysfunction and lipid accumulation. Lipid β-oxidative markers, phosphorylated-AMP-activated protein kinase α and phosphorylated-acetyl-CoA carboxylase levels were increased in 1A8 antibody-treated obese mouse group. The mitochondrial number and function were also reversed after 1A8 antibody treatment, including increased mitochondrial number, reduced lipid oxidative damage and enhanced mitochondrial activity. Furthermore, the expression of inflammatory cytokines, tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 were obviously reduced after neutrophil depletion, accompanied with decreased F4/80 mRNA level and macrophage percentage in liver. The decreased NF-κB signaling activity was also involved in the beneficial effect of neutrophil depletion. Taken together, neutrophil depletion could attenuate metabolic syndromes and hepatic dysfunction.

  20. GH administration rescues fatty liver regeneration impairment by restoring GH/EGFR pathway deficiency.

    PubMed

    Collin de l'Hortet, A; Zerrad-Saadi, A; Prip-Buus, C; Fauveau, V; Helmy, N; Ziol, M; Vons, C; Billot, K; Baud, V; Gilgenkrantz, Hélène; Guidotti, Jacques-Emmanuel

    2014-07-01

    GH pathway has been shown to play a major role in liver regeneration through the control of epidermal growth factor receptor (EGFR) activation. This pathway is down-regulated in nonalcoholic fatty liver disease. Because regeneration is known to be impaired in fatty livers, we wondered whether a deregulation of the GH/EGFR pathway could explain this deficiency. Hepatic EGFR expression and triglyceride levels were quantified in liver biopsies of 32 obese patients with different degrees of steatosis. We showed a significant inverse correlation between liver EGFR expression and the level of hepatic steatosis. GH/EGFR down-regulation was also demonstrated in 2 steatosis mouse models, a genetic (ob/ob) and a methionine and choline-deficient diet mouse model, in correlation with liver regeneration defect. ob/ob mice exhibited a more severe liver regeneration defect after partial hepatectomy (PH) than methionine and choline-deficient diet-fed mice, a difference that could be explained by a decrease in signal transducer and activator of transcription 3 phosphorylation 32 hours after PH. Having checked that GH deficiency accounted for the GH signaling pathway down-regulation in the liver of ob/ob mice, we showed that GH administration in these mice led to a partial rescue in hepatocyte proliferation after PH associated with a concomitant restoration of liver EGFR expression and signal transducer and activator of trnascription 3 activation. In conclusion, we propose that the GH/EGFR pathway down-regulation is a general mechanism responsible for liver regeneration deficiency associated with steatosis, which could be partially rescued by GH administration.

  1. Nonalcoholic Fatty Liver Disease Management: Dietary and Lifestyle Modifications.

    PubMed

    Nguyen, Vi; George, Jacob

    2015-08-01

    Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of abnormalities that can range from bland liver fat (steatosis), to hepatic inflammation and liver injury (steatohepatitis). It is estimated that NAFLD will become the principal cause of liver disease in Western nations and the leading indication for liver transplantation. Advancements in disease recognition and management are therefore paramount. Although the development of new, reliable drug therapies is vital, lifestyle interventions remain the most effective treatment modality. In addition to weight loss as a primary measure of treatment success, there is growing recognition that other endpoints, including the prevention or delay of diabetes onset, reduced cardiovascular events, prevention of cancer, and improved overall mortality, are equally important outcomes that can be independently modified by lifestyle change. Moreover, NAFLD is inextricably part of a complex, systemic disease process that is linked with deeply entrenched maladaptive lifestyle behaviors. Thus, a holistic, multidisciplinary, and individualized approach to disease management will be the key to achieving any realistic population-level change. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  2. Fenofibrate, but not ezetimibe, prevents fatty liver disease in mice lacking phosphatidylethanolamine N-methyltransferase[S

    PubMed Central

    van der Veen, Jelske N.; Lingrell, Susanne; Gao, Xia; Takawale, Abhijit; Kassiri, Zamaneh; Vance, Dennis E.; Jacobs, René L.

    2017-01-01

    Mice lacking phosphatidylethanolamine N-methyltransferase (PEMT) are protected from high-fat diet (HFD)-induced obesity and insulin resistance. However, these mice develop severe nonalcoholic fatty liver disease (NAFLD) when fed the HFD, which is mainly due to inadequate secretion of VLDL particles. Our aim was to prevent NAFLD development in mice lacking PEMT. We treated Pemt−/− mice with either ezetimibe or fenofibrate to see if either could ameliorate liver disease in these mice. Ezetimibe treatment did not reduce fat accumulation in Pemt−/− livers, nor did it reduce markers for hepatic inflammation or fibrosis. Fenofibrate, conversely, completely prevented the development of NAFLD in Pemt−/− mice: hepatic lipid levels, as well as markers of endoplasmic reticulum stress, inflammation, and fibrosis, in fenofibrate-treated Pemt−/− mice were similar to those in Pemt+/+ mice. Importantly, Pemt−/− mice were still protected against HFD-induced obesity and insulin resistance. Moreover, fenofibrate partially reversed hepatic steatosis and fibrosis in Pemt−/− mice when treatment was initiated after NAFLD had already been established. Increasing hepatic fatty acid oxidation can compensate for the lower VLDL-triacylglycerol secretion rate and prevent/reverse fatty liver disease in mice lacking PEMT. PMID:28159867

  3. Silibinin Capsules improves high fat diet-induced nonalcoholic fatty liver disease in hamsters through modifying hepatic de novo lipogenesis and fatty acid oxidation.

    PubMed

    Cui, Chun-Xue; Deng, Jing-Na; Yan, Li; Liu, Yu-Ying; Fan, Jing-Yu; Mu, Hong-Na; Sun, Hao-Yu; Wang, Ying-Hong; Han, Jing-Yan

    2017-08-17

    Silibinin Capsules (SC) is a silybin-phospholipid complex with silybin as the bioactive component. Silybin accounts for 50-70% of the seed extract of Silybum marianum (L.) Gaertn.. As a traditional medicine, silybin has been used for treatment of liver diseases and is known to provide a wide range of hepatoprotective effects. High fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) is a worldwide health problem. This study was to investigate the role of SC in NAFLD with focusing on its underlying mechanism and likely target. Male hamsters (Cricetidae) received HFD for 10 weeks to establish NAFLD model. NAFLD was assessed by biochemical assays, histology and immunohistochemistry. Proton nuclear magnetic resonance spectroscopy and western blot were conducted to gain insight into the mechanism. Hamsters fed HFD for 10 weeks developed fatty liver accompanying with increased triglyceride (TG) accumulation, enhancing de novo lipogenesis, increase in fatty acid (FA) uptake and reducing FA oxidation and TG lipolysis, as well as a decrease in the expression of phospho-adenosine monophosphate activated protein kinase α (p-AMPKα) and Sirt 1. SC treatment at 50mg/kg silybin and 100mg/kg silybin for 8 weeks protected hamsters from development of fatty liver, reducing de novo lipogenesis and increasing FA oxidation and p-AMPKα expression, while having no effect on FA uptake and TG lipolysis. SC protected against NAFLD in hamsters by inhibition of de novo lipogenesis and promotion of FA oxidation, which was likely mediated by activation of AMPKα. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  4. Molecular pathways in non-alcoholic fatty liver disease

    PubMed Central

    Berlanga, Alba; Guiu-Jurado, Esther; Porras, José Antonio; Auguet, Teresa

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological change characterized by the accumulation of triglycerides in hepatocytes and has frequently been associated with obesity, type 2 diabetes mellitus, hyperlipidemia, and insulin resistance. It is an increasingly recognized condition that has become the most common liver disorder in developed countries, affecting over one-third of the population and is associated with increased cardiovascular- and liver-related mortality. NAFLD is a spectrum of disorders, beginning as simple steatosis. In about 15% of all NAFLD cases, simple steatosis can evolve into non-alcoholic steatohepatitis, a medley of inflammation, hepatocellular injury, and fibrosis, often resulting in cirrhosis and even hepatocellular cancer. However, the molecular mechanism underlying NAFLD progression is not completely understood. Its pathogenesis has often been interpreted by the “double-hit” hypothesis. The primary insult or the “first hit” includes lipid accumulation in the liver, followed by a “second hit” in which proinflammatory mediators induce inflammation, hepatocellular injury, and fibrosis. Nowadays, a more complex model suggests that fatty acids (FAs) and their metabolites may be the true lipotoxic agents that contribute to NAFLD progression; a multiple parallel hits hypothesis has also been suggested. In NAFLD patients, insulin resistance leads to hepatic steatosis via multiple mechanisms. Despite the excess hepatic accumulation of FAs in NAFLD, it has been described that not only de novo FA synthesis is increased, but FAs are also taken up from the serum. Furthermore, a decrease in mitochondrial FA oxidation and secretion of very-low-density lipoproteins has been reported. This review discusses the molecular mechanisms that underlie the pathophysiological changes of hepatic lipid metabolism that contribute to NAFLD. PMID:25045276

  5. T1-weighted dual-echo MRI for fat quantification in pediatric nonalcoholic fatty liver disease.

    PubMed

    Pacifico, Lucia; Martino, Michele Di; Catalano, Carlo; Panebianco, Valeria; Bezzi, Mario; Anania, Caterina; Chiesa, Claudio

    2011-07-07

    To determine in obese children with nonalcoholic fatty liver disease (NAFLD) the accuracy of magnetic resonance imaging (MRI) in assessing liver fat concentration. A case-control study was performed. Cases were 25 obese children with biopsy-proven NAFLD. Controls were 25 obese children matched for age and gender, without NAFLD at ultrasonography and with normal levels of aminotransferases and insulin. Hepatic fat fraction (HFF) by MRI was obtained using a modification of the Dixon method. HFF ranged from 2% to 44% [mean, 19.0% (95% CI, 15.1-27.4)] in children with NAFLD, while in the controls this value ranged from 0.08% to 4.69% [2.0% (1.3-2.5), P < 0.0001]. HFF was highly correlated with histological steatosis (r = 0.883, P < 0.0001) in the NAFLD children. According to the histological grade of steatosis, the mean HFF was 8.7% (95% CI, 6.0-11.6) for mild, 21.6% (15.3-27.0) for moderate, and 39.7% (34.4-45.0) for severe fatty liver infiltration. With a cutoff of 4.85%, HFF had a sensitivity of 95.8% for the diagnosis of histological steatosis ≥ 5%. All control children had HFF lower than 4.85%; thus, the specificity was 100%. After 12 mo, children with weight loss displayed a significant decrease in HFF. MRI is an accurate methodology for liver fat quantification in pediatric NAFLD.

  6. Improving effect of dietary soybean phospholipids supplement on hepatic and serum indexes relevant to fatty liver hemorrhagic syndrome in laying hens.

    PubMed

    Yang, Fei; Ruan, Jiming; Wang, Tiancheng; Luo, Junrong; Cao, Huabin; Song, Yalu; Huang, Jianzhen; Hu, Guoliang

    2017-11-01

    In order to investigate the effect of dietary soybean phospholipid supplement on hepatic and serum indexes relevant to fatty liver hemorrhagic syndrome (FLHS) in layers, 135 300-day-old Hyline Brown layers were randomly divided into three groups (control, pathology and prevention), and each group had 45 layers with three replicates. Birds in the three groups were respectively fed the control diet, high-energy low-protein diet and high-energy high-protein diet affixed with 3% soybean phospholipid instead of maize. Results showed in the 30th day, birds' livers in the pathology group became yellowish, enlarged in size and had hemorrhagic spots, while the prevention and control groups' layers did not have such pathological changes. Contents of triglyceride, total cholesterol, low-density lipoprotein - cholesterol, non-esterified fatty acid and malondialdehyde in serum or liver homogenate in prevention and control groups were remarkably lower than those in the pathology group (P < 0.05 or P < 0.01), as with the activities of glutamic oxalacetic transaminase and glutamic-pyruvic transaminase (P < 0.01); high-density lipoprotein - cholesterol value was strikingly higher than that of the pathology group (P < 0.01). It is suggested dietary soybean phospholipids supplement may effectively improve hepatic and blood indexes relevant to FLHS, which provides a new point for preventing FLHS occurrence rate in laying flocks and treating human non-alcohol fatty liver disease. © 2017 Japanese Society of Animal Science.

  7. Serial volumetric assessment of large for size liver grafts after whole cadaveric liver transplant in adults: do large liver grafts shrink in size?

    PubMed

    Bekheit, Mohamed; Rajakannu, Muthukumarassamy; Bucur, Petru; Adam, Rene; SaCunha, Antonio; Castaing, Denis; Cherqui, Daniel; Vibert, Eric

    2016-02-01

    After whole graft orthotopic liver transplantation (OLT), adaptation of the large grafts' volume to recipient weight is widely accepted despite the paucity of evidence on this subject. Thirty nine patients with GRWR > 2.5% were included in this study and subsequently divided into two groups with 3 ≥ GRWR > 3%. Patients had CT scans at three predetermined time points after OLT used for measuring the liver volume. The objective of this study is to evaluate the volumetric changes of whole large liver grafts after adult OLT. At LT, the mean graft recipient body weight ratio (GRWR) was 3.1 ± 0.4%. The mean liver weight was 1881 ± 68 g at LT, 2014 ± 99 ml at one week, 1725 ± 126 ml at 3 months, and 1632 ± 117 (ml) at >6 months. There is an initial increase at 1 week after LT and a subsequent decrease of liver volume on later measurements. None of the late volume measurements were significantly different from the initial graft volume at liver transplant in pair wise comparisons ANOVA repeated measures (p > 0.05). Similarly, the mean GRWR did not change significantly between the initial calculation at transplantation date and the subsequent measurements during the different study time points (F = 0.04, p = 0.96) with a mean of 3.1% (95% CI = 2.2-4.2). AUC ROC discriminated a cutoff of 3% for the initial GRWR above which grafts tend to decrease in size over time (c statistics = 0.74, p = 0.036). In a Clustered ANOVA repeated measures, there was no significant difference in the changes of liver volume between both groups. However, patients with GRWR > 3 showed a trend towards a latent reduction in volume over the tracing period. There was a tendency, but none significant; towards a higher bilirubin, AST, ALT levels over the first postoperative days in recipients with GRWR > 3. Large grafts do not significantly decrease in size. Nonetheless, grafts weighing >3% of the GRWR show a different trend towards decrease in size over time. Copyright © 2015. Published by

  8. Identification of Potential Plasma Biomarkers for Nonalcoholic Fatty Liver Disease by Integrating Transcriptomics and Proteomics in Laying Hens.

    PubMed

    Tsai, Meng-Tsz; Chen, Yu-Jen; Chen, Ching-Yi; Tsai, Mong-Hsun; Han, Chia-Li; Chen, Yu-Ju; Mersmann, Harry J; Ding, Shih-Torng

    2017-03-01

    Background: Prevalent worldwide obesity is associated with increased incidence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. The identification of noninvasive biomarkers for NAFLD is of recent interest. Because primary de novo lipogenesis occurs in chicken liver as in human liver, adult chickens with age-associated steatosis resembling human NAFLD is an appealing animal model. Objective: The objective of this study was to screen potential biomarkers in the chicken model for NAFLD by transcriptomic and proteomic analysis. Methods: Hy-Line W-36 laying hens were fed standard feed from 25 to 45 wk of age to induce fatty liver. They were killed every 4 wk, and liver and plasma were collected at each time point to assess fatty liver development and for transcriptomic and proteomic analysis. Next, selected biomarkers were confirmed in additional experiments by providing supplements of the hepatoprotective nutrients betaine [300, 600, or 900 parts per million (ppm) in vivo; 2 mM in vitro] or docosahexaenoic acid (DHA; 1% in vivo; 100 μM in vitro) to 30-wk-old Hy-Line W-36 laying hens for 4 mo and to Hy-Line W-36 chicken primary hepatocytes with oleic acid-induced steatosis. Liver or hepatocyte lipid contents and the expression of biomarkers were then examined. Results: Plasma acetoacetyl-CoA synthetase (AACS), dipeptidyl-peptidase 4 (DPP4), glutamine synthetase (GLUL), and glutathione S -transferase (GST) concentrations are well-established biomarkers for NAFLD. Selected biomarkers had significant positive associations with hepatic lipid deposition ( P < 0.001). Betaine (900 ppm in vivo; 2 mM in vitro) and DHA (1% in vivo; 100 μM in vitro) supplementation both resulted in lower steatosis accompanied by the reduced expression of selected biomarkers in vivo and in vitro ( P < 0.05). Conclusion: This study used adult laying hens to identify biomarkers for NAFLD and indicated that AACS, DPP4, GLUL, and GST could be considered to be potential diagnostic

  9. Comparative clinical study between the effect of fenofibrate alone and its combination with pentoxifylline on biochemical parameters and liver stiffness in patients with non-alcoholic fatty liver disease.

    PubMed

    El-Haggar, Sahar Mohamed; Mostafa, Tarek Mohamed

    2015-07-01

    Non-alcoholic fatty liver disease is a common health problem associated with increased liver and vascular specific complications. The purpose of this study was to assess and compare the effect of fenofibrate alone or in combination with pentoxifylline on the measured biochemical parameters, inflammatory pathway and liver stiffness in patients with non-alcoholic fatty liver disease. The study design was randomized controlled trial. From July 2013 to June 2014, we recruited 90 non-alcoholic fatty liver patients from the Internal Medicine Department at Tanta University Hospital, Egypt. They were classified randomly into two groups to receive fenofibrate 300 mg daily or fenofibrate 300 mg daily plus pentoxifylline 1200 mg/day in three divided doses for 24 weeks. Fasting blood sample was obtained before and 24 weeks after treatment for biochemical analysis of liver and lipid panels, tumor necrosis factor-alpha, hyaluronic acid, transforming growth factor beta 1, fasting plasma insulin and fasting glucose. Liver stiffness measurement was carried out using fibro-scan. Data were statistically analyzed by paired and unpaired Student's t test. The data obtained suggests that adding pentoxifylline to fenofibrate does not provide a beneficial effect on lipid panel, but has a beneficial effect on indirect biochemical markers of hepatic fibrosis, a direct marker linked to matrix deposition (hyaluronic acid), a cytokine/growth factor linked to liver fibrosis (transforming growth factor beta 1), the inflammatory pathway, insulin resistance and liver stiffness as compared to fenofibrate alone. The combination pentoxifylline plus fenofibrate may represent a new therapeutic strategy for non-alcoholic fatty liver disease as it resulted in more beneficial effects on direct and indirect markers of liver fibrosis, liver stiffness, insulin resistance and inflammatory pathway implicated in NAFLD.

  10. Acute fatty liver of pregnancy: a clinical study of 12 episodes in 11 patients.

    PubMed Central

    Reyes, H; Sandoval, L; Wainstein, A; Ribalta, J; Donoso, S; Smok, G; Rosenberg, H; Meneses, M

    1994-01-01

    Twelve episodes of acute fatty liver of pregnancy (AFLP) were diagnosed in 11 patients during the past 18 years in a general hospital in Santiago, Chile, with a prevalence of 1 per 15,900 deliveries. Acute fatty liver of pregnancy started between the 31st and 38th weeks of pregnancy, with malaise, vomiting, jaundice, and lethargy as the main clinical manifestations. Polydipsia (in nine episodes) and skin pruritus (in seven episodes) were unusual clinical findings. In two patients, pruritus started two and four weeks before AFLP, suggesting that an intrahepatic cholestasis of pregnancy preceded AFLP in those patients. Considering the current prevalence of both diseases in Chile, their association should be considered fortuitous. In another patient, two consecutive pregnancies were affected by AFLP, raising to three the number of reported patients with recurrent AFLP. In 11 episodes, liver biopsies supported the diagnosis of AFLP by showing small and midsized vacuolar cytoplasmic transformation as the most prominent histopathological feature. Positive intracellular fat staining was found in the four samples analysed. Studies by electron microscopy showed megamitochondria with paracrystalline inclusions in four samples. All the mothers survived, but fetal mortality was 58.3%. Several extrahepatic complications delayed maternal recovery for up to four weeks after delivery. This study confirms an improvement in maternal prognosis in AFLP, discusses the possibility of an epidemiological association with intrahepatic cholestasis of pregnancy, and increases the number of patients reported with recurrent AFLP. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8307428

  11. The Role of TCA Cycle Anaplerosis in Ketosis and Fatty Liver in Periparturient Dairy Cows

    PubMed Central

    White, Heather M.

    2015-01-01

    The transition to lactation period in dairy cattle is characterized by metabolic challenges, negative energy balance, and adipose tissue mobilization. Metabolism of mobilized adipose tissue is part of the adaptive response to negative energy balance in dairy cattle; however, the capacity of the liver to completely oxidize nonesterified fatty acids may be limited and is reflective of oxaloacetate pool, the carbon carrier of the tricarboxylic acid cycle. Alternative metabolic fates of acetyl-CoA from nonesterified fatty acids include esterification to triacylglycerides and ketogenesis, and when excessive, these pathways lead to fatty liver and ketosis. Examination of the anaplerotic and cataplerotic pull of oxaloacetate by the tricarboxylic acid cycle and gluconeogenesis may provide insight into the balance of oxidation and esterification of acetyl-CoA within the liver of periparturient dairy cows. PMID:26479386

  12. The Role of TCA Cycle Anaplerosis in Ketosis and Fatty Liver in Periparturient Dairy Cows.

    PubMed

    White, Heather M

    2015-08-18

    The transition to lactation period in dairy cattle is characterized by metabolic challenges, negative energy balance, and adipose tissue mobilization. Metabolism of mobilized adipose tissue is part of the adaptive response to negative energy balance in dairy cattle; however, the capacity of the liver to completely oxidize nonesterified fatty acids may be limited and is reflective of oxaloacetate pool, the carbon carrier of the tricarboxylic acid cycle. Alternative metabolic fates of acetyl-CoA from nonesterified fatty acids include esterification to triacylglycerides and ketogenesis, and when excessive, these pathways lead to fatty liver and ketosis. Examination of the anaplerotic and cataplerotic pull of oxaloacetate by the tricarboxylic acid cycle and gluconeogenesis may provide insight into the balance of oxidation and esterification of acetyl-CoA within the liver of periparturient dairy cows.

  13. Bicyclol attenuates tetracycline-induced fatty liver associated with inhibition of hepatic ER stress and apoptosis in mice.

    PubMed

    Yao, Xiao-Min; Li, Yue; Li, Hong-Wei; Cheng, Xiao-Yan; Lin, Ai-Bin; Qu, Jun-Ge

    2016-01-01

    Endoplasmic reticulum (ER) stress is known to be involved in the development of several metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). Tetracycline can cause hepatic steatosis, and ER stress may be involved in tetracycline-induced fatty liver. Our previous study showed that bicyclol has been proven to protect against tetracycline-induced fatty liver in mice, and ER stress may also be involved in bicyclol's hepatoprotective effect. Therefore, this study was performed to investigate the underlying mechanisms associated with ER stress and apoptosis, by which bicyclol attenuated tetracycline-induced fatty liver in mice. Bicyclol (300 mg/kg) was given to mice by gavage 3 times. Tetracycline (200 mg/kg, intraperitoneally) was injected at 1 h after the last dose of bicyclol. At 6 h and 24 h after single dose of tetracycline injection, serum ALT, AST, TG, CHO and hepatic histopathological examinations were performed to evaluate liver injuries. Hepatic steatosis was assessed by the accumulation of hepatic TG and CHO. Moreover, hepatic apoptosis and ER stress related markers were determined by TUNEL, real-time PCR, and western blot. As a result, bicyclol significantly protected against tetracycline-induced fatty liver as evidenced by the decrease of elevated serum transaminases and hepatic triglyceride, and the attenuation of histopathological changes in mice. In addition, bicyclol remarkably alleviated hepatic apoptosis and the gene expression of caspase-3, and increased the gene expression of XIAP. The gene expressions of ER stress-related markers, including CHOP, GRP78, IRE-1α, and ATF6, which were downregulated by bicyclol pretreatment in tetracycline-injected mice. These results suggested that bicyclol protected tetracycline-induced fatty liver partly due to its ability of anti-apoptosis associated with ER stress.

  14. Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: the role of the PPARα-FGF21 axis

    PubMed Central

    Chen, Xue; Ward, Stephen C.; Cederbaum, Arthur I.; Xiong, Huabao; Lu, Yongke

    2017-01-01

    Background & Aims Cytochrome P450 2A5 (CYP2A5) is induced by ethanol, and the ethanol induction of CYP2A5 is regulated by nuclear factor-erythroid 2-related factor 2 (NRF2). Cyp2a5 knockout (Cyp2a5−/−) mice develop more severe alcoholic fatty liver than Cyp2a5+/+ mice. Fibroblast growth factor 21 (FGF21), a PPARα-regulated liver hormone, is involved in hepatic lipid metabolism. Alcoholic and non-alcoholic fatty liver are enhanced in Pparα knockout (Pparα−/−) mice. This study investigates the relationship between the PPARα-FGF21 axis and the enhanced alcoholic fatty liver in Cyp2a5−/− mice. Methods Mice were fed the Lieber-Decarli ethanol diet to induce alcoholic fatty liver. Results More severe alcoholic fatty liver disease was developed in Cyp2a5−/− mice than in Cyp2a5+/+ mice. Basal FGF21 levels were higher in Cyp2a5−/− mice than in Cyp2a5+/+ mice, but ethanol did not further increase the elevated FGF21 levels in Cyp2a5−/− mice while FGF21 was induced by ethanol in Cyp2a5+/+ mice. Basal levels of serum FGF21 were lower in Pparα−/− mice than in Pparα+/+ mice; ethanol induced FGF21 in Pparα+/+ mice but not in Pparα−/− mice, whereas ethanol induced hypertriglyceridemia in Pparα−/− mice but not in Pparα+/+ mice. Administration of recombinant FGF21 normalized serum FGF21 and triglyceride in Pparα−/− mice. Alcoholic fatty liver was enhanced in liver-specific Fgf21 knockout mice. Pparα and Cyp2a5 double knockout (Pparα−/−/Cyp2a5−/−) mice developed more severe alcoholic fatty liver than Pparα+/+/Cyp2a5−/− mice. Conclusions These results suggest that CYP2A5 protects against the development of alcoholic fatty liver disease, and the PPARα-FGF21 axis contributes to the protective effects of CYP2A5 on alcoholic fatty liver disease. PMID:28131861

  15. Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: The role of the PPARα-FGF21 axis.

    PubMed

    Chen, Xue; Ward, Stephen C; Cederbaum, Arthur I; Xiong, Huabao; Lu, Yongke

    2017-03-15

    Cytochrome P450 2A5 (CYP2A5) is induced by ethanol, and the ethanol induction of CYP2A5 is regulated by nuclear factor-erythroid 2-related factor 2 (NRF2). Cyp2a5 knockout (Cyp2a5 -/- ) mice develop more severe alcoholic fatty liver than Cyp2a5 +/+ mice. Fibroblast growth factor 21 (FGF21), a PPARα-regulated liver hormone, is involved in hepatic lipid metabolism. Alcoholic and non-alcoholic fatty liver are enhanced in Pparα knockout (Pparα -/- ) mice. This study investigates the relationship between the PPARα-FGF21 axis and the enhanced alcoholic fatty liver in Cyp2a5 -/- mice. Mice were fed the Lieber-Decarli ethanol diet to induce alcoholic fatty liver. More severe alcoholic fatty liver disease was developed in Cyp2a5 -/- mice than in Cyp2a5 +/+ mice. Basal FGF21 levels were higher in Cyp2a5 -/- mice than in Cyp2a5 +/+ mice, but ethanol did not further increase the elevated FGF21 levels in Cyp2a5 -/- mice while FGF21 was induced by ethanol in Cyp2a5 +/+ mice. Basal levels of serum FGF21 were lower in Pparα -/- mice than in Pparα +/+ mice; ethanol induced FGF21 in Pparα +/+ mice but not in Pparα -/- mice, whereas ethanol induced hypertriglyceridemia in Pparα -/- mice but not in Pparα +/+ mice. Administration of recombinant FGF21 normalized serum FGF21 and triglyceride in Pparα -/- mice. Alcoholic fatty liver was enhanced in liver-specific Fgf21 knockout mice. Pparα and Cyp2a5 double knockout (Pparα -/- /Cyp2a5 -/- ) mice developed more severe alcoholic fatty liver than Pparα +/+ /Cyp2a5 -/- mice. These results suggest that CYP2A5 protects against the development of alcoholic fatty liver disease, and the PPARα-FGF21 axis contributes to the protective effects of CYP2A5 on alcoholic fatty liver disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection—Liver: The “Musketeer” in the Spotlight

    PubMed Central

    Ballestri, Stefano; Nascimbeni, Fabio; Romagnoli, Dante; Baldelli, Enrica; Targher, Giovanni; Lonardo, Amedeo

    2016-01-01

    The pathogenesis of type 2 diabetes (T2D) involves chronic hyperinsulinemia due to systemic and hepatic insulin resistance (IR), which if uncorrected, will lead to progressive pancreatic beta cell failure in predisposed individuals. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty (simple steatosis and steatohepatitis) and non-fatty liver changes (NASH-cirrhosis with or without hepatocellular carcinoma (HCC)) that are commonly observed among individuals with multiple metabolic derangements, notably including visceral obesity, IR and T2D. Hepatitis C virus (HCV) infection is also often associated with both hepatic steatosis and features of a specific HCV-associated dysmetabolic syndrome. In recent years, the key role of the steatotic liver in the development of IR and T2D has been increasingly recognized. Thus, in this comprehensive review we summarize the rapidly expanding body of evidence that links T2D with NAFLD and HCV infection. For each of these two liver diseases with systemic manifestations, we discuss the epidemiological burden, the pathophysiologic mechanisms and the clinical implications. To date, substantial evidence suggests that NAFLD and HCV play a key role in T2D development and that the interaction of T2D with liver disease may result in a “vicious circle”, eventually leading to an increased risk of all-cause mortality and liver-related and cardiovascular complications. Preliminary evidence also suggests that improvement of NAFLD is associated with a decreased incidence of T2D. Similarly, the prevention of T2D following HCV eradication in the era of direct-acting antiviral agents is a biologically plausible result. However, additional studies are required for further clarification of mechanisms involved. PMID:27005620

  17. Association of nonalcoholic fatty liver disease with low bone mass in postmenopausal women.

    PubMed

    Moon, Seong-Su; Lee, Young-Sil; Kim, Sung Woo

    2012-10-01

    Osteoporosis is a disease associated with insulin resistant states such as central obesity, diabetes, and metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) is also increased in such conditions. However, little is known about whether osteoporosis and nonalcoholic fatty liver disease are etiologically related to each other or not. We examined whether bone mineral density (BMD) is associated with NAFLD in pre- and postmenopausal women. Four hundred eighty-one female subjects (216 premenopausal and 265 postmenopausal) were enrolled. Lumbar BMD was measured using dual-energy X-ray absorptiometry. Liver ultrasonography was done to check the severity of fatty liver. We excluded subjects with a secondary cause of liver disease. Blood pressure, lipid profile, fasting plasma glucose, alanine aminotransferase (ALT), aspartate aminotransferase, and body mass index were measured in every subject. Mean lumbar BMD was lower in subjects with NAFLD than those without NAFLD in postmenopausal women (0.98 ± 0.01 vs. 1.01 ± 0.02 g/cm², P = 0.046). Multiple correlation analysis revealed a significant association between mean lumbar BMD and NAFLD in postmenopausal subjects after adjusting for age, body mass index, ALT, smoking status, and alcohol consumption (β coefficient -0.066, 95% CI -0.105 to -0.027, P = 0.001). Even after adjusting the presence of metabolic syndrome, the significance was maintained (β coefficient -0.043, 95% CI -0.082 to -0.004, P = 0.031). Lumbar BMD is related with NAFLD in postmenopausal females. We suggest that postmenopausal women with NAFLD may have a higher risk of osteoporosis than those without.

  18. Oxyresveratrol ameliorates nonalcoholic fatty liver disease by regulating hepatic lipogenesis and fatty acid oxidation through liver kinase B1 and AMP-activated protein kinase.

    PubMed

    Lee, Ju-Hee; Baek, Su Youn; Jang, Eun Jeong; Ku, Sae Kwang; Kim, Kyu Min; Ki, Sung Hwan; Kim, Chang-Eop; Park, Kwang Il; Kim, Sang Chan; Kim, Young Woo

    2018-06-01

    Oxyresveratrol (OXY) is a naturally occurring polyhydroxylated stilbene that is abundant in mulberry wood (Morus alba L.), which has frequently been supplied as a herbal medicine. It has been shown that OXY has regulatory effects on inflammation and oxidative stress, and may have potential in preventing or curing nonalcoholic fatty liver disease (NAFLD). This study examined the effects of OXY on in vitro model of NAFLD in hepatocyte by the liver X receptor α (LXRα)-mediated induction of lipogenic genes and in vivo model in mice along with its molecular mechanism. OXY inhibited the LXRα agonists-mediated sterol regulatory element binding protein-1c (SREBP-1c) induction and expression of the lipogenic genes and upregulated the mRNA of fatty acid β-oxidation-related genes in hepatocytes, which is more potent than genistein and daidzein. OXY also induced AMP-activated protein kinase (AMPK) activation in a time-dependent manner. Moreover, AMPK activation by the OXY treatment helped inhibit SREBP-1c using compound C as an AMPK antagonist. Oral administration of OXY decreased the Oil Red O stained-positive areas significantly, indicating lipid droplets and hepatic steatosis regions, as well as the serum parameters, such as fasting glucose, total cholesterol, and low density lipoprotein-cholesterol in high fat diet fed-mice, as similar with orally treatment of atorvastatin. Overall, this result suggests that OXY has the potency to inhibit hepatic lipogenesis through the AMPK/SREBP-1c pathway and can be used in the development of pharmaceuticals to prevent a fatty liver. Copyright © 2018. Published by Elsevier B.V.

  19. Extended hepatectomy using the bipolar tissue sealer: an experimental model of small-for-size syndrome in pigs.

    PubMed

    Athanasiou, Antonios; Kontos, Michael; Pikoulis, Emmanouil; Griniatsos, John; Papalois, Apostolos; Spartalis, Eleftherios; Moris, Demetrios; Felekouras, Evangelos; Liakakos, Theodoros

    2016-01-01

    After liver transplantation with a small-for-size liver graft or after extensive hepatectomy for liver malignancies or other non malignant conditions with an insufficient liver volume, the survival of patients depends on liver regeneration. This study was carried out in order to create a new porcine model for the study of small-for-size syndrome (SFSS) after extensive hepatectomy. In the present study we used 23 domestic Landrace pigs weighing 28.3±3 kg and aged 19-21 weeks. We describe our detailed surgical procedure for 75% partial hepatectomy a in porcine model, using the saline-coupled bipolar sealing device (Aquamantys®) for hepatectomy. The Aquamantis 2.3 bipolar sealer was connected to the Aquamantis generator and was adjusted to produce 150 watts at a medium flow rate of 20 ml/min. The device temperature was programmed to remain at approximately 100° C and, as a consequence, it produced a tissue ablation without charring. The mean operating time was 153.8 min and the mean blood loss 81.9 ml. The estimated residual liver weight (ERL) was 177 g, whereas the mean proportion of ERL was 24.5%. There was no perioperative mortality. A large animal model, such as pig, is extremely useful in order to reproduce and understand the SFSS. Our simple technique for successful resection of 75% of the liver in pigs, using the Aquamantys system, achieves effective and safe liver parenchymal transection with significant decrease of intraoperative blood loss and can provide useful information for researchers.

  20. Remote ischemic preconditioning protects liver ischemia-reperfusion injury by regulating eNOS-NO pathway and liver microRNA expressions in fatty liver rats.

    PubMed

    Duan, Yun-Fei; An, Yong; Zhu, Feng; Jiang, Yong

    2017-08-15

    Ischemic preconditioning (IPC) is a strategy to reduce ischemia-reperfusion (I/R) injury. The protective effect of remote ischemic preconditioning (RIPC) on liver I/R injury is not clear. This study aimed to investigate the roles of RIPC in liver I/R in fatty liver rats and the involvement of endothelial nitric oxide synthase-nitric oxide (eNOS-NO) pathway and microRNA expressions in this process. A total of 32 fatty rats were randomly divided into the sham group, I/R group, RIPC group and RIPC+I/R group. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and nitric oxide (NO) were measured. Hematoxylin-eosin staining was used to observe histological changes of liver tissues, TUNEL to detect hepatocyte apoptosis, and immunohistochemistry assay to detect heat shock protein 70 (HSP70) expression. Western blotting was used to detect liver inducible NOS (iNOS) and eNOS protein levels and real-time quantitative polymerase chain reaction to detect miR-34a, miR-122 and miR-27b expressions. Compared with the sham and RIPC groups, serum ALT, AST and iNOS in liver tissue were significantly higher in other two groups, while serum NO and eNOS in liver tissue were lower, and varying degrees of edema, degeneration and inflammatory cell infiltration were found. Cell apoptosis number was slightly lower in the RIPC+I/R group than that in I/R group. Compared with the sham group, HSP70 expressions were significantly increased in other three groups (all P<0.05). Compared with the sham and RIPC groups, elevated miR-34a expressions were found in I/R and RIPC+I/R groups (P<0.05). MiR-122 and miR-27b were found significantly decreased in I/R and RIPC+I/R groups compared with the sham and RIPC groups (all P<0.05). RIPC can reduce fatty liver I/R injury by affecting the eNOS-NO pathway and liver microRNA expressions. Copyright © 2017 The Editorial Board of Hepatobiliary & Pancreatic Diseases International. Published by Elsevier B.V. All rights reserved.

  1. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Buzzetti, Elena; Pinzani, Massimo; Tsochatzis, Emmanuel A

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency.

    PubMed

    Spencer, Melanie D; Hamp, Timothy J; Reid, Robert W; Fischer, Leslie M; Zeisel, Steven H; Fodor, Anthony A

    2011-03-01

    Nonalcoholic fatty liver disease affects up to 30% of the US population, but the mechanisms underlying this condition are incompletely understood. We investigated how diet standardization and choline deficiency influence the composition of the microbial community in the human gastrointestinal tract and the development of fatty liver under conditions of choline deficiency. We performed a 2-month inpatient study of 15 female subjects who were placed on well-controlled diets in which choline levels were manipulated. We used 454-FLX pyrosequencing of 16S ribosomal RNA bacterial genes to characterize microbiota in stool samples collected over the course of the study. The compositions of the gastrointestinal microbial communities changed with choline levels of diets; each individual's microbiome remained distinct for the duration of the experiment, even though all subjects were fed identical diets. Variations between subjects in levels of Gammaproteobacteria and Erysipelotrichi were directly associated with changes in liver fat in each subject during choline depletion. Levels of these bacteria, change in amount of liver fat, and a single nucleotide polymorphism that affects choline were combined into a model that accurately predicted the degree to which subjects developed fatty liver on a choline-deficient diet. Host factors and gastrointestinal bacteria each respond to dietary choline deficiency, although the gut microbiota remains distinct in each individual. We identified bacterial biomarkers of fatty liver that result from choline deficiency, adding to the accumulating evidence that gastrointestinal microbes have a role in metabolic disorders. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  3. Appropriate donor size for porcine liver xenotransplant.

    PubMed

    Soleimani, Mehrdad; Fonouni, Hamidreza; Esmaeilzadeh, Majid; Kashfi, Arash; Fani Yazdi, Seyed Hashem; Golriz, Mohammad; Hafezi, Mohammadreza; Rahbari, Nuh N; Schmidt, Jan; Mehrabi, Arianeb

    2012-04-01

    Owing to an imbalance between demand and supply, which is more prominent in pediatric transplant, every year more patients lose their lives on waiting lists. In addition to the use of deceased-donor split and living-donor organs, xenotransplant could provide a solution if associated problems, such as immunologic and physiologic ones, are solved. This study sought to analyze the surgical aspects for liver xenotransplant in a porcine model. Landrace pigs (n=22, 23 to 37 kg) underwent a laparotomy under general anesthesia. The hepatic hilum was prepared and the common bile ducts, common hepatic artery, portal vein, supra- and infrahepatic inferior vena cava were identified. The length and diameter of each vessel and bile duct and the weight of the liver were measured. Pearson tests showed a clear correlation between the increase of the pigs' weight and the livers' weight, and the length of the vessels and the bile ducts. We did not find a clear correlation between the increase of the pigs' liver weight and the diameters of the vessels and the bile duct. As the first reporting, this study on xenotransplants from the surgical point of view, we postulate that it could be possible to estimate the size of the liver and the proper length of its vessels and bile duct by weighing only the pigs. It was not feasible to match the diameter of mentioned structures by the livers' weight. However, the weight of pig's liver as well as vascular anatomy of pigs appeared to be suitable alternative for the human liver.

  4. Choline Metabolism Provides Novel Insights into Non-alcoholic Fatty Liver Disease and its Progression

    PubMed Central

    Corbin, Karen D.; Zeisel, Steven H.

    2013-01-01

    Purpose of review Choline is an essential nutrient and the liver is a central organ responsible for choline metabolism. Hepatosteatosis and liver cell death occur when humans are deprived of choline. In the last few years there have been significant advances in our understanding of the mechanisms that influence choline requirements in humans and in our understanding of choline’s effects on liver function. These advances are useful in elucidating why non-alcoholic fatty liver disease (NAFLD) occurs and progresses sometimes to hepatocarcinogenesis. Recent findings Humans eating low choline diets develop fatty liver and liver damage,. This dietary requirement for choline is modulated by estrogen and by single nucleotide polymorphisms (SNPs) in specific genes of choline and folate metabolism. The spectrum of choline’s effects on liver range from steatosis to development of hepatocarcinomas, and several mechanisms for these effects have been identified. They include abnormal phospholipid synthesis, defects in lipoprotein secretion, oxidative damage caused by mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Furthermore, the hepatic steatosis phenotype and can be characterized more fully via metabolomic signatures and is influenced by the gut microbiome. Importantly, the intricate connection between liver function, one carbon metabolism, and energy metabolism is just beginning to be elucidated. Summary Choline influences liver function, and the dietary requirement for this nutrient varies depending on an individual’s genotype and estrogen status. Understanding these individual differences is important for gastroenterologists seeking to understand why some individuals develop NAFLD and others do not, and why some patients tolerate total parenteral nutrition and others develop liver dysfunction. PMID:22134222

  5. Association between liver fibrosis and coronary heart disease risk in patients with nonalcoholic fatty liver disease.

    PubMed

    Dogan, Serkan; Celikbilek, Mehmet; Yilmaz, Yunus K; Sarikaya, Savas; Zararsiz, Gokmen; Serin, Halil I; Borekci, Elif; Akyol, Lütfi; Pirti, Ilyas; Davarci, Sena E

    2015-03-01

    Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as the most common cause of chronic liver disease worldwide. It has been shown that NAFLD in adults is associated with increased risk of coronary heart disease (CHD). Because of the limitations of liver biopsy, noninvasive scoring indexes such as the NAFLD fibrosis score (NFS) were developed. The Framingham risk score (FRS) provides an estimate of CHD risk. In our study we aimed to investigate whether the severity of liver fibrosis estimated with the NFS is associated with a higher risk of CHD among individuals with ultrasonography-diagnosed NAFLD. A total of 155 patients and controls (81 patients with NAFLD and 74 controls) with ages ranging from 18 to 70 years were enrolled in this cross-sectional prospective study. Demographic, anthropometric, clinical, and laboratory data were obtained from each individual. The NAFLD patients were divided into subgroups on the basis of the severity of fatty liver. The FRS and NFS were adopted to predict the risk of CHD and the severity of hepatic fibrosis. In our study, we found that the FRS was higher in NAFLD patients than in controls (P<0.05). According to the FRS category, NFSs were higher in the intermediate/high probability CHD risk group in NAFLD (P<0.05). In multiple models, only age, sex, cholesterol, and HDL were independently associated with intermediate/high CHD risk (P<0.05). We also found a positive correlation between the NFS and the FRS (r=0.373, P<0.001). The optimum NFS cutoff point for identifying intermediate/high CHD risk in NAFLD patients was -2.1284, with a sensitivity and specificity of 95.20 and 48.30%, respectively. The predictive performance of the NFS in the determination of intermediate/high CHD risk in NAFLD patients was found to be 72% based on the area under the curve value. The FRS is associated with the NFS in NAFLD. The assessment of liver fibrosis may be useful for the risk stratification of CHD in the absence of liver

  6. Nonalcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis in Childhood: Endocrine-Metabolic “Mal-Programming”

    PubMed Central

    Manti, Sara; Romano, Claudio; Chirico, Valeria; Filippelli, Martina; Cuppari, Caterina; Loddo, Italia; Salpietro, Carmelo; Arrigo, Teresa

    2014-01-01

    Context: Nonalcoholic Fatty Liver Disease (NAFLD) is the major chronic liver disease in the pediatric population. NAFLD includes a broad spectrum of abnormalities (inflammation, fibrosis and cirrhosis), ranging from accumulation of fat (also known as steatosis) towards non-alcoholic steatohepatitis (NASH). The development of NAFLD in children is significantly increased. Evidence Acquisition: A literature search of electronic databases was undertaken for the major studies published from 1998 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the key words: "non-alcoholic fatty liver disease, children, non-alcoholic steatohepatitis and fatty liver". Results: NAFLD/NASH is probably promoted by “multiple parallel hits”: environmental and genetic factors, systemic immunological disorders (oxidative stress, persistent-low grade of inflammation) as well as obesity and metabolic alterations (insulin resistance and metabolic syndrome). However its exact cause still underdiagnosed and unknown. Conclusions: Pediatric NAFLD/NASH is emerging problem. Longitudinal follow-up studies, unfortunately still insufficient, are needed to better understand the natural history and outcome of NAFLD in children. This review focuses on the current knowledge regarding the epidemiology, pathogenesis, environmental, genetic and metabolic factors of disease. The review also highlights the importance of studying the underlying mechanisms of pediatric NAFLD and the need for complete and personalized approach in the management of NAFLD/NASH. PMID:24829591

  7. Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury.

    PubMed

    Llacuna, Laura; Fernández, Anna; Montfort, Claudia Von; Matías, Núria; Martínez, Laura; Caballero, Francisco; Rimola, Antoni; Elena, Montserrat; Morales, Albert; Fernández-Checa, José C; García-Ruiz, Carmen

    2011-05-01

    Liver steatosis enhances ischemia/reperfusion (I/R) injury and is considered a primary factor in graft failure after liver transplantation. Although previous reports have shown a role for qualitative steatosis (macrovesicular vs. microvesicular) in hepatic I/R injury, no studies have compared side by side the specific contribution of individual lipids accumulating in fatty liver to I/R damage. We used nutritional and genetic models of micro and macrovesicular fatty livers exhibiting specific lipid profiles to assess their susceptibility to normothermic I/R injury. Unlike choline-deficient (CD) diet-fed mice, characterized by predominant liver triglycerides/free fatty acids (TG/FFA) accumulation, mice fed a cholesterol-enriched (HC) diet, which exhibited enhanced hepatic cholesterol loading in mitochondria, were highly sensitive to I/R-induced liver injury. In vivo two-photon confocal imaging revealed enhanced mitochondrial depolarization and generation of reactive oxygen species following hepatic I/R in HC-fed but not in CD-fed mice, consistent with decreased mitochondrial GSH (mGSH) observed in HC-fed mice. Moreover, ob/ob mice, characterized by increased hepatic TG, FFA, and cholesterol levels, were as sensitive to I/R-mediated liver injury as mice fed the HC diet. Livers from ob/ob mice displayed increased StAR expression and mitochondrial cholesterol accumulation, resulting in mGSH depletion. Interestingly, atorvastatin therapy or squalene synthase inhibition in vivo attenuated StAR overexpression, mitochondrial cholesterol loading, and mGSH depletion, protecting ob/ob mice from I/R-mediated liver injury. Cholesterol accumulation, particularly in mitochondria, sensitizes to hepatic I/R injury, and thus represents a novel target to prevent the enhanced damage of steatotic livers to I/R-mediated damage. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  8. Oily fish, coffee and walnuts: Dietary treatment for nonalcoholic fatty liver disease.

    PubMed

    Gupta, Vikas; Mah, Xian-Jun; Garcia, Maria Carmela; Antonypillai, Christina; van der Poorten, David

    2015-10-07

    Rates of non-alcoholic fatty liver disease (NAFLD) are increasing worldwide in tandem with the metabolic syndrome, with the progressive form of disease, non-alcoholic steatohepatitis (NASH) likely to become the most common cause of end stage liver disease in the not too distant future. Lifestyle modification and weight loss remain the main focus of management in NAFLD and NASH, however, there has been growing interest in the benefit of specific foods and dietary components on disease progression, with some foods showing protective properties. This article provides an overview of the foods that show the most promise and their potential benefits in NAFLD/NASH, specifically; oily fish/ fish oil, coffee, nuts, tea, red wine, avocado and olive oil. Furthermore, it summarises results from animal and human trials and highlights potential areas for future research.

  9. Dietary β-conglycinin prevents fatty liver induced by a high-fat diet by a decrease in peroxisome proliferator-activated receptor γ2 protein.

    PubMed

    Yamazaki, Tomomi; Kishimoto, Kyoko; Miura, Shinji; Ezaki, Osamu

    2012-02-01

    Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). Mice fed a high-fat diet, especially that of saturated-fat-rich oil, develop fatty liver with an increase in peroxisome proliferator-activated receptor (PPAR) γ2 protein in liver. The fatty liver induced by a high-fat diet is improved by knockdown of liver PPARγ2. In this study, we investigated whether β-conglycinin (a major protein of soy protein) could reduce PPARγ2 protein and prevent high-fat-diet-induced fatty liver in ddY mice. Mice were fed a high-starch diet (70 energy% [en%] starch) plus 20% (wt/wt) sucrose in their drinking water or a high-safflower-oil diet (60 en%) or a high-butter diet (60 en%) for 11 weeks, by which fatty liver is developed. As a control, mice were fed a high-starch diet with drinking water. Either β-conglycinin or casein (control) was given as dietary protein. β-Conglycinin supplementation completely prevented fatty liver induced by each type of diet, along with a reduction in adipose tissue weight. β-Conglycinin decreased sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP) messenger RNAs (mRNAs) in sucrose-supplemented mice, whereas it decreased PPARγ2 mRNA (and its target genes CD36 and FSP27), but did not decrease SREBP-1c and ChREBP mRNAs, in mice fed a high-fat diet. β-Conglycinin decreased PPARγ2 protein and liver triglyceride (TG) concentration in a dose-dependent manner in mice fed a high-butter diet; a significant decrease in liver TG concentration was observed at a concentration of 15 en%. In conclusion, β-conglycinin effectively prevents fatty liver induced by a high-fat diet through a decrease in liver PPARγ2 protein. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease.

    PubMed

    Jensen, Thomas; Abdelmalek, Manal F; Sullivan, Shelby; Nadeau, Kristen J; Green, Melanie; Roncal, Carlos; Nakagawa, Takahiko; Kuwabara, Masanari; Sato, Yuka; Kang, Duk-Hee; Tolan, Dean R; Sanchez-Lozada, Laura G; Rosen, Hugo R; Lanaspa, Miguel A; Diehl, Anna Mae; Johnson, Richard J

    2018-05-01

    Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome; its rising prevalence parallels the rise in obesity and diabetes. Historically thought to result from overnutrition and a sedentary lifestyle, recent evidence suggests that diets high in sugar (from sucrose and/or high-fructose corn syrup [HFCS]) not only increase the risk of NAFLD, but also non-alcoholic steatohepatitis (NASH). Herein, we review the experimental and clinical evidence that fructose precipitates fat accumulation in the liver, due to both increased lipogenesis and impaired fat oxidation. Recent evidence suggests that the predisposition to fatty liver is linked to the metabolism of fructose by fructokinase C, which results in ATP consumption, nucleotide turnover and uric acid generation that mediate fat accumulation. Alterations to gut permeability, the microbiome, and associated endotoxemia contribute to the risk of NAFLD and NASH. Early clinical studies suggest that reducing sugary beverages and total fructose intake, especially from added sugars, may have a significant benefit on reducing hepatic fat accumulation. We suggest larger, more definitive trials to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation, may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  11. Osthole improves glucose and lipid metabolism via modulation of PPARα/γ-mediated target gene expression in liver, adipose tissue, and skeletal muscle in fatty liver rats.

    PubMed

    Qi, Zhi-Gang; Zhao, Xi; Zhong, Wen; Xie, Mei-Lin

    2016-01-01

    Osthole may be a dual agonist of peroxisome proliferator-activated receptors (PPAR) α/γ and ameliorate the insulin resistance (IR), but its mechanisms are not yet understood completely. We investigated the effects of osthole on PPARα/γ-mediated target genes involved in glucose and lipid metabolism in liver, adipose tissue, and skeletal muscle in fatty liver and IR rats. The rat model was established by orally feeding high-fat and high-sucrose emulsion for 9 weeks. The experimental rats were treated with osthole 5-10 mg/kg by gavage after feeding the emulsion for 6 weeks, and were sacrificed 4 weeks after administration. After treatment with osthole 5-10 mg/kg for 4 weeks, the lipid levels in serum and liver were decreased by 37.9-67.2% and 31.4-38.5% for triglyceride, 33.1-47.5% and 28.5-31.2% for free fatty acid, respectively, the fasting blood glucose, fasting serum insulin, and homeostasis model assessment of IR were also decreased by 17.2-22.7%, 25.9-26.7%, and 37.5-42.8%, respectively. Osthole treatment might simultaneously decrease the sterol regulatory element binding protein-1c, diacylglycerol acyltransferase, and fatty acid synthase mRNA expressions in liver and adipose tissue, and increase the carnitine palmitoyltransferase-1A mRNA expression in liver and glucose transporter-4 mRNA expression in skeletal muscle, especially in the osthole 10 mg/kg group (p < 0.01). Osthole can improve glucose and lipid metabolism in fatty liver and IR rats, and its mechanisms may be associated with synergic modulation of PPARα/γ-mediated target genes involved in glucose and lipid metabolism in liver, adipose tissue, and skeletal muscle.

  12. IMM-H007, a new therapeutic candidate for nonalcoholic fatty liver disease, improves hepatic steatosis in hamsters fed a high-fat diet.

    PubMed

    Shi, Huijie; Wang, Qingchun; Yang, Liu; Xie, Shouxia; Zhu, Haibo

    2017-09-01

    Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in humans, is characterized by the accumulation of triacylglycerols (TGs) in hepatocytes. We tested whether 2',3',5'-tri-acetyl-N6-(3-hydroxylaniline) adenosine (IMM-H007) can eliminate hepatic steatosis in hamsters fed a high-fat diet (HFD), as a model of NAFLD. Compared with HFD-only controls, IMM-H007 treatment significantly lowered serum levels of TG, total cholesterol, and free fatty acids (FFAs) in hamsters fed the HFD, with a prominent decrease in levels of serum transaminases and fasting insulin, without affecting fasting glucose levels. Moreover, 1 H-MRI and histopathological analyses revealed that hepatic lipid accumulation and fibrosis were improved by IMM-H007 treatment. These changes were accompanied by improvement of insulin resistance and oxidative stress, and attenuation of inflammation. IMM-H007 reduced expression of proteins involved in uptake of hepatic fatty acids and lipogenesis, and increased very low density lipoprotein secretion and expression of proteins responsible for fatty acid oxidation and autophagy. In studies in vivo , IMM-H007 inhibited fatty acid import into hepatocytes and liver lipogenesis, and concomitantly stimulated fatty acid oxidation, autophagy, and export of hepatic lipids. These data suggest that IMM-H007 resolves hepatic steatosis in HFD-fed hamsters by the regulation of lipid metabolism. Thus, IMM-H007 has therapeutic potential for NAFLD.

  13. Nonalcoholic fatty liver disease: Evolving paradigms

    PubMed Central

    Lonardo, Amedeo; Nascimbeni, Fabio; Maurantonio, Mauro; Marrazzo, Alessandra; Rinaldi, Luca; Adinolfi, Luigi Elio

    2017-01-01

    In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including ”lean NAFLD” has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extra-hepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible. PMID:29085206

  14. Prognostic Factors Affecting Rotator Cuff Healing After Arthroscopic Repair in Small to Medium-sized Tears.

    PubMed

    Park, Ji Soon; Park, Hyung Jun; Kim, Sae Hoon; Oh, Joo Han

    2015-10-01

    Small and medium-sized rotator cuff tears usually have good clinical and anatomic outcomes. However, healing failure still occurs in some cases. To evaluate prognostic factors for rotator cuff healing in patients with only small to medium-sized rotator cuff tears. Case-control study; Level of evidence, 3. Data were prospectively collected from 339 patients with small to medium-sized rotator cuff tears who underwent arthroscopic repair by a single surgeon between March 2004 and August 2012 and who underwent magnetic resonance imaging or computed tomographic arthrography at least 1 year after surgery. The mean age of the patients was 59.8 years (range, 39-80 years), and the mean follow-up time was 20.8 months (range, 12-66 months). The functional evaluation included the visual analog scale (VAS) for pain, American Shoulder and Elbow Surgeons score, Constant-Murley score, and Simple Shoulder Test. Postoperative VAS for pain and functional scores improved significantly compared with preoperative values (P < .001). Forty-five healing failures occurred (13.3%), and fatty degeneration of the infraspinatus muscle, tear size (anteroposterior dimension), and age were significant factors affecting rotator cuff healing (P < .001, = .018, and = .011, respectively) in multivariate logistic regression analysis. Grade II and higher infraspinatus fatty degeneration correlated with a higher failure rate. The failure rate was also significantly higher in patients with a tear >2 cm in size (34.2%) compared with patients with a tear ≤2 cm (10.6%) (P < .001). A receiver operating characteristic curve was used to determine the predictive cut-off value for the oldest age and the largest tear size for successful healing, which were calculated as 69 years and 2 cm, respectively, with a specificity of 90%. In small to medium-sized rotator cuff tears, grade II fatty degeneration of the infraspinatus muscle according to the Goutallier classification could be a reference point for successful

  15. The Fatty Liver Index has limited utility for the detection and quantification of hepatic steatosis in obese patients.

    PubMed

    Borman, Meredith A; Ladak, Farah; Crotty, Pam; Pollett, Aaron; Kirsch, Richard; Pomier-Layrargues, Gilles; Beaton, Melanie; Duarte-Rojo, Andres; Elkashab, Magdy; Myers, Robert P

    2013-06-01

    Noninvasive tools for the detection of hepatic steatosis are needed. The Fatty Liver Index (FLI), which includes body mass index (BMI), waist circumference, triglycerides, and γ-glutamyl-transferase, has been proposed as a screening tool for fatty liver. Our objective was to validate the FLI for the detection and quantification of hepatic steatosis in an obese population. Patients with chronic liver disease and BMI ≥ 28 kg/m(2) underwent liver biopsy and FLI determination. FLI performance for diagnosing steatosis compared with biopsy was assessed using areas under receiver operating characteristic curves (AUROCs), and a novel model for the prediction of significant steatosis (≥5 %) was derived. Among 250 included patients, 65 % were male, and the median BMI was 33 kg/m(2); 48 % had nonalcoholic fatty liver disease, and 77 % had significant (≥5 %) steatosis. The FLI was weakly correlated with the percentage (ρ = 0.25, p = 0.0001) and grade of steatosis (ρ = 0.28, p < 0.00005). The median FLI was higher among patients with significant steatosis (91 vs. 80 with <5 % steatosis; p = 0.0001) and the AUROC for this outcome was 0.67 (95 % CI 0.59-0.76). At an optimal FLI cut-off of 79, the FLI was 81 % sensitive and 49 % specific, and had positive and negative predictive values of 84 and 43 %, respectively. A novel index including triglycerides, glucose, alkaline phosphatase, and BMI outperformed the FLI for predicting significant steatosis [AUROCs 0.78 vs. 0.68; p = 0.009 (n = 247)]. In obese patients, the FLI is a poor predictor of significant steatosis and has limited utility for steatosis quantification compared with liver histology. A novel index including triglycerides, glucose, alkaline phosphatase, and BMI may be useful, but requires validation.

  16. Low-ω3 Fatty Acid and Soy Protein Attenuate Alcohol-Induced Fatty Liver and Injury by Regulating the Opposing Lipid Oxidation and Lipogenic Signaling Pathways

    PubMed Central

    Reyes-Gordillo, Karina; Shah, Ruchi; Varatharajalu, Ravi; Garige, Mamatha; Leckey, Leslie C.

    2016-01-01

    Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β) affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-ω3 fatty acid (Low-ω3FA) that primarily regulates PGC1α and soy protein (SP) that seems to have its major regulatory effect on PGC1β were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low ω3FA fish oil and soy protein. Low-ω3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver. They also prevented the downregulation of hepatic Sirtuin 1 (SIRT1) and PGC1α and their target fatty acid oxidation pathway genes and attenuated the upregulation of hepatic PGC1β and sterol regulatory element-binding protein 1c (SREBP1c) and their target lipogenic pathway genes via the phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK). Thus, these two novel modulators attenuate ethanol-induced hepatosteatosis and consequent liver injury potentially by regulating the two opposing lipid oxidation and lipogenic pathways. PMID:28074114

  17. Keap1-knockdown decreases fasting-induced fatty liver via altered lipid metabolism and decreased fatty acid mobilization from adipose tissue.

    PubMed

    Xu, Jialin; Donepudi, Ajay C; Moscovitz, Jamie E; Slitt, Angela L

    2013-01-01

    The purpose of this study was to determine whether Nrf2 activation, via Keap1-knockdown (Keap1-KD), regulates lipid metabolism and mobilization induced by food deprivation (e.g. fasting). Male C57BL/6 (WT) and Keap1-KD mice were either fed ad libitum or food deprived for 24 hours. After fasting, WT mice exhibited a marked increase in hepatic lipid accumulation, but Keap1-KD mice had an attenuated increase of lipid accumulation, along with reduced expression of lipogenic genes (acetyl-coA carboxylase, stearoyl-CoA desaturase-1, and fatty acid synthase) and reduced expression of genes related to fatty acid transport, such as fatty acid translocase/CD36 (CD36) and Fatty acid transport protein (FATP) 2, which may attribute to the reduced induction of Peroxisome proliferator-activated receptor (Ppar) α signaling in the liver. Additionally, enhanced Nrf2 activity by Keap1-KD increased AMP-activated protein kinase (AMPK) phosphorylation in liver. In white adipose tissue, enhanced Nrf2 activity did not change the lipolysis rate by fasting, but reduced expression of fatty acid transporters--CD36 and FATP1, via a PPARα-dependent mechanism, which impaired fatty acid transport from white adipose tissue to periphery circulation system, and resulted in increased white adipose tissue fatty acid content. Moreover, enhanced Nrf2 activity increased glucose tolerance and Akt phosphorylation levels upon insulin administration, suggesting Nrf2 signaling pathway plays a key role in regulating insulin signaling and enhanced insulin sensitivity in skeletal muscle. Enhanced Nrf2 activity via Keap1-KD decreased fasting-induced steatosis, pointing to an important function of Nrf2 on lipid metabolism under the condition of nutrient deprivation.

  18. FT3/FT4 ratio predicts non-alcoholic fatty liver disease independent of metabolic parameters in patients with euthyroidism and hypothyroidism

    PubMed Central

    Gökmen, Fatma Yahyaoğlu; Ahbab, Süleyman; Ataoğlu, Hayriye Esra; Türker, Betül Çavuşoğlu; Çetin, Faik; Türker, Fatih; Mamaç, Rabia Yahyaoğlu; Yenigün, Mustafa

    2016-01-01

    OBJECTIVE: This study was performed to evaluate the effects of metabolic parameters and thyroid dysfunction on the development of non-alcoholic fatty liver disease (NAFLD). METHODS: The current study evaluated a total of 115 patients, 75 female and 40 male. Physical examination and anthropometric measurements were applied to all participants. Hypothyroidism was considered at a thyroid stimulating hormone level ≥ 4.1 mIU/L. Patients with euthyroidism and patients with hypothyroidism were compared. Abdominal ultrasonography was used to diagnose non-alcoholic fatty liver disease. The participants were further compared with regard to the presence of non-alcoholic fatty liver disease. Logistic regression modeling was performed to identify the relationship between non-alcoholic fatty liver disease and independent variables, such as metabolic parameters and insulin resistance. RESULTS: Non-alcoholic fatty liver disease was identified in 69 patients. The mean waist circumference, body mass index, fasting plasma insulin, HOMA-IR (p<0.001) and FT3/FT4 ratio (p=0.01) values were significantly higher in the patients with NAFLD compared to those without it. Multivariate regression analysis revealed that FT3/FT4 ratio, waist circumference and insulin resistance were independent risk factors for non-alcoholic fatty liver disease. CONCLUSION: Insulin resistance, enlarged waist circumference, elevated body mass index, higher FT3/FT4 ratio and hypertriglyceridemia are independent risk factors for NADLF, whereas hypothyroidism is not directly related to the condition. PMID:27166773

  19. Non-alcoholic fatty liver disease and dyslipidemia: An update.

    PubMed

    Katsiki, Niki; Mikhailidis, Dimitri P; Mantzoros, Christos S

    2016-08-01

    Non-alcoholic fatty liver (NAFLD) is the most common liver disease worldwide, progressing from simple steatosis to necroinflammation and fibrosis (leading to non-alcoholic steatohepatitis, NASH), and in some cases to cirrhosis and hepatocellular carcinoma. Inflammation, oxidative stress and insulin resistance are involved in NAFLD development and progression. NAFLD has been associated with several cardiovascular (CV) risk factors including obesity, dyslipidemia, hyperglycemia, hypertension and smoking. NAFLD is also characterized by atherogenic dyslipidemia, postprandial lipemia and high-density lipoprotein (HDL) dysfunction. Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality. In this narrative review, the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients are discussed. NAFLD treatment is also reviewed with a focus on lipid-lowering drugs. Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Fructose as a key player in the development of fatty liver disease.

    PubMed

    Basaranoglu, Metin; Basaranoglu, Gokcen; Sabuncu, Tevfik; Sentürk, Hakan

    2013-02-28

    We aimed to investigate whether increased consumption of fructose is linked to the increased prevalence of fatty liver. The prevalence of nonalcoholic steatohepatitis (NASH) is 3% and 20% in nonobese and obese subjects, respectively. Obesity is a low-grade chronic inflammatory condition and obesity-related cytokines such as interleukin-6, adiponectin, leptin, and tumor necrosis factor-α may play important roles in the development of nonalcoholic fatty liver disease (NAFLD). Additionally, the prevalence of NASH associated with both cirrhosis and hepatocellular carcinoma was reported to be high among patients with type 2 diabetes with or without obesity. Our research group previously showed that consumption of fructose is associated with adverse alterations of plasma lipid profiles and metabolic changes in mice, the American Lifestyle-Induced Obesity Syndrome model, which included consumption of a high-fructose corn syrup in amounts relevant to that consumed by some Americans. The observation reinforces the concerns about the role of fructose in the obesity epidemic. Increased availability of fructose (e.g., high-fructose corn syrup) increases not only abnormal glucose flux but also fructose metabolism in the hepatocyte. Thus, the anatomic position of the liver places it in a strategic buffering position for absorbed carbohydrates and amino acids. Fructose was previously accepted as a beneficial dietary component because it does not stimulate insulin secretion. However, since insulin signaling plays an important role in central mechanisms of NAFLD, this property of fructose may be undesirable. Fructose has a selective hepatic metabolism, and provokes a hepatic stress response involving activation of c-Jun N-terminal kinases and subsequent reduced hepatic insulin signaling. As high fat diet alone produces obesity, insulin resistance, and some degree of fatty liver with minimal inflammation and no fibrosis, the fast food diet which includes fructose and fats produces

  1. Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver.

    PubMed

    Lanaspa, Miguel A; Sanchez-Lozada, Laura G; Choi, Yea-Jin; Cicerchi, Christina; Kanbay, Mehmet; Roncal-Jimenez, Carlos A; Ishimoto, Takuji; Li, Nanxing; Marek, George; Duranay, Murat; Schreiner, George; Rodriguez-Iturbe, Bernardo; Nakagawa, Takahiko; Kang, Duk-Hee; Sautin, Yuri Y; Johnson, Richard J

    2012-11-23

    Uric acid is an independent risk factor in fructose-induced fatty liver, but whether it is a marker or a cause remains unknown. Hepatocytes exposed to uric acid developed mitochondrial dysfunction and increased de novo lipogenesis, and its blockade prevented fructose-induced lipogenesis. Rather than a consequence, uric acid induces fatty liver Hyperuricemic people are more prone to develop fructose-induced fatty liver. Metabolic syndrome represents a collection of abnormalities that includes fatty liver, and it currently affects one-third of the United States population and has become a major health concern worldwide. Fructose intake, primarily from added sugars in soft drinks, can induce fatty liver in animals and is epidemiologically associated with nonalcoholic fatty liver disease in humans. Fructose is considered lipogenic due to its ability to generate triglycerides as a direct consequence of the metabolism of the fructose molecule. Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis. These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states.

  2. Characterization of fat metabolism in the fatty liver caused by a high-fat, low-carbohydrate diet: A study under equal energy conditions

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kurosaka, Yuka; Shiroya, Yoko; Yamauchi, Hideki

    The pathology of fatty liver due to increased percentage of calories derived from fat without increased overall caloric intake is largely unclear. In this study, we aimed to characterize fat metabolism in rats with fatty liver resulting from consumption of a high-fat, low-carbohydrate (HFLC) diet without increased caloric intake. Four-week-old male Sprague-Dawley rats were randomly assigned to the control (Con) and HFLC groups, and rats were fed the corresponding diets ad libitum. Significant decreases in food intake per gram body weight were observed in the HFLC group compared with that in the Con group. Thus, there were no significant differencesmore » in body weights or caloric intake per gram body weight between the two groups. Marked progressive fat accumulation was observed in the livers of rats in the HFLC group, accompanied by suppression of de novo lipogenesis (DNL)-related proteins in the liver and increased leptin concentrations in the blood. In addition, electron microscopic observations revealed that many lipid droplets had accumulated within the hepatocytes, and mitochondrial numbers were reduced in the hepatocytes of rats in the HFLC group. Our findings confirmed that consumption of the HFLC diet induced fatty liver, even without increased caloric intake. Furthermore, DNL was not likely to be a crucial factor inducing fatty liver with standard energy intake. Instead, ultrastructural abnormalities found in mitochondria, which may cause a decline in β-oxidation, could contribute to the development of fatty liver. - Highlights: • The high-fat, low-carbohydrate diet did not affect body weight or caloric intake. • The high-fat, low-carbohydrate diet caused fatty liver in rats. • De novo lipogenesis was not a crucial factor in fatty liver. • Mitochondria were altered in fatty livers of rats consuming this diet.« less

  3. Physical Activity is Related to Fatty Liver Marker in Obese Youth, Independently of Central Obesity or Cardiorespiratory Fitness

    PubMed Central

    Martins, Clarice; Aires, Luisa; Júnior, Ismael Freitas; Silva, Gustavo; Silva, Alexandre; Lemos, Luís; Mota, Jorge

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent complications associated with excess adiposity and has been identified as the leading cause of liver disease in pediatric populations worldwide. Because cardiorespiratory fitness (CRF) is related to physical activity (PA) levels, and increased PA plays a protective role against NAFLD risk factors, the aim of this study was to analyze the association between PA and a fatty liver marker (alanine aminotransferase - ALT) in obese children and adolescents, independently of central adiposity or CRF. 131 obese children (83 girls, 7-15 year-olds) involved in a PA promotion program comprised the sample. Measurements included anthropometric and body composition evaluations (DEXA), biological measurements (venipuncture), CRF (progressive treadmill test), PA (accelerometry), and maturational stage (Tanner criteria). The associations between ALT with PA intensities, central obesity, and CRF were calculated by three different models of linear regression, adjusted for potential confounders. Level of significance was set at 95%. RESULTS: ALT was negatively associated with MVPA (β = -0.305), and CRF (β = -0.426), and positively associated with central obesity (β=.468). After adjustment for central obesity the negative and statistically significant association between ALT with MVPA (β = -0.364) and CRF (β = -0.550) still persists while a positive and significantly correlation was shown between ALT and SB (β = 0.382). Additional adjustment for CRF (Model 3) showed significant associations for all the PA intensities analyzed including light activity. PA at different intensities is associated to a fatty liver marker in obese children and adolescents, independently of central adiposity or CRF. Key points In a previous study our group observed that there might be a potential protective effect of cardiorespiratory fitness (CRF) against abnormal ALT values; Considering that CRF is related to physical activity (PA

  4. Plasma plasminogen activator inhibitor-1 levels and nonalcoholic fatty liver in individuals with features of metabolic syndrome.

    PubMed

    de Larrañaga, Gabriela; Wingeyer, Silvia Perés; Graffigna, Mabel; Belli, Susana; Bendezú, Karla; Alvarez, Silvia; Levalle, Oscar; Fainboim, Hugo

    2008-07-01

    Fatty liver represents the liver component of metabolic syndrome and may be involved in plasminogen activator inhibitor-1 (PAI-1) synthesis. We studied plasma PAI-1 levels and relationships with risk factors for metabolic syndrome, including fatty liver, in 170 patients. Liver ultrasound scan was performed on all patients, and a liver biopsy was performed on those patients with chronically elevated transaminase levels. Plasma PAI-1 levels correlated significantly (P < .05) with body mass index, degree of steatosis, insulin resistance, insulin level, waist circumference, triglycerides, and high-density lipoprotein (HDL) -cholesterol. However, only body mass index (beta = .455) and HDL-cholesterol (beta = .293) remained predictors of PAI-1 levels. Liver biopsy revealed a significant correlation (P < .05) between insulin resistance (r = 0.381) or insulin level (r = 0.519) and liver fibrosis. In patients presenting features of metabolic syndrome, plasma PAI-1 levels were mainly conditioned by the whole-body fat content.

  5. Design and rationale of the WELCOME trial: A randomised, placebo controlled study to test the efficacy of purified long chainomega-3 fatty acid treatment in non-alcoholic fatty liver disease [corrected].

    PubMed

    Scorletti, E; Bhatia, L; McCormick, K G; Clough, G F; Nash, K; Calder, P C; Byrne, C D

    2014-03-01

    Non-alcoholic fatty liver disease (NAFLD) represents a range of liver conditions from simple fatty liver to progressive end stage liver disease requiring liver transplantation. NAFLD is common in the population and in certain sub groups (e.g. type 2 diabetes) up to 70% of patients may be affected. NAFLD is not only a cause of end stage liver disease and hepatocellular carcinoma, but is also an independent risk factor for type 2 diabetes and cardiovascular disease. Consequently, effective treatments for NAFLD are urgently needed. The WELCOME study is testing the hypothesis that treatment with high dose purified long chain omega-3 fatty acids will have a beneficial effect on a) liver fat percentage and b) two histologically validated algorithmically-derived biomarker scores for liver fibrosis. In a randomised double blind placebo controlled trial, 103 participants with NAFLD were randomised to 15-18months treatment with either 4g/day purified long chain omega-3 fatty acids (Omacor) or 4g/day olive oil as placebo. Erythrocyte percentage DHA and EPA enrichment (a validated proxy for hepatic enrichment) was determined by gas chromatography. Liver fat percentage was measured in three discrete liver zones by magnetic resonance spectroscopy (MRS). We also measured body fat distribution, physical activity and a range of cardiometabolic risk factors. Recruitment started in January 2010 and ended in June 2011. We identified 178 potential participants, and randomised 103 participants who met the inclusion criteria. The WELCOME study was approved by the local ethics committee (REC: 08/H0502/165; www.clinicalTrials.gov registration number NCT00760513). Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Hepatic steatosis and non-alcoholic fatty liver disease are not associated with decline in renal function in people with Type 2 diabetes.

    PubMed

    Jenks, S J; Conway, B R; Hor, T J; Williamson, R M; McLachlan, S; Robertson, C; Morling, J R; Strachan, M W J; Price, J F

    2014-09-01

    We aimed to determine whether the presence of hepatic steatosis and/or non-alcoholic fatty liver disease was associated with decline in renal function or onset of microalbuminuria in a cohort of people with Type 2 diabetes, including those managed in both primary and secondary care. Nine hundred and thirty-three patients from the Edinburgh Type 2 Diabetes Study, a cohort of Scottish men and women aged 60-74 years with Type 2 diabetes, underwent assessment for hepatic steatosis by liver ultrasonography 1 year after recruitment. Non-alcoholic fatty liver disease was defined as the presence of steatosis following exclusion of secondary causes of liver disease. Patients were followed for 4 years and decline in renal function was assessed by the change in estimated glomerular filtration rate over time. Of the 933 subjects, 530 had hepatic steatosis and, of those with hepatic steatosis, 388 had non-alcoholic fatty liver disease. Neither hepatic steatosis nor non-alcoholic fatty liver disease were significantly associated with rate of decline in renal function, with the mean rate of decline in estimated glomerular filtration rate being -1.55 ml min(-1) 1.73 m(-2) per year for participants with hepatic steatosis compared with -1.84 ml min(-1) 1.73 m(-2) for those without steatosis (P = 0.19). Similar results were obtained when the analysis was restricted to participants with and without non-alcoholic fatty liver disease (-1.44 vs. -1.64 ml min(-1) 1.73 m(-2) per year, respectively; P = 0.44). Additionally, neither hepatic steatosis nor non-alcoholic fatty liver disease were associated with the onset or regression of albuminuria during follow-up (all P ≥ 0.05). The presence of hepatic steatosis/non-alcoholic fatty liver disease was not associated with decline in renal function during a 4-year follow-up in our cohort of older people with Type 2 diabetes. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

  7. Docosahexaenoic acid for the treatment of fatty liver: randomised controlled trial in children.

    PubMed

    Nobili, V; Alisi, A; Della Corte, C; Risé, P; Galli, C; Agostoni, C; Bedogni, G

    2013-11-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children. We tested whether dietary supplementation with docosahexaenoic acid (DHA) can decrease liver fat content in children with NAFLD. We performed a randomized controlled trial of DHA supplementation (250 mg/day and 500 mg/day) vs. placebo in 60 children with NAFLD (20 children per group). The main outcome was the change in liver fat as detected by ultrasonography after 6, 12, 18 and 24 months of treatment. Secondary outcomes were changes in triglycerides, alanine transaminase (ALT), body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA). The odds of more severe versus less severe liver steatosis decreased to the same degree at 6 months in children treated with DHA 250 mg/day and DHA 500 mg/day vs. placebo and persisted virtually unmodified for 24 months (OR ≤ 0.02, p ≤ 0.05 for all time points). Triglycerides were lower in the DHA groups than in the placebo group at any time point and ALT was lower in these groups from month 12 onwards. HOMA was lower in the DHA 250 mg group vs. placebo at months 6 and 12. DHA supplementation improves liver steatosis in children with NAFLD. Doses of 250 mg/day and 500 mg/day of DHA appear to be equally effective in reducing liver fat content. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Role of APN and TNF-α in type 2 diabetes mellitus complicated by nonalcoholic fatty liver disease.

    PubMed

    Lin, X; Zhang, Z; Chen, J M; Xu, Y Y; Ye, H R; Cui, J; Fang, Y; Jin, Y; Zhu, D R; Yuan, L

    2015-04-10

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by non-excessive alcohol consumption and is the most common cause of elevated levels of serum liver enzymes. We examined changes in adiponectin (APN) and tumor necrosis factor-α (TNF-α) in type 2 diabetes mellitus (T2DM) complicated by NAFLD and their relationships with insulin resistance (IR). Forty-two T2DM, 39 NAFLD, and 45 T2DM complicated with NAFLD (complicated group) patients were enrolled in this study. Body mass index, fasting blood plasma glucose (FPG), fasting insulin, triglyceride (TG), alanine aminotransferase, gamma-glutamyl transpeptidase, APN, TNF-α, and homeostasis model of assessment (HOMA)-IR were determined. The degree of fatty liver was graded according to liver/spleen computed tomography ratio and intrahepatic vessel manifestations. Compared with the T2DM and NAFLD groups, fasting blood plasma glucose, alanine aminotransferase, gamma-glutamyl transpeptidase, TG, TNF-α, and HOMA-IR in the complicated group were significantly increased, while APN was significantly reduced. Body mass index in the complicated group was significantly higher than in the T2DM group. The complicated group was prone to severe fatty liver compared with the NAFLD group. APN was negatively correlated with body mass index, fasting blood plasma glucose, TG, TNF-α, and HOMA-IR. TNF-α was negatively correlated with APN, but positively correlated with FPG, fasting insulin, TG, and HOMA-IR. The complicated group had clear IR. A more severe degree of fatty liver was associated with higher HOMA-IR and TNF-α and lower APN. APN was an important factor for antagonizing inflammation and mitigating IR.

  9. Effects of Delta-tocotrienol Supplementation on Liver Enzymes, Inflammation, Oxidative stress and Hepatic Steatosis in Patients with Nonalcoholic Fatty Liver Disease.

    PubMed

    Pervez, Muhammad Amjad; Khan, Dishad Ahmet; Ijaz, Aamir; Khan, Shamrez

    2018-03-01

    Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and is associated with increased morbidity and mortality. Currently, there is no definitive treatment for this disease. δ-Tocotrienol has potent anti-inflammatory and antioxidant properties and may reduce liver injury in NAFLD. The present study aims to evaluate the efficacy and safety of δ-tocotrienol in the treatment of NAFLD. The present study was a randomized, double-blind, placebo-controlled pilot study conducted in patients aged > 20 years, belonging to both sexes, having ultrasound-proven fatty liver disease, having a fatty liver index (FLI) of ≥ 60, and persistent elevation of alanine transaminase. A total of 71 patients were assigned to receive either oral δ-tocotrienol (n=35, 300 mg twice daily) or placebo (n=36) for 12 weeks. At the baseline and at the end of the study, clinical and biochemical parameters, including lipid profile, liver function tests, high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde (MDA) were measured. Body mass index and FLI were calculated, and ultrasound grading of hepatic steatosis was performed. Out of 71 enrolled patients, 64 patients, 31 in the δ-tocotrienol group and 33 in the placebo group, completed the study. After 12 weeks of supplementation, δ-tocotrienol showed greater efficacy than placebo by decreasing serum aminotransferases, hs-CRP, MDA, and FLI score (p<0.001). However, it did not improve hepatic steatosis on ultrasound examination. No adverse effects were reported. δ-Tocotrienol was safe, and it effectively improved aminotransferase levels and inflammatory and oxidative stress markers in patients with NAFLD. Large-scale randomized clinical trials are warranted to further support these findings.

  10. n-3 fatty acid-based parenteral nutrition improves postoperative recovery for cirrhotic patients with liver cancer: A randomized controlled clinical trial.

    PubMed

    Zhang, Binhao; Wei, Gang; Li, Rui; Wang, Yanjun; Yu, Jie; Wang, Rui; Xiao, Hua; Wu, Chao; Leng, Chao; Zhang, Bixiang; Chen, Xiao-Ping

    2017-10-01

    A new lipid emulsion enriched in n-3 fatty acid has been reported to prevent hepatic inflammation in patients following major surgery. However, the role of n-3 fatty acid-based parenteral nutrition for postoperative patients with cirrhosis-related liver cancer is unclear. We investigated the safety and efficacy of n-3 fatty acid-based parenteral nutrition for cirrhotic patients with liver cancer followed hepatectomy. A prospective randomized controlled clinical trial (Registered under ClinicalTrials.gov Identifier no. NCT02321202) was conducted for cirrhotic patients with liver cancer that underwent hepatectomy between March 2010 and September 2013 in our institution. We compared isonitrogenous total parenteral nutrition with 20% Structolipid and 10% n-3 fatty acid (Omegaven, Fresenius-Kabi, Germany) (treatment group) to Structolipid alone (control group) for five days postoperatively, in the absence of enteral nutrition. We enrolled 320 patients, and 312 (97.5%) were included in analysis (155 in the control group and 157 in the treatment group). There was a significant reduction of morbidity and mortality in the treatment group, when compared with the control group (total complications 78 [50.32%] vs. 46 [29.30%]; P < 0.001, total infective complications, 30 [19.35%] vs. 15 [9.55%]; P = 0.014), overall mortality (5 [3.23%] vs. 1 [0.64%]; P = 0.210), and hospital stay (12.56 ± 3.21 d vs. 10.17 ± 3.15 d; P = 0.018). We found that addition of n-3 fatty acid-based parenteral nutrition significantly improved postoperative recovery for cirrhotic patients with liver cancer following hepatectomy, with a significant reduction in overall mortality and length of hospital stay. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  11. STRUCTURAL AND FUNCTIONAL INTERACTION OF FATTY ACIDS WITH HUMAN LIVER FATTY ACID BINDING PROTEIN (L-FABP) T94A VARIANT

    PubMed Central

    Huang, Huan; McIntosh, Avery L.; Martin, Gregory G.; Landrock, Kerstin K.; Landrock, Danilo; Gupta, Shipra; Atshaves, Barbara P.; Kier, Ann B.; Schroeder, Friedhelm

    2014-01-01

    The human liver fatty acid binding protein (L-FABP) T94A variant, the most common in the FABP family, has been associated with elevated liver triglyceride (TG) levels. How this amino acid substitution elicits these effects is not known. This issue was addressed with human recombinant wild-type (WT, T94T) and T94A variant L-FABP proteins as well as cultured primary human hepatocytes expressing the respective proteins (genotyped as TT, TC, and CC). T94A substitution did not or only slightly alter L-FABP binding affinities for saturated, monounsaturated, or polyunsaturated long chain fatty acids (LCFA), nor did it change the affinity for intermediates in TG synthesis. Nevertheless, T94A substitution markedly altered the secondary structural response of L-FABP induced by binding LCFA or intermediates of TG synthesis. Finally, T94A substitution markedly diminished polyunsaturated fatty acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), induction of peroxisome proliferator-activated receptor alpha (PPARα) - regulated proteins such as L-FABP, fatty acid transport protein 5 (FATP5), and PPARα itself in cultured primary human hepatocytes. Thus, while T94A substitution did not alter the affinity of human L-FABP for LCFAs, it significantly altered human L-FABP structure and stability as well as conformational and functional response to these ligands. PMID:24628888

  12. Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis: a novel therapeutic target for fatty liver disease.

    PubMed

    Chen, Shuai; Kang, Yujia; Sun, Yan; Zhong, Yanhong; Li, Yanli; Deng, Lijuan; Tao, Jin; Li, Yang; Tian, Yingpu; Zhao, Yinan; Cheng, Jianghong; Liu, Wenjie; Feng, Gen-Sheng; Lu, Zhongxian

    2016-12-01

    Fatty liver disease is a serious health problem worldwide and is the most common cause for chronic liver disease and metabolic disorders. The major challenge in the prevention and intervention of this disease is the incomplete understanding of the underlying mechanism and thus lack of potent therapeutic targets due to multifaceted and interdependent disease factors. In this study, we investigated the role of a signaling adaptor protein, GRB2-associated-binding protein 2 (Gab2), in fatty liver using an animal disease model. Gab2 expression in hepatocytes responded to various disease factor stimulations, and Gab2 knockout mice exhibited resistance to fat-induced obesity, fat- or alcohol-stimulated hepatic steatosis, as well as methionine and choline deficiency-induced steatohepatitis. Concordantly, the forced expression or knockdown of Gab2 enhanced or diminished oleic acid (OA)- or ethanol-induced lipid production in hepatocytes in vitro, respectively. During lipid accumulation in hepatocytes, both fat and alcohol induced the recruitment of PI3K or Socs3 by Gab2 and the activation of their downstream signaling proteins AKT, ERK, and Stat3. Therefore, Gab2 may be a disease-associated protein that is induced by pathogenic factors to amplify and coordinate multifactor-induced signals to govern disease development in the liver. Our research provides a novel potential target for the prevention and intervention of fatty liver disease. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.

  13. Higher dietary choline intake is associated with lower risk of nonalcoholic fatty liver in normal-weight Chinese women.

    PubMed

    Yu, Danxia; Shu, Xiao-Ou; Xiang, Yong-Bing; Li, Honglan; Yang, Gong; Gao, Yu-Tang; Zheng, Wei; Zhang, Xianglan

    2014-12-01

    Choline deficiency has been shown to induce liver fat accumulation in both rodent and human studies. However, it is unclear whether dietary choline intake is related to fatty liver in the general population. We examined the association between choline intake and nonalcoholic fatty liver. Participants included 56,195 Chinese women and men, 40-75 y of age, with no or negligible alcohol consumption and with no history of hepatitis, cardiovascular disease, or cancer. All participants reported undergoing liver ultrasonography. Fatty liver was defined by self-report of a physician diagnosis. Habitual dietary intakes were assessed via validated food-frequency questionnaires. The average total choline intakes were 289 ± 85 mg/d in women and 318 ± 92 mg/d in men. Major food sources were eggs, soy foods, red meat, fish, and vegetables. A higher choline intake was associated with lower risk of fatty liver; after adjustment for sociodemographic characteristics, lifestyle factors, and other dietary intakes, the ORs (95% CIs) for the highest vs. the lowest quintiles of choline intake were 0.68 (0.59, 0.79) in women and 0.75 (0.60, 0.93) in men (both P-trend < 0.01). The inverse association was attenuated after further adjustment for history of metabolic disease and, in particular, BMI. The corresponding ORs (95% CIs) were 0.88 (0.75, 1.03) in women (P-trend = 0.05) and 0.85 (0.68, 1.06) in men (P-trend = 0.09). Stratified analyses suggested a potential effect modification by obesity status in women; the OR (95% CI) across extreme quintiles was 0.72 (0.57, 0.91) in normal-weight women vs. 1.05 (0.84, 1.31) in overweight or obese women (P-trend = 0.007 vs. 0.99, P-interaction < 0.0001). Higher dietary choline intake may be associated with lower risk of nonalcoholic fatty liver only in normal-weight Chinese women. © 2014 American Society for Nutrition.

  14. New scoring system combining the FIB-4 index and cytokeratin-18 fragments for predicting steatohepatitis and liver fibrosis in patients with nonalcoholic fatty liver disease.

    PubMed

    Tada, Toshifumi; Kumada, Takashi; Toyoda, Hidenori; Saibara, Toshiji; Ono, Masafumi; Kage, Masayoshi

    To establish a new scoring system as a noninvasive tool for predicting steatohepatitis and liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). A total of 170 patients histologically diagnosed with nonalcoholic steatohepatitis (NASH) (n = 130) or nonalcoholic fatty liver (NAFL) (n = 40) were enrolled. We analyzed receiver operating characteristic (ROC) curves and performed multivariate analysis to predict steatohepatitis and liver fibrosis. Multivariate analysis showed that cytokeratin-18 fragment (CK18-F) levels (≥278 U/L) (odds ratio [OR], 4.46; 95% confidence interval [CI], 1.42-14.00; p = 0.010) and the FIB-4 index (≥1.46) (OR, 4.54; 95% CI, 1.93-29.50; p = 0.004) were independently associated with prediction of NASH. We then established a new scoring system (named the FIC-22 score) for predicting NASH using CK18-F levels and FIB-4 index. The areas under the ROC curve (AUROCs) of the FIC-22 score and NAFIC score were 0.82 (95% CI, 0.75-0.89) and 0.71 (95% CI, 0.62-0.78) (p = 0.044). Additionally, the AUROC of the FIC-22 score for predicting the presence of fibrosis (F ≥ 1) was 0.78 (95% CI, 0.70-0.85). In patients with NAFLD, the FIC-22 score had high predictive accuracy not only for steatohepatitis but also for the presence of liver fibrosis.

  15. Breath volatile organic compounds for the gut-fatty liver axis: Promise, peril, and path forward

    PubMed Central

    Solga, Steven Francis

    2014-01-01

    The worldwide interest in the gut microbiome and its impact on the upstream liver highlight a critical upside to breath research: it can uniquely measure otherwise unmeasurable biology. Bacteria make gases [volatile organic compounds (VOCs)] that are directly relevant to pathophysiology of the fatty liver and associated conditions, including obesity. Measurement of these VOCs and their metabolites in the exhaled breath, therefore, present an opportunity to safely and easily evaluate, on both a personal and a population level, some of our most pressing public health threats. This is an opportunity that must be pursued. To date, however, breath analysis remains a slowly evolving field which only occasionally impacts clinical research or patient care. One major obstacle to progress is that breath analysis is inherently and emphatically mutli-disciplinary: it connects engineering, chemistry, breath mechanics, biology and medicine. Unbalanced or incomplete teams may produce inconsistent and often unsatisfactory results. A second impediment is the lack of a well-known stepwise structure for the development of non-invasive diagnostics. As a result, the breath research landscape is replete with orphaned single-center pilot studies. Often, important hypotheses and key observations have not been pursued to maturation. This paper reviews the rationale and requirements for breath VOC research applied to the gut-fatty liver axis and offers some suggestions for future development. PMID:25083075

  16. Isocaloric Dietary Changes and Non-Alcoholic Fatty Liver Disease in High Cardiometabolic Risk Individuals.

    PubMed

    Della Pepa, Giuseppe; Vetrani, Claudia; Lombardi, Gianluca; Bozzetto, Lutgarda; Annuzzi, Giovanni; Rivellese, Angela Albarosa

    2017-09-26

    Non-alcoholic fatty liver disease (NAFLD) incorporates an extensive spectrum of histologic liver abnormalities, varying from simple triglyceride accumulation in hepatocytes non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), and it is the most frequent chronic liver disease in the industrialized world. Beyond liver related complications such as cirrhosis and hepatocellular carcinoma, NAFLD is also an emerging risk factor for type 2 diabetes and cardiovascular disease. Currently, lifestyle intervention including strategies to reduce body weight and to increase regular physical activity represents the mainstay of NAFLD management. Total caloric intake plays a very important role in both the development and the treatment of NAFLD; however, apart from the caloric restriction alone, modifying the quality of the diet and modulating either the macro- or micronutrient composition can also markedly affect the clinical evolution of NAFLD, offering a more realistic and feasible treatment alternative. The aim of the present review is to summarize currently available evidence from randomized controlled trials on the effects of different nutrients including carbohydrates, lipids, protein and other dietary components, in isocaloric conditions, on NAFLD in people at high cardiometabolic risk. We also describe the plausible mechanisms by which different dietary components could modulate liver fat content.

  17. Isocaloric Dietary Changes and Non-Alcoholic Fatty Liver Disease in High Cardiometabolic Risk Individuals

    PubMed Central

    Della Pepa, Giuseppe; Vetrani, Claudia; Lombardi, Gianluca; Bozzetto, Lutgarda; Annuzzi, Giovanni; Rivellese, Angela Albarosa

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) incorporates an extensive spectrum of histologic liver abnormalities, varying from simple triglyceride accumulation in hepatocytes non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), and it is the most frequent chronic liver disease in the industrialized world. Beyond liver related complications such as cirrhosis and hepatocellular carcinoma, NAFLD is also an emerging risk factor for type 2 diabetes and cardiovascular disease. Currently, lifestyle intervention including strategies to reduce body weight and to increase regular physical activity represents the mainstay of NAFLD management. Total caloric intake plays a very important role in both the development and the treatment of NAFLD; however, apart from the caloric restriction alone, modifying the quality of the diet and modulating either the macro- or micronutrient composition can also markedly affect the clinical evolution of NAFLD, offering a more realistic and feasible treatment alternative. The aim of the present review is to summarize currently available evidence from randomized controlled trials on the effects of different nutrients including carbohydrates, lipids, protein and other dietary components, in isocaloric conditions, on NAFLD in people at high cardiometabolic risk. We also describe the plausible mechanisms by which different dietary components could modulate liver fat content. PMID:28954437

  18. Evidence and Recommendations for Imaging Liver Fat in Children, Based upon Systematic Review

    PubMed Central

    Awai, Hannah I.; Newton, Kimberly P.; Sirlin, Claude B.; Behling, Cynthia; Schwimmer, Jeffrey B.

    2013-01-01

    Background & Aims Fatty liver is a common problem in children, and increases their risk for cirrhosis, diabetes, and cardiovascular disease. Liver biopsy is the clinical standard for diagnosing and grading fatty liver. However, non-invasive imaging modalities are needed to assess liver fat in children. We performed a systematic review of studies that evaluated imaging of liver fat in children. Methods We searched PubMed for original research articles in peer-reviewed journals from January 1, 1982 through December 31, 2012 using the key words “imaging liver fat.” Studies included those in English, and those performed in children from birth to 18 y of age. To be eligible for inclusion, studies were required to measure hepatic steatosis via an imaging modality and a quantitative comparator as the reference standard. Results We analyzed 9 studies comprising 610 children; 4 studies assessed ultrasonography and 5 assessed magnetic resonance imaging (MRI). Ultrasonography was used in the diagnosis of fatty liver with positive predictive values of 47–62%. There was not a consistent relationship between ultrasound steatosis score and the reference measurement of hepatic steatosis. Liver fat as measurements by MRI or by spectroscopy varied with the methodologies used. Liver fat measurements by MRI correlated with results from histologic analyses, but sample size did not allow for assessment of diagnostic accuracy. Conclusions Available evidence does not support the use of ultrasonography for the diagnosis or grading of fatty liver in children. Although MRI is a promising approach, the data are insufficient to make evidence-based recommendations regarding its use in children for assessment of hepatic steatosis. PMID:24090729

  19. Evidence and recommendations for imaging liver fat in children, based on systematic review.

    PubMed

    Awai, Hannah I; Newton, Kimberly P; Sirlin, Claude B; Behling, Cynthia; Schwimmer, Jeffrey B

    2014-05-01

    Fatty liver is a common problem in children and increases their risk for cirrhosis, diabetes, and cardiovascular disease. Liver biopsy is the clinical standard for diagnosing and grading fatty liver. However, noninvasive imaging modalities are needed to assess liver fat in children. We performed a systematic review of studies that evaluated imaging liver fat in children. We searched PubMed for original research articles in peer-reviewed journals from January 1, 1982, through December 31, 2012, using the key words "imaging liver fat." Studies included those in English, and those performed in children from birth to 18 years of age. To be eligible for inclusion, studies were required to measure hepatic steatosis via an imaging modality and a quantitative comparator as the reference standard. We analyzed 9 studies comprising 610 children; 4 studies assessed ultrasonography and 5 studies assessed magnetic resonance imaging (MRI). Ultrasonography was used in the diagnosis of fatty liver with positive predictive values of 47% to 62%. There was not a consistent relationship between ultrasound steatosis score and the reference measurement of hepatic steatosis. Liver fat as measurements by MRI or by spectroscopy varied with the methodologies used. Liver fat measurements by MRI correlated with results from histologic analyses, but sample size did not allow for an assessment of diagnostic accuracy. Available evidence does not support the use of ultrasonography for the diagnosis or grading of fatty liver in children. Although MRI is a promising approach, the data are insufficient to make evidence-based recommendations regarding its use in children for the assessment of hepatic steatosis. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  20. Fibrosis Assessment in Nonalcoholic Fatty Liver Disease (NAFLD) in 2016.

    PubMed

    Kaswala, Dharmesh H; Lai, Michelle; Afdhal, Nezam H

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver pathologies characterized by hepatic steatosis with a history of little to no alcohol consumption or secondary causes of hepatic steatosis. The prevalence of NAFLD is 20-25 % of the general population in the Western countries and is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. The spectrum of disease ranges from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis. Advanced fibrosis is the most significant predictor of mortality in NAFLD. It is crucial to assess for the presence and degree of hepatic fibrosis in order to make therapeutic decisions and predict clinical outcomes. Liver biopsy, the current gold standard to assess the liver fibrosis, has a number of drawbacks such as invasiveness, sampling error, cost, and inter-/intra-observer variability. There are currently available a number of noninvasive tests as an alternative to liver biopsy for fibrosis staging. These noninvasive fibrosis tests are increasingly used to rule out advanced fibrosis and help guide disease management. While these noninvasive tests perform relatively well for ruling out advanced fibrosis, they also have limitations. Understanding the strengths and limitations of liver biopsy and the noninvasive tests is necessary for deciding when to use the appropriate tests in the evaluation of patients with NAFLD.

  1. Over-dose insulin and stable gastric pentadecapeptide BPC 157. Attenuated gastric ulcers, seizures, brain lesions, hepatomegaly, fatty liver, breakdown of liver glycogen, profound hypoglycemia and calcification in rats.

    PubMed

    Ilic, S; Brcic, I; Mester, M; Filipovic, M; Sever, M; Klicek, R; Barisic, I; Radic, B; Zoricic, Z; Bilic, V; Berkopic, L; Brcic, L; Kolenc, D; Romic, Z; Pazanin, L; Seiwerth, S; Sikiric, P

    2009-12-01

    We focused on over-dose insulin (250 IU/kg i.p.) induced gastric ulcers and then on other disturbances that were concomitantly induced in rats, seizures (eventually fatal), severely damaged neurons in cerebral cortex and hippocampus, hepatomegaly, fatty liver, increased AST, ALT and amylase serum values, breakdown of liver glycogen with profound hypoglycemia and calcification development. Calcium deposits were present in the blood vessel walls, hepatocytes surrounding blood vessels and sometimes even in parenchyma of the liver mainly as linear and only occasionally as granular accumulation. As an antidote after insulin, we applied the stable gastric pentadecapeptide BPC 157 (10 microg/kg) given (i) intraperitoneally or (ii) intragastrically immediately after insulin. Controls received simultaneously an equivolume of saline (5 ml/kg). Those rats that survived till the 180 minutes after over-dose application were further assessed. Interestingly, pentadecapeptide BPC 157, as an antiulcer peptide, may besides stomach ulcer consistently counteract all insulin disturbances and fatal outcome. BPC 157 rats showed no fatal outcome, they were mostly without hypoglycemic seizures with apparently higher blood glucose levels (glycogen was still present in hepatocytes), less liver pathology (i.e., normal liver weight, less fatty liver), decreased ALT, AST and amylase serum values, markedly less damaged neurons in brain and they only occasionally had small gastric lesions. BPC 157 rats exhibited mostly only dot-like calcium presentation. In conclusion, the success of BPC 157 therapy may indicate a likely role of BPC 157 in insulin controlling and BPC 157 may influence one or more causative process(es) after excessive insulin application.

  2. Oily fish, coffee and walnuts: Dietary treatment for nonalcoholic fatty liver disease

    PubMed Central

    Gupta, Vikas; Mah, Xian-Jun; Garcia, Maria Carmela; Antonypillai, Christina; van der Poorten, David

    2015-01-01

    Rates of non-alcoholic fatty liver disease (NAFLD) are increasing worldwide in tandem with the metabolic syndrome, with the progressive form of disease, non-alcoholic steatohepatitis (NASH) likely to become the most common cause of end stage liver disease in the not too distant future. Lifestyle modification and weight loss remain the main focus of management in NAFLD and NASH, however, there has been growing interest in the benefit of specific foods and dietary components on disease progression, with some foods showing protective properties. This article provides an overview of the foods that show the most promise and their potential benefits in NAFLD/NASH, specifically; oily fish/ fish oil, coffee, nuts, tea, red wine, avocado and olive oil. Furthermore, it summarises results from animal and human trials and highlights potential areas for future research. PMID:26457022

  3. Ethanol Extract of Pinus koraiensis Leaf Ameliorates Alcoholic Fatty Liver via the Activation of LKB1-AMPK Signaling In Vitro and In Vivo.

    PubMed

    Hong, Sang-Hyuk; Lee, Hyemin; Lee, Hyo-Jung; Kim, Bonglee; Nam, Min-Ho; Shim, Bum-Sang; Kim, Sung-Hoon

    2017-05-01

    Although Pinus koraiensis leaf (PKL) was reported for its anti-diabetes, anti-obesity and anticancer effects as a folk remedy, the inhibitory effect of PKL on alcoholic fatty liver has never been elucidated yet. This study investigated the molecular mechanisms of PKL on alcoholic fatty liver in HepG2 cells, Sprague Dawley (SD) rats and Imprinting Control Region (ICR) mice. Pinus koraiensis leaf increased phosphorylation of liver kinase B1 (LKB1)/AMP-activated protein kinase signaling, low-density lipoprotein receptor and decreased fatty acid biosynthesis-related proteins such as sterol regulatory element-binding protein 1c, fatty acid synthase, 3-hydroxy-3-methylglutaryl-CoA reductase in HepG2 cells. In SD rats with 25% alcohol-induced fatty liver, PKL suppressed the levels of aspartate aminotransferase and triglyceride and also enhanced the activities of antioxidant enzymes including superoxide dismutase, glutathione peroxidase and glutathione s-transferase compared with untreated control. Furthermore, PKL increased serum alcohol dehydrogenase and serum aldehyde dehydrogenase, but decreased serum alcohol concentration in ICR mice after alcohol administration. Consistently, histochemical analysis revealed that PKL attenuated alcohol-induced fatty liver in SD rats. Overall, these findings suggest that PKL ameliorates alcohol-induced fatty liver via activation of LKB1-AMP-activated protein kinase and modulation of proteins related to lipogenesis synthesis, cholesterol synthesis and fatty acid oxidation. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  4. Intrahepatic vascular changes in non-alcoholic fatty liver disease: Potential role of insulin-resistance and endothelial dysfunction.

    PubMed

    Pasarín, Marcos; Abraldes, Juan G; Liguori, Eleonora; Kok, Beverley; La Mura, Vincenzo

    2017-10-07

    Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and insulin resistance can be a frequent comorbidity in several chronic liver diseases, in particular hepatitis C virus infection and/or cirrhosis. Several studies have demonstrated that insulin action is not only relevant for glucose control, but also for vascular homeostasis. Insulin regulates nitric oxide production, which mediates to a large degree the vasodilating, anti-inflammatory and antithrombotic properties of a healthy endothelium, guaranteeing organ perfusion. The effects of insulin on the liver microvasculature and the effects of IR on sinusoidal endothelial cells have been studied in animal models of non-alcoholic fatty liver disease. The hypotheses derived from these studies and the potential translation of these results into humans are critically discussed in this review.

  5. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease.

    PubMed

    Softic, Samir; Cohen, David E; Kahn, C Ronald

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar-sweetened beverages are major risk factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced DNL. Hepatic DNL is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism, and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation, resulting in increased production of reactive oxygen species. Furthermore, fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD.

  6. Genetic background in nonalcoholic fatty liver disease: A comprehensive review

    PubMed Central

    Macaluso, Fabio Salvatore; Maida, Marcello; Petta, Salvatore

    2015-01-01

    In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease. PMID:26494964

  7. Ligand-activated PPARα-dependent DNA demethylation regulates the fatty acid β-oxidation genes in the postnatal liver.

    PubMed

    Ehara, Tatsuya; Kamei, Yasutomi; Yuan, Xunmei; Takahashi, Mayumi; Kanai, Sayaka; Tamura, Erina; Tsujimoto, Kazutaka; Tamiya, Takashi; Nakagawa, Yoshimi; Shimano, Hitoshi; Takai-Igarashi, Takako; Hatada, Izuho; Suganami, Takayoshi; Hashimoto, Koshi; Ogawa, Yoshihiro

    2015-03-01

    The metabolic function of the liver changes sequentially during early life in mammals to adapt to the marked changes in nutritional environment. Accordingly, hepatic fatty acid β-oxidation is activated after birth to produce energy from breast milk lipids. However, how it is induced during the neonatal period is poorly understood. Here we show DNA demethylation and increased mRNA expression of the fatty acid β-oxidation genes in the postnatal mouse liver. The DNA demethylation does not occur in the fetal mouse liver under the physiologic condition, suggesting that it is specific to the neonatal period. Analysis of mice deficient in the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and maternal administration of a PPARα ligand during the gestation and lactation periods reveal that the DNA demethylation is PPARα dependent. We also find that DNA methylation of the fatty acid β-oxidation genes are reduced in the adult human liver relative to the fetal liver. This study represents the first demonstration that the ligand-activated PPARα-dependent DNA demethylation regulates the hepatic fatty acid β-oxidation genes during the neonatal period, thereby highlighting the role of a lipid-sensing nuclear receptor in the gene- and life-stage-specific DNA demethylation of a particular metabolic pathway. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  8. Relevant Aspects of Nutritional and Dietary Interventions in Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Hernandez-Rodas, Maria Catalina; Valenzuela, Rodrigo; Videla, Luis A.

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver disease worldwide. NAFLD is linked to circumstances such as type 2 diabetes, insulin resistance, obesity, hyperlipidemia, and hypertension. Since the obesity figures and related comorbidities are increasing, NAFLD has turned into a liver problem that has become progressively more common. Currently, there is no effective drug therapy for NAFLD; therefore, interventions in lifestyles remain the first line of treatment. Bearing in mind that adherence rates to this type of treatment are poor, great efforts are currently focused on finding novel therapeutic agents for the prevention in the development of hepatic steatosis and its progression to nonalcoholic steatohepatitis and cirrhosis. This review presents a compilation of the scientific evidence found in the last years showing the results of interventions in lifestyle, diet, and behavioral therapies and research results in human, animal and cell models. Possible therapeutic agents ranging from supplementation with vitamins, amino acids, prebiotics, probiotics, symbiotics, polyunsaturated fatty acids and polyphenols to interventions with medicinal plants are analyzed. PMID:26512643

  9. Relationship between Non-Alcoholic Fatty Liver Disease and Breast Cancer.

    PubMed

    Nseir, William; Abu-Rahmeh, Zuhair; Tsipis, Alex; Mograbi, Julnar; Mahamid, Mahmud

    2017-04-01

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease which refers to the presence of hepatic steatosis. Breast cancer is now the most common cancer in women and is the leading cause of death from cancer among women. To assess the relationship between NAFLD and newly diagnosed cases of breast cancer. The results of mammography screening examinations in women referred to the Breast Center, Holy Family Hospital, Nazareth during a 4 year period were collected. We identified cases of women who were newly diagnosed with breast cancer and who underwent abdominal computed tomography (CT) within 1 month of the diagnosis. The control group comprised 73 women with normal mammography and breast ultrasonography who underwent abdominal CT within 3 months from the date of the breast cancer screening during the same study period. The control cases were matched by age and body mass index (BMI). We compared the cases with the controls in terms of the presence of diffuse hepatic fatty liver and other known risk factors for breast cancer. Of the 133 women who were screened, 73 with new diagnosis of breast cancer were eligible for the study. NAFLD was found in 33 of the women with breast cancer and in 12 in the control group (45.2% vs.16.4%, respectively, P = 0.002). Multivariate analysis showed NAFLD (odds ratio 2.82, 95% confidence interval 1.2-5.5, P = 0.016) to be associated with breast cancer. NAFLD is associated with breast cancer.

  10. Keap1-Knockdown Decreases Fasting-Induced Fatty Liver via Altered Lipid Metabolism and Decreased Fatty Acid Mobilization from Adipose Tissue

    PubMed Central

    Xu, Jialin; Donepudi, Ajay C.; Moscovitz, Jamie E.; Slitt, Angela L.

    2013-01-01

    Aims The purpose of this study was to determine whether Nrf2 activation, via Keap1-knockdown (Keap1-KD), regulates lipid metabolism and mobilization induced by food deprivation (e.g. fasting). Methods and Results Male C57BL/6 (WT) and Keap1-KD mice were either fed ad libitum or food deprived for 24 hours. After fasting, WT mice exhibited a marked increase in hepatic lipid accumulation, but Keap1-KD mice had an attenuated increase of lipid accumulation, along with reduced expression of lipogenic genes (acetyl-coA carboxylase, stearoyl-CoA desaturase-1, and fatty acid synthase) and reduced expression of genes related to fatty acid transport, such as fatty acid translocase/CD36 (CD36) and Fatty acid transport protein (FATP) 2, which may attribute to the reduced induction of Peroxisome proliferator-activated receptor (Ppar) α signaling in the liver. Additionally, enhanced Nrf2 activity by Keap1-KD increased AMP-activated protein kinase (AMPK) phosphorylation in liver. In white adipose tissue, enhanced Nrf2 activity did not change the lipolysis rate by fasting, but reduced expression of fatty acid transporters — CD36 and FATP1, via a PPARα-dependent mechanism, which impaired fatty acid transport from white adipose tissue to periphery circulation system, and resulted in increased white adipose tissue fatty acid content. Moreover, enhanced Nrf2 activity increased glucose tolerance and Akt phosphorylation levels upon insulin administration, suggesting Nrf2 signaling pathway plays a key role in regulating insulin signaling and enhanced insulin sensitivity in skeletal muscle. Conclusion Enhanced Nrf2 activity via Keap1-KD decreased fasting-induced steatosis, pointing to an important function of Nrf2 on lipid metabolism under the condition of nutrient deprivation. PMID:24224011

  11. Prevalence, risk factors, and predictors of nonalcoholic fatty liver disease among schoolchildren: a hospital-based study in Alexandria, Egypt.

    PubMed

    Alkassabany, Yasmine M; Farghaly, Azza G; El-Ghitany, Engy M

    2014-06-01

    Nonalcoholic fatty liver disease (NAFLD) is an emerging problem in children and adolescents worldwide. This study was done to investigate the prevalence of NAFLD in children and adolescents as well as to determine the associated risk factors of fatty liver and to explore the ability of some obesity indices to predict and consequently be used as a screening method of fatty liver disease at certain cutoff points in schoolchildren. A cross-sectional, nested case-control study was carried out. Cases and controls were randomly selected from outpatient schoolchildren aged 6-18years attending the radiology clinic at Sporting Health Insurance Paediatric Hospital in Alexandria. They were subjected to ultrasonic examination as well as complete anthropometric and laboratory measurements including fasting plasma glucose (FPG) level, fasting insulin, alanine aminotransferase (ALT) level, and lipid profile. Fatty liver was prevalent in schoolchildren (15.8%) and increased significantly with age (p=0.004). Positive family history of diabetes mellitus (DM), hypertension (HTN), obesity, and liver disease were all statistically significant risk factors for fatty liver. Waist circumference (WC), body mass index (BMI) and its Z-score were significantly sensitive predictors. BMI was considered the best predictor of paediatric NAFLD at a cutoff=22.9. NAFLD was significantly associated with high triglycerides (TGs), low high-density lipoprotein cholesterol (HDL), homoeostatic model assessment (HOMA) percentile, and the number of metabolic syndrome (MS) components. Paediatric NAFLD is a substantial problem in schoolchildren and has a close relationship with obesity, dyslipidaemia, insulin resistance (IR), and consequently MS. BMI and WC can be used as useful predictors and screening tools for NAFLD in schoolchildren. Copyright © 2014 Arab Journal of Gastroenterology. Published by Elsevier Ltd. All rights reserved.

  12. Steatosis induced CCL5 contributes to early-stage liver fibrosis in nonalcoholic fatty liver disease progress.

    PubMed

    Li, Bing-Hang; He, Fang-Ping; Yang, Xin; Chen, Yuan-Wen; Fan, Jian-Gao

    2017-02-01

    The rapidly increasing prevalence of nonalcoholic fatty liver disease (NAFLD) has become one of the major public health threats in China and worldwide. However, during the development of NAFLD, the key mechanism underlying the progression of related fibrosis remains unclear, which greatly impedes the development of optimal NAFLD therapy. In the current study, we were endeavored to characterize a proinflammatory cytokine, CCL5, as a major contributor for fibrosis in NAFLD. The results showed that CCL5 was highly expressed in fatty liver and NASH patients. In NAFLD rats induced by 8-week-HFD, CCL5 and its receptor, CCR5, were significantly up-regulated and liver fibrosis exclusively occurred in this group. In addition, we showed that hepatocytes are the major source contributing to this CCL5 elevation. Interestingly, a CCL5 inhibitor Met-CCL5, significantly decreased liver fibrosis but not hepatic steatosis. Using a cell model of hepatic steatosis, we found that the conditioned medium of lipid-overloaded hepatocytes (Fa2N-4 cells) which produced excessive CCL5 stimulated the profibrotic activities of hepatic stellate cells (LX-2) as manifested by increased migration rate, proliferation and collagen production of LX-2 cells. CCL5 knockdown in Fa2N-4 cells, Met-CCL5 or CCR5 antibody treatment on LX-2 cells all significantly inhibited the conditioned medium of FFA-treated Fa2N-4 cells to exert stimulatory effects on LX-2 cells. Consistently, the conditioned medium of Fa2N-4 cells with CCL5 over-expression significantly enhanced migration rate, cell proliferation and collagen production of LX-2 cells. All these results support that CCL5 produced by steatotic hepatocytes plays an essential role in fibrotic signaling machinery of NAFLD. In addition, we were able to identify C/EBP-β as the up-stream regulator of CCL5 gene transcription in hepatocytes treated with free fatty acid (FFA). Our data strongly supported that CCL5 plays a pivotal regulatory role in

  13. Betaine attenuates chronic alcohol‑induced fatty liver by broadly regulating hepatic lipid metabolism.

    PubMed

    Yang, Wenjuan; Huang, Luming; Gao, Jinhang; Wen, Shilei; Tai, Yang; Chen, Meng; Huang, Zhiyin; Liu, Rui; Tang, Chengwei; Li, Jing

    2017-10-01

    Betaine has previously been demonstrated to protect the liver against alcohol‑induced fat accumulation. However, the mechanism through which betaine affects alcohol‑induced hepatic lipid metabolic disorders has not been extensively studied. The present study aimed to investigate the effect of betaine on alcoholic simple fatty liver and hepatic lipid metabolism disorders. A total of 36 rats were randomly divided into control, ethanol and ethanol + betaine groups. Liver function, morphological alterations, lipid content and tumor necrosis factor (TNF)‑α levels were determined. Hepatic expression levels of diacylglycerol acyltransferase (DGAT) 1, DGAT2, sterol regulatory element binding protein (SREBP)‑1c, SREBP‑2, fatty acid synthase (FAS), 3‑hydroxy‑3‑methyl‑glutaryl (HMG)‑CoA reductase, peroxisome proliferator-activated receptor λ coactivator (PGC)‑1α, adiponectin receptor (AdipoR) 1 and AdipoR2 were quantified. Serum and adipose tissue adiponectin levels were assessed using an enzyme‑linked immunoassay. The results demonstrated that alcohol‑induced ultramicrostructural alterations in hepatocytes, including the presence of lipid droplets and swollen mitochondria, were attenuated by betaine. Hepatic triglyceride, free fatty acid, total cholesterol and cholesterol ester contents and the expression of DGAT1, DGAT2, SREBP‑1c, SREBP‑2, FAS and HMG‑CoA reductase were increased following ethanol consumption, however were maintained at control levels following betaine supplementation. Alcohol‑induced decreases in hepatic PGC‑1α mRNA levels and serum and adipose tissue adiponectin concentrations were prevented by betaine. The downregulation of hepatic AdipoR1 which resulted from alcohol exposure was partially attenuated by betaine. No significant differences in liver function, TNF‑α, phospholipid and AdipoR2 levels were observed among the control, ethanol and ethanol + betaine groups. Overall, these results indicated that

  14. ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis.

    PubMed

    DeZwaan-McCabe, Diane; Sheldon, Ryan D; Gorecki, Michelle C; Guo, Deng-Fu; Gansemer, Erica R; Kaufman, Randal J; Rahmouni, Kamal; Gillum, Matthew P; Taylor, Eric B; Teesch, Lynn M; Rutkowski, D Thomas

    2017-05-30

    The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  15. SREBP-1c overactivates ROS-mediated hepatic NF-κB inflammatory pathway in dairy cows with fatty liver.

    PubMed

    Li, Xinwei; Huang, Weikun; Gu, Jingmin; Du, Xiliang; Lei, Lin; Yuan, Xue; Sun, Guoquan; Wang, Zhe; Li, Xiaobing; Liu, Guowen

    2015-10-01

    Dairy cows with fatty liver are characterized by hepatic lipid accumulation and a severe inflammatory response. Sterol receptor element binding protein-1c (SREBP-1c) and nuclear factor κB (NF-κB) are components of the main pathways for controlling triglyceride (TG) accumulation and inflammatory levels, respectively. A previous study demonstrated that hepatic inflammatory levels are positively correlated with hepatic TG content. We therefore speculated that SREBP-1c might play an important role in the overactivation of the hepatic NF-κB inflammatory pathway in cows with fatty liver. Compared with healthy cows, cows with fatty liver exhibited severe hepatic injury and high blood concentrations of the inflammatory cytokines TNF-α, IL-6 and IL-1β. Hepatic SREBP-1c-mediated lipid synthesis and the NF-κB inflammatory pathway were both overinduced in cows with fatty liver. In vitro, treatment with non-esterified fatty acids (NEFA) further increased SREBP-1c expression and NF-κB pathway activation, which then promoted TG and inflammatory cytokine synthesis. SREBP-1c overexpression overactivated the NF-κB inflammatory pathway in hepatocytes by increasing ROS content and not through TLR4. Furthermore, SREBP-1c silencing decreased ROS content and further attenuated the activation of the NEFA-induced NF-κB pathway, thereby decreasing TNF-α, IL-6 and IL-1β synthesis. SREBP-1c-overexpressing mice exhibited hepatic steatosis and an overinduced hepatic NF-κB pathway. Taken together, these results indicate that SREBP-1c enhances the NEFA-induced overactivation of the NF-κB inflammatory pathway by increasing ROS in cow hepatocytes, thereby further increasing hepatic inflammatory injury in cows with fatty liver. Copyright © 2015. Published by Elsevier Inc.

  16. Glycosyltransferases and non-alcoholic fatty liver disease

    PubMed Central

    Zhan, Yu-Tao; Su, Hai-Ying; An, Wei

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and its incidence is increasing worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. Glycosyltransferases (GTs) are a diverse class of enzymes involved in catalyzing the transfer of one or multiple sugar residues to a wide range of acceptor molecules. GTs mediate a wide range of functions from structure and storage to signaling, and play a key role in many fundamental biological processes. Therefore, it is anticipated that GTs have a role in the pathogenesis of NAFLD. In this article, we present an overview of the basic information on NAFLD, particularly GTs and glycosylation modification of certain molecules and their association with NAFLD pathogenesis. In addition, the effects and mechanisms of some GTs in the development of NAFLD are summarized. PMID:26937136

  17. Role of docosahexaenoic acid treatment in improving liver histology in pediatric nonalcoholic fatty liver disease.

    PubMed

    Nobili, Valerio; Carpino, Guido; Alisi, Anna; De Vito, Rita; Franchitto, Antonio; Alpini, Gianfranco; Onori, Paolo; Gaudio, Eugenio

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most important causes of liver-related morbidity and mortality in children. Recently, we have reported the effects of docosahexaenoic acid (DHA), the major dietary long-chain polyunsaturated fatty acids, in children with NAFLD. DHA exerts a potent anti-inflammatory activity through the G protein-coupled receptor (GPR)120. Our aim was to investigate in pediatric NAFLD the mechanisms underlying the effects of DHA administration on histo-pathological aspects, GPR120 expression, hepatic progenitor cell activation and macrophage pool. 20 children with untreated NAFLD were included. Children were treated with DHA for 18 months. Liver biopsies before and after the treatment were analyzed. Hepatic progenitor cell activation, macrophage pool and GPR120 expression were evaluated and correlated with clinical and histo-pathological parameters. GPR120 was expressed by hepatocytes, liver macrophages, and hepatic progenitor cells. After DHA treatment, the following modifications were present: i) the improvement of histo-pathological parameters such as NAFLD activity score, ballooning, and steatosis; ii) the reduction of hepatic progenitor cell activation in correlation with histo-pathological parameters; iii) the reduction of the number of inflammatory macrophages; iv) the increase of GPR120 expression in hepatocytes; v) the reduction of serine-311-phosphorylated nuclear factor kappa B (NF-κB) nuclear translocation in hepatocytes and macrophages in correlation with serum inflammatory cytokines. DHA could modulate hepatic progenitor cell activation, hepatocyte survival and macrophage polarization through the interaction with GPR120 and NF-κB repression. In this scenario, the modulation of GPR120 exploits a novel crucial role in the regulation of the cell-to-cell cross-talk that drives inflammatory response, hepatic progenitor cell activation and hepatocyte survival.

  18. Pathology and biopsy assessment of non-alcoholic fatty liver disease.

    PubMed

    Straub, Beate Katharina; Schirmacher, Peter

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases in Western industrialized countries with dramatically rising incidence. The diagnosis of NAFLD requires the existence of steatosis in the absence of significant alcohol consumption. In cases of relevant inflammation pathogenetically linked to steatosis, it is termed non-alcoholic steatohepatitis (NASH). While pure steatosis represents a relatively harmless and rapidly reversible condition without a significant tendency to progression, NASH carries a significant morbidity and progression risk. Noninvasive methods neither reliably establish the diagnosis nor define the extent of disease in NASH, making histopathology the diagnostic gold standard. Since current therapeutic options in NASH are limited, indication for biopsy is made in the clinical context, predominantly in unclear clinical constellations, prior to invasive measures, for follow-up purposes and in the context of clinical studies. Histological hallmarks of NASH are steatosis, hepatocellular ballooning (with and without Mallory-Denk bodies), necroinflammation, and progressing disease a characteristic with perisinusoidal fibrosis. For semiquantitative assessment of necroinflammation (grading) and fibrosis (staging), a score has recently been implemented. Although histology does not reliably distinguish alcoholic steatohepatitis/alcoholic fatty liver disease from NASH/NAFLD, it may give valuable hints. NASH has a tendency for more steatosis, the so-called glycogenated nuclei, and less necroinflammatory activity. Future development of biopsy diagnosis will be coupled to the development of differential systemic therapeutic approaches. Especially in the context of clinical studies, detailed histological evaluation should be considered for the detection of predictive parameters. Copyright 2010 S. Karger AG, Basel.

  19. Hepatoprotective effects of Spirulina maxima in patients with non-alcoholic fatty liver disease: a case series

    PubMed Central

    2010-01-01

    Introduction Non-alcoholic fatty liver diseases range from simple steatosis to non-alcoholic steatohepatitis. The "two hits" hypothesis is widely accepted for its pathogenesis: the first hit is an increased fat flux to the liver, which predisposes our patient to a second hit where increasing free fatty acid oxidation into the mitochondria leads to oxidative stress, lipoperoxidation and a chain reaction with increased ROS. Clinical indications include abdominal cramps, meteorism and fatigue. Most patients, however, are asymptomatic, and diagnosis is based on aminotransferase elevation and ultrasonography (or "brilliant liver"). Spirulina maxima has been experimentally proven to possess in vivo and in vitro hepatoprotective properties by maintaining the liver lipid profile. This case report evaluates the hepatoprotective effects of orally supplied Spirulina maxima. Case presentation Three Hispanic Mexican patients (a 43-year-old man, a 77-year-old man and a 44-year-old woman) underwent ultrasonography and were treated with 4.5 g/day of Spirulina maxima for three months. Their blood samples before and after the treatment determined triacylglycerols, total cholesterol, high-density lipoprotein cholesterol, alanine aminotransferase and low-density lipoprotein cholesterol levels. The results were assessed using ultrasound. Conclusion Treatment had therapeutic effects as evidenced by ultrasonography and the aminotransferase data. Hypolipidemic effects were also shown. We conclude that Spirulina maxima may be considered an alternative treatment for patients with non-alcoholic fatty liver diseases and dyslipidemic disorder. PMID:20370930

  20. Losartan reduces liver expression of plasminogen activator inhibitor-1 (PAI-1) in a high fat-induced rat nonalcoholic fatty liver disease model.

    PubMed

    Rosselli, Maria Soledad; Burgueño, Adriana L; Carabelli, Julieta; Schuman, Mariano; Pirola, Carlos J; Sookoian, Silvia

    2009-09-01

    To evaluate the effect of losartan-an angiotensin II type 1 receptor (AT1R) antagonist- and telmisartan-an AT1R blocker with insulin-sensitizing properties-, on the hepatic expression of plasminogen activator inhibitor-1 (PAI-1) in a rat model of nonalcoholic fatty liver disease (NAFLD). Rats were given a high-fat diet (HFD) for 8 weeks and after this period were randomly divided into 3 groups. For 12 weeks along with the same access to HFD, one group (9 rats) received losartan and another group received telmisartan (10 rats), both at 10mg/kg intraperitoneally (ip) every 24h. The third group (8 rats) received saline ip along with the HFD. Finally, a control group (6 rats) was fed with standard chow diet for 20 weeks. Fatty liver was reverted by both losartan and telmisartan. Both drugs had beneficial effects on insulin resistance, reaching statistical significance in telmisartan group. Expression of hepatic mRNA of PAI-1 showed a 42% decrease in losartan-treated rats in comparison with both HFD group and telmisartan-treated rats. To further evaluate this differential effect on PAI-1 expression, we explored the effect of the drugs on liver expression of TNFalpha, PEPCK-C and PPARalpha, and no significant differences were observed. These results indicate that AT1R blockers could be eligible drugs for reducing hepatic lipid accumulation in patients with NAFLD. However, only 12 weeks of losartan treatment strongly reduced hepatic PAI-1 gene expression. These differences could provide even more effective options for preventing fatty liver disease and its cardiovascular complications.

  1. Prevalence of Fatty Liver Disease and Hepatic Iron Overload in a Northeastern German Population by Using Quantitative MR Imaging.

    PubMed

    Kühn, Jens-Peter; Meffert, Peter; Heske, Christian; Kromrey, Marie-Luise; Schmidt, Carsten O; Mensel, Birger; Völzke, Henry; Lerch, Markus M; Hernando, Diego; Mayerle, Julia; Reeder, Scott B

    2017-09-01

    Purpose To quantify liver fat and liver iron content by measurement of confounder-corrected proton density fat fraction (PDFF) and R2* and to identify clinical associations for fatty liver disease and liver iron overload and their prevalence in a large-scale population-based study. Materials and Methods From 2008 to 2013, 2561 white participants (1336 women; median age, 52 years; 25th and 75th quartiles, 42 and 62 years) were prospectively recruited to the Study of Health in Pomerania (SHIP). Complex chemical shift-encoded magnetic resonance (MR) examination of the liver was performed, from which PDFF and R2* were assessed. On the basis of previous histopathologic calibration, participants were stratified according to their liver fat and iron content as follows: none (PDFF, ≤5.1%; R2*, ≤41.0 sec -1 ), mild (PDFF, >5.1%; R2*, >41 sec -1 ), moderate (PDFF, >14.1%; R2*, >62.5 sec -1 ), high (PDFF: >28.0%; R2*: >70.1 sec -1 ). Prevalence of fatty liver diseases and iron overload was calculated (weighted by probability of participation). Clinical associations were identified by using boosting for generalized linear models. Results Median PDFF was 3.9% (range, 0.6%-41.5%). Prevalence of fatty liver diseases was 42.2% (1082 of 2561 participants); mild, 28.5% (730 participants); moderate, 12.0% (307 participants); high content, 1.8% (45 participants). Median R2* was 34.4 sec -1 (range, 14.0-311.8 sec -1 ). Iron overload was observed in 17.4% (447 of 2561 participants; mild, 14.7% [376 participants]; moderate, 0.8% [20 participants]; high content, 2.0% [50 participants]). Liver fat content correlated with waist-to-height ratio, alanine transaminase, uric acid, serum triglycerides, and blood pressure. Liver iron content correlated with mean serum corpuscular hemoglobin, male sex, and age. Conclusion In a white German population, the prevalence of fatty liver diseases and liver iron overload is 42.2% (1082 of 2561) and 17.4% (447 of 2561). Whereas liver fat is associated

  2. Damage to enteric neurons occurs in mice that develop fatty liver disease but not diabetes in response to a high-fat diet.

    PubMed

    Rivera, L R; Leung, C; Pustovit, R V; Hunne, B L; Andrikopoulos, S; Herath, C; Testro, A; Angus, P W; Furness, J B

    2014-08-01

    Disorders of gastrointestinal functions that are controlled by enteric neurons commonly accompany fatty liver disease. Established fatty liver disease is associated with diabetes, which itself induces enteric neuron damage. Here, we investigate the relationship between fatty liver disease and enteric neuropathy, in animals fed a high-fat, high-cholesterol diet in the absence of diabetes. Mice were fed a high-fat, high-cholesterol diet (21% fat, 2% cholesterol) or normal chow for 33 weeks. Liver injury was assessed by hematoxylin and eosin, picrosirius red staining, and measurement of plasma alanine aminotransaminase (ALT). Quantitative immunohistochemistry was performed for different types of enteric neurons. The mice developed steatosis, steatohepatitis, fibrosis, and a 10-fold increase in plasma ALT, indicative of liver disease. Oral glucose tolerance was unchanged. Loss and damage to enteric neurons occurred in the myenteric plexus of ileum, cecum, and colon. Total numbers of neurons were reduced by 15-30% and neurons expressing nitric oxide synthase were reduced by 20-40%. The RNA regulating protein, Hu, became more concentrated in the nuclei of enteric neurons after high-fat feeding, which is an indication of stress on the enteric nervous system. There was also disruption of the neuronal cytoskeletal protein, neurofilament medium. Enteric neuron loss and damage occurs in animals with fatty liver disease in the absence of glucose intolerance. The enteric neuron damage may contribute to the gastrointestinal complications of fatty liver disease. © 2014 John Wiley & Sons Ltd.

  3. Nonalcoholic Fatty Liver Disease: MR Imaging of Liver Proton Density Fat Fraction to Assess Hepatic Steatosis

    PubMed Central

    Tang, An; Tan, Justin; Sun, Mark; Hamilton, Gavin; Bydder, Mark; Wolfson, Tanya; Gamst, Anthony C.; Middleton, Michael; Brunt, Elizabeth M.; Loomba, Rohit; Lavine, Joel E.; Schwimmer, Jeffrey B.

    2013-01-01

    Purpose: To evaluate the diagnostic performance of magnetic resonance (MR) imaging–estimated proton density fat fraction (PDFF) for assessing hepatic steatosis in nonalcoholic fatty liver disease (NAFLD) by using centrally scored histopathologic validation as the reference standard. Materials and Methods: This prospectively designed, cross-sectional, internal review board–approved, HIPAA-compliant study was conducted in 77 patients who had NAFLD and liver biopsy. MR imaging–PDFF was estimated from magnitude-based low flip angle multiecho gradient-recalled echo images after T2* correction and multifrequency fat modeling. Histopathologic scoring was obtained by consensus of the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network Pathology Committee. Spearman correlation, additivity and variance stabilization for regression for exploring the effect of a number of potential confounders, and receiver operating characteristic analyses were performed. Results: Liver MR imaging–PDFF was systematically higher, with higher histologic steatosis grade (P < .001), and was significantly correlated with histologic steatosis grade (ρ = 0.69, P < .001). The correlation was not confounded by age, sex, lobular inflammation, hepatocellular ballooning, NASH diagnosis, fibrosis, or magnetic field strength (P = .65). Area under the receiver operating characteristic curves was 0.989 (95% confidence interval: 0.968, 1.000) for distinguishing patients with steatosis grade 0 (n = 5) from those with grade 1 or higher (n = 72), 0.825 (95% confidence interval: 0.734, 0.915) to distinguish those with grade 1 or lower (n = 31) from those with grade 2 or higher (n = 46), and 0.893 (95% confidence interval: 0.809, 0.977) to distinguish those with grade 2 or lower (n = 58) from those with grade 3 (n = 19). Conclusion: MR imaging–PDFF showed promise for assessment of hepatic steatosis grade in patients with NAFLD. For validation, further studies with larger sample sizes are

  4. Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis.

    PubMed

    Tang, An; Tan, Justin; Sun, Mark; Hamilton, Gavin; Bydder, Mark; Wolfson, Tanya; Gamst, Anthony C; Middleton, Michael; Brunt, Elizabeth M; Loomba, Rohit; Lavine, Joel E; Schwimmer, Jeffrey B; Sirlin, Claude B

    2013-05-01

    To evaluate the diagnostic performance of magnetic resonance (MR) imaging-estimated proton density fat fraction (PDFF) for assessing hepatic steatosis in nonalcoholic fatty liver disease (NAFLD) by using centrally scored histopathologic validation as the reference standard. This prospectively designed, cross-sectional, internal review board-approved, HIPAA-compliant study was conducted in 77 patients who had NAFLD and liver biopsy. MR imaging-PDFF was estimated from magnitude-based low flip angle multiecho gradient-recalled echo images after T2* correction and multifrequency fat modeling. Histopathologic scoring was obtained by consensus of the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network Pathology Committee. Spearman correlation, additivity and variance stabilization for regression for exploring the effect of a number of potential confounders, and receiver operating characteristic analyses were performed. Liver MR imaging-PDFF was systematically higher, with higher histologic steatosis grade (P < .001), and was significantly correlated with histologic steatosis grade (ρ = 0.69, P < .001). The correlation was not confounded by age, sex, lobular inflammation, hepatocellular ballooning, NASH diagnosis, fibrosis, or magnetic field strength (P = .65). Area under the receiver operating characteristic curves was 0.989 (95% confidence interval: 0.968, 1.000) for distinguishing patients with steatosis grade 0 (n = 5) from those with grade 1 or higher (n = 72), 0.825 (95% confidence interval: 0.734, 0.915) to distinguish those with grade 1 or lower (n = 31) from those with grade 2 or higher (n = 46), and 0.893 (95% confidence interval: 0.809, 0.977) to distinguish those with grade 2 or lower (n = 58) from those with grade 3 (n = 19). MR imaging-PDFF showed promise for assessment of hepatic steatosis grade in patients with NAFLD. For validation, further studies with larger sample sizes are needed. © RSNA, 2013.

  5. Hydrogen peroxide impairs autophagic flux in a cell model of nonalcoholic fatty liver disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jiang, Pengtao; University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049; Huang, Zhen

    2013-04-19

    Highlights: •Free fatty acids exposure induces elevated autophagy. •H{sub 2}O{sub 2} inhibits autophagic flux through impairing the fusion between autophagosomes and lysosomes. •Inhibition of autophagy potentiates H{sub 2}O{sub 2}-induced cell death. -- Abstract: Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, but the pathogenesis of NAFLD is not fully clear. The aim of this study was to determine whether autophagy plays a role in the pathogenesis of NAFLD. We found that the levels of autophagy were elevated in hepatoma cells upon exposure to free fatty acids, as confirmed by the increase in the numbermore » of autophagosomes. However, exposure of hepatoma cells to H{sub 2}O{sub 2} and TNF-α, two typical “second hit” factors, increased the initiation of autophagy but inhibited the autophagic flux. The inhibition of autophagy sensitized cells to pro-apoptotic stimuli. Taken together, our results suggest that autophagy acts as a protective mechanism in the pathogenesis of NAFLD and that impairment of autophagy might induce more severe lesions of the liver. These findings will be a benefit to the understanding of the pathogenesis of NAFLD and might suggest a strategy for the prevention and cure of NAFLD.« less

  6. Intrahepatic Size Regulation in a Surgical Model: Liver Resection-Induced Liver Regeneration Counteracts the Local Atrophy following Simultaneous Portal Vein Ligation.

    PubMed

    Wei, Weiwei; Zhang, Tianjiao; Fang, Haoshu; Dirsch, Olaf; Schenk, Andrea; Homeyer, André; Gremse, Felix; Zafarnia, Sara; Settmacher, Utz; Dahmen, Uta

    2016-01-01

    Liver size regulation is based on the balance between hepatic regeneration and atrophy. To achieve a better understanding of intrahepatic size regulation, we explored the size regulation of a portally deprived liver lobe on a liver subjected to concurrent portal vein ligation (PVL) and partial hepatectomy (PHx). Using a surgical rat model consisting of right PVL (rPVL) plus 70% PHx, we evaluated the size regulation of liver lobes 1, 2, 3, and 7 days after the operation in terms of liver weight and hepatocyte proliferation. Portal hyperperfusion was confirmed by measuring portal flow. The portal vascular tree was visualized by injection of a contrast agent followed by CT imaging of explanted livers. Control groups consisted of 70% PHx, rPVL, and sham operation. The size of the ligated right lobe increased to 1.4-fold on postoperative day 7 when subjected to rPVL + 70% PHx. The right lobe increased to 3-fold when subjected to 70% PHx alone and decreased to 0.3-fold when subjected to rPVL only. The small but significant increase in liver weight after the combined procedure was accompanied by a low proliferative response. In contrast, hepatocyte proliferation was undetectable in the right lobe undergoing atrophy after PVL only. The caudate lobe in the rPVL + 70% PHx group increased to 4.6-fold, which is significantly more than in the other groups. This increase in liver weight was paralleled by persisting portal hyperperfusion and a prolonged proliferative phase of 3 days. A discontinued portal blood supply does not always result in atrophy of the ligated lobe. The concurrent regenerative stimulus induced by 70% PHx seemed to counteract the local atrophy after a simultaneously performed rPVL, leading to a low but prolonged regenerative response of the portally deprived liver lobe. This observation supports the conclusion that portal flow is not necessary for liver regeneration. The persisting portal hyperperfusion may be crucial for the specific kinetics of prolonged

  7. Spontaneous nonalcoholic fatty liver disease and ER stress in Sidt2 deficiency mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gao, Jialin; Anhui Province Key Laboratory of Biological Macro-molecules Research, Wannan Medical College, Wuhu, 241001; Zhang, Yao

    Sidt2 is a newly discovered lysosomal membrane protein that is closely related to glucose metabolism. In the present study, we found that Sidt2 is also closely related to lipid metabolism. Gradual increases in serum triglyceride (TG) and free fatty acid, as well as elevated aspartate transaminase and alanine transaminase levels were observed in Sidt2{sup −/−} mice fed a normal diet from the age of 3 months, suggesting the presence of lipid metabolism disorders and impaired liver function in these mice. In the liver slices of 6-month-old Sidt2{sup −/−} mice, there were obvious fat degeneration and inflammatory changes. Almost all ofmore » the liver cells demonstrated different levels of lipid droplet accumulation and cell swelling, and some of the cells demonstrated balloon-like changes. Infiltration of inflammatory cells was observed in the portal area and hepatic lobule. Electron microscopy showed that macrophages tended to be attached to the endothelial cells, and a large number of lipid droplets were present in the liver cells. Oil red O staining showed that there were significantly increased number of deep straining particles in the liver cells of Sidt2{sup −/−} mice, and the TG content in liver tissue was also significantly increased. Detection of key genes and proteins related to fat synthesis showed that mRNA and protein levels of the SREBP1c in the liver of Sidt2{sup −/−} mice were significantly elevated, and the downstream genes acetyl-CoA carboxylase, fatty acid synthase, and mitochondrial glycerol 3-phosphate acyltransferase were significantly upregulated. In addition, there was severe endoplasmic reticulum stress (ERS) in the liver of Sidt2{sup −/−} mice, which had significantly increased levels of markers specific for unfolded protein response activation, Grp78 and CHOP, as well as significant elevation of downstream p-PERK, p-eIF2a, p-IRE1a, along with ER damage. These results suggest that Sidt2{sup −/−} mice had spontaneous

  8. Nonalcoholic fatty liver disease: A comprehensive review of a growing epidemic

    PubMed Central

    Hassan, Kareem; Bhalla, Varun; Ezz El Regal, Mohammed; A-Kader, H Hesham

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is quickly becoming one of the most prominent causes of liver disease worldwide. The increasing incidence of NAFLD is tied to the obesity epidemic and the subsequent metabolic derangements brought along with it. Current efforts to elucidate the mechanism and causes of the disease have answered some questions, but much remains unknown about NAFLD. The aim of this article is to discuss the current knowledge regarding the pathogenesis of the disease, as well as the current and future diagnostic, preventative, and therapeutic options available to clinicians for the management of NAFLD. PMID:25232245

  9. Therapeutic Mechanisms of Bile Acids and Nor-Ursodeoxycholic Acid in Non-Alcoholic Fatty Liver Disease.

    PubMed

    Steinacher, Daniel; Claudel, Thierry; Trauner, Michael

    2017-01-01

    Non-alcoholic fatty liver disease is one of the most rapidly rising clinical problems in the 21st century. So far no effective drug treatment has been established to cure this disease. Bile acids (BAs) have a variety of signaling properties, which can be used therapeutically for modulating hepatic metabolism and inflammation. A side-chain shorted derivative of ursodeoxycholic acid (UDCA) is 24 nor-ursodeoxycholic acid (NorUDCA) and it represents a new class of drugs for treatment of liver diseases. NorUDCA has unique biochemical and therapeutic properties, since it is relatively resistant to conjugation with glycine or taurine compared to UDCA. NorUDCA undergoes cholehepatic shunting, resulting in ductular targeting, bicarbonate-rich hypercholeresis, and cholangiocyte protection. Furthermore, it showed anti-fibrotic, anti-inflammatory, and anti-lipotoxic properties in several animal models. As such, NorUDCA is a promising new approach in the treatment of cholestatic and metabolic liver diseases. This review is a summary of current BA-based therapeutic approaches in the treatment of the fatty liver disease. © 2017 S. Karger AG, Basel.

  10. The persistence of fatty liver has a differential impact on the development of diabetes: The Kangbuk Samsung Health Study.

    PubMed

    Bae, Ji Cheol; Han, Ji Min; Cho, Jung Hwan; Kwon, Hyemi; Park, Se Eun; Park, Cheol-Young; Lee, Won-Young; Oh, Ki-Won; Kwon, Sam; Park, Sung-Woo; Rhee, Eun Jung

    2018-01-01

    To evaluate whether variable fatty liver status over time influence the risk of type 2 diabetes differently. We analyzed the data from 7849 subjects without type 2 diabetes who underwent comprehensive health check-ups annually for 5 years. All subjects had an abdominal ultrasonography annually. The risk of incident diabetes was assessed in individuals with sustained non-alcoholic fatty liver disease (NAFLD), individuals with changed fatty liver status (intermittent NAFLD group), and individuals who did not have NAFLD (never NAFLD group) during the study period. A subgroup analysis was done in subjects of the intermittent NAFLD group. Incident diabetes was compared according to the number of time diagnosed as NAFLD by annual ultrasonography. During the mean follow-up of 4 years, subjects in the sustained NAFLD group had a HR of 1.50 (95% CI 1.13-1.98) for the development of diabetes compared with those in the never NAFLD group, whereas the risk was not higher in the intermittent NAFLD group (HR 0.99, 95% CI 0.76-1.31). When compared with the intermittent NAFLD group, multivariable adjusted HR for incident diabetes was 1.50 (95% CI 1.20-1.89) in the sustained NAFLD group. As the number of times diagnosed as NAFLD increased, the proportion of subjects who developed diabetes also increased (p = .002). The presence of fatty liver was differentially associated with incident diabetes based on its duration. The persistence of fatty liver status is an important factor for an independent association between NAFLD and incident diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Nonalcoholic fatty liver disease in Asia: emerging perspectives.

    PubMed

    Seto, Wai-Kay; Yuen, Man-Fung

    2017-02-01

    As in the West, nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease in Asia, with a prevalence higher than 40 % in some countries. The risk factors for NAFLD development are similar to those in Western countries, including increased body mass index, diabetes, insulin resistance, and metabolic syndrome. NAFLD in Asians is associated with different extrahepatic manifestations involving the cardiovascular, gastrointestinal, and renal systems. A considerable proportion of Asians with NAFLD are described as having "lean" NAFLD. Present in approximately 20 % of the Asian population, lean NAFLD is closely linked with insulin resistance, diabetes, and other metabolic complications, but its association with disease progression to nonalcoholic steatohepatitis and cirrhosis remains to be defined. There is emerging evidence of the interactions of NAFLD with hepatitis B virus and hepatitis C virus infection in Asia. Unlike in Western countries, NAFLD constitutes only a minority of cirrhosis and hepatocellular carcinoma cases in Asia. Possible explanations are the lower prevalence of obesity and the overwhelming problem of viral hepatitis in Asia. With aging of the obesity cohort in Asia, NAFLD-related liver complications are expected to increase.

  12. G0S2: A small giant controller of lipolysis and adipose-liver fatty acid flux.

    PubMed

    Zhang, Xiaodong; Heckmann, Bradlee L; Campbell, Latoya E; Liu, Jun

    2017-10-01

    The discovery of adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58) provided a major paradigm shift in the understanding of intracellular lipolysis in both adipocytes and nonadipocyte cells. The subsequent discovery of G0/G1 switch gene 2 (G0S2) as a potent endogenous inhibitor of ATGL revealed a unique mechanism governing lipolysis and fatty acid (FA) availability. G0S2 is highly conserved in vertebrates, and exhibits cyclical expression pattern between adipose tissue and liver that is critical to lipid flux and energy homeostasis in these two tissues. Biochemical and cell biological studies have demonstrated that a direct interaction with ATGL mediates G0S2's inhibitory effects on lipolysis and lipid droplet degradation. In this review we examine evidence obtained from recent in vitro and in vivo studies that lends support to the proof-of-principle concept that G0S2 functions as a master regulator of tissue-specific balance of TG storage vs. mobilization, partitioning of metabolic fuels between adipose and liver, and the whole-body adaptive energy response. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Identification of a differentially-expressed gene in fatty liver of overfeeding geese.

    PubMed

    Zhao, Ayong; Tang, Huachun; Lu, Sufang; He, Ruiguo

    2007-09-01

    In response to overfeeding, geese develop fatty liver. To understand the fattening mechanism, mRNA differential display reverse transcription PCR was used to study the gene expression differences between French Landes grey geese and Xupu white geese in conditions of overfeeding and normal feeding. One gene was found to be up-regulated in the fatty liver in both breeds, and it has a 1797 bp cDNA with 83% identity to chicken SELENBP1. The sequence analysis revealed that its open reading frame of 1413 bp encodes a protein of 471 amino acids, which contains a putative conserved domain of 56 kDa selenium binding protein with high homology to its homologues of chicken (95%), rat (86%), mouse (84%), human (86%), monkey (86%), dog (86%), and cattle (86%). The function of this protein has been briefly reviewed based on published information. In tissue expression analysis, the expression of geese SELENBP1 mRNA was found to be higher in liver or kidney than in other tested tissues. The results showed that overfeeding could increase the mRNA expression level of geese SELENBP1.

  14. Role of Dietary Fructose and Hepatic de novo Lipogenesis in Fatty Liver Disease

    PubMed Central

    Softic, Samir; Cohen, David E.; Kahn, C. Ronald

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar sweetened beverages are major risk-factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced de novo lipogenesis. Hepatic de novo lipogenesis is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation resulting in increased production of reactive oxygen species. Furthermore fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD. PMID:26856717

  15. Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Yu-Kun Jennifer; Yeager, Ronnie L.; Tanaka, Yuji

    Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione andmore » exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gst{alpha}1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities.« less

  16. Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet.

    PubMed

    Zhang, Yu-Kun Jennifer; Yeager, Ronnie L; Tanaka, Yuji; Klaassen, Curtis D

    2010-06-15

    Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione and exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gstalpha1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities. Copyright 2010. Published by Elsevier Inc.

  17. Genetic dissection of the fatty liver QTL Fl1sa by using congenic mice and identification of candidate genes in the liver and epididymal fat.

    PubMed

    Suzuki, Miyako; Kobayashi, Misato; Ohno, Tamio; Kanamori, Shinsaku; Tateishi, Soushi; Murai, Atsushi; Horio, Fumihiko

    2016-11-17

    Nonalcoholic fatty liver disease (NAFLD) is a multifactorial disease caused by interactions between environmental and genetic factors. The SMXA-5 mouse is a high-fat diet-induced fatty liver model established from SM/J and A/J strains. We have previously identified Fl1sa, a quantitative trait locus (QTL) for fatty liver on chromosome 12 (centromere-53.06 Mb) of SMXA-5 mice. However, the chromosomal region containing Fl1sa was too broad. The aim of this study was to narrow the Fl1sa region by genetic dissection using novel congenic mice and to identify candidate genes within the narrowed Fl1sa region. We established two congenic strains, R2 and R3, from parental A/J-12 SM and A/J strains. R2 and R3 strains have genomic intervals of centromere-29.20 Mb and 29.20-46.75 Mb of chromosome 12 derived from SM/J, respectively. Liver triglyceride content in R2 and R3 mice was significantly lower than that in A/J mice fed with a high-fat diet for 7 weeks. This result suggests that at least one of the genes responsible for fatty liver exists within the two chromosomal regions centromere-29.20 Mb (R2) and 29.20-46.75 Mb (R3). We found that liver triglyceride accumulation is inversely correlated with epididymal fat weight among the parental and congenic strains. Therefore, the ectopic fat accumulation in the liver may be due to organ-organ interactions between the liver and epididymal fat. To identify candidate genes in Fl1sa, we performed a DNA microarray analysis using the liver and epididymal fat in A/J and A/J-12 SM mice fed with a high-fat diet for 7 weeks. In epididymal fat, mRNA levels of Zfp125 (in R2) and Nrcam (in R3) were significantly different in A/J-12 SM mice from those in A/J mice. In the liver, mRNA levels of Iah1 (in R2) and Rrm2 (in R2) were significantly different in A/J-12 SM mice from those in A/J mice. In this study, using congenic mice analysis, we narrowed the chromosomal region containing Fl1sa to two regions of mouse chromosome 12. We then

  18. Glucomannan- and glucomannan plus spirulina-enriched pork affect liver fatty acid profile, LDL receptor expression and antioxidant status in Zucker fa/fa rats fed atherogenic diets

    PubMed Central

    González-Torres, Laura; Matos, Cátia; Vázquez-Velasco, Miguel; Santos-López, Jorge A.; Sánchez-Martínez, Iria; García–Fernández, Camino; Bastida, Sara; Benedí, Juana; Sánchez-Muniz, Francisco J.

    2017-01-01

    ABSTRACT We evaluated the effects of glucomannan or glucomannan plus spirulina-restructured pork (RP) on liver fatty acid profile, desaturase/elongase enzyme activities and oxidative status of Zucker fa/fa rats for seven weeks. Control (C), glucomannan (G) and glucomannan/spirulina (GS)-RP; HC (cholesterol-enriched control), HG and HGS (cholesterol-enriched glucomannan and glucomannan/spirulina-RP) experimental diets were tested. Increased metabolic syndrome markers were found in C, G and GS rats. Cholesterol feeding increased liver size, fat, and cholesterol and reduced antioxidant enzyme levels and expressions. Cholesterolemia was lower in HG and HGS than in HC. GS vs. G showed higher stearic but lower oleic levels. SFA and PUFA decreased while MUFA increased by cholesterol feeding. The arachidonic/linoleic and docosahexaenoic/alpha-linolenic ratios were lower in HC, HG, and HGS vs. C, G, and GS, respectively, suggesting a delta-6-elongase-desaturase system inhibition. Moreover, cholesterol feeding, mainly in HGS, decreased low-density-lipoprotein receptor expression and the delta-5-desaturase activity and increased the delta-9-desaturase activity. In conclusion, the liver production of highly unsaturated fatty acids was limited to decrease their oxidation in presence of hypercholesterolaemia. Glucomannan or glucomannan/spirulina-RP has added new attributes to their functional properties in meat, partially arresting the negative effects induced by high-fat-high-cholesterol feeding on the liver fatty acid and antioxidant statuses. PMID:28325998

  19. Higher Dietary Choline Intake Is Associated with Lower Risk of Nonalcoholic Fatty Liver in Normal-Weight Chinese Women12

    PubMed Central

    Yu, Danxia; Shu, Xiao-Ou; Xiang, Yong-Bing; Li, Honglan; Yang, Gong; Gao, Yu-Tang; Zheng, Wei; Zhang, Xianglan

    2014-01-01

    Background: Choline deficiency has been shown to induce liver fat accumulation in both rodent and human studies. However, it is unclear whether dietary choline intake is related to fatty liver in the general population. Objective: We examined the association between choline intake and nonalcoholic fatty liver. Methods: Participants included 56,195 Chinese women and men, 40–75 y of age, with no or negligible alcohol consumption and with no history of hepatitis, cardiovascular disease, or cancer. All participants reported undergoing liver ultrasonography. Fatty liver was defined by self-report of a physician diagnosis. Habitual dietary intakes were assessed via validated food-frequency questionnaires. Results: The average total choline intakes were 289 ± 85 mg/d in women and 318 ± 92 mg/d in men. Major food sources were eggs, soy foods, red meat, fish, and vegetables. A higher choline intake was associated with lower risk of fatty liver; after adjustment for sociodemographic characteristics, lifestyle factors, and other dietary intakes, the ORs (95% CIs) for the highest vs. the lowest quintiles of choline intake were 0.68 (0.59, 0.79) in women and 0.75 (0.60, 0.93) in men (both P-trend < 0.01). The inverse association was attenuated after further adjustment for history of metabolic disease and, in particular, BMI. The corresponding ORs (95% CIs) were 0.88 (0.75, 1.03) in women (P-trend = 0.05) and 0.85 (0.68, 1.06) in men (P-trend = 0.09). Stratified analyses suggested a potential effect modification by obesity status in women; the OR (95% CI) across extreme quintiles was 0.72 (0.57, 0.91) in normal-weight women vs. 1.05 (0.84, 1.31) in overweight or obese women (P-trend = 0.007 vs. 0.99, P-interaction < 0.0001). Conclusion: Higher dietary choline intake may be associated with lower risk of nonalcoholic fatty liver only in normal-weight Chinese women. PMID:25320186

  20. Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1

    PubMed Central

    Shao, Di; Han, Jingyan; Hou, Xiuyun; Fry, Jessica; Behring, Jessica B.; Seta, Francesca; Long, Michelle T.; Roy, Hemant K.; Cohen, Richard A.

    2017-01-01

    Abstract Aims: Nonalcoholic fatty liver (NAFL) is a common liver disease associated with metabolic syndrome, obesity, and diabetes that is rising in prevalence worldwide. Various molecular perturbations of key regulators and enzymes in hepatic lipid metabolism cause NAFL. However, redox regulation through glutathione (GSH) adducts in NAFL remains largely elusive. Glutaredoxin-1 (Glrx) is a small thioltransferase that removes protein GSH adducts without having direct antioxidant properties. The liver contains abundant Glrx but its metabolic function is unknown. Results: Here we report that normal diet-fed Glrx-deficient mice (Glrx−/−) spontaneously develop obesity, hyperlipidemia, and hepatic steatosis by 8 months of age. Adenoviral Glrx repletion in the liver of Glrx−/− mice corrected lipid metabolism. Glrx−/− mice exhibited decreased sirtuin-1 (SirT1) activity that leads to hyperacetylation and activation of SREBP-1 and upregulation of key hepatic enzymes involved in lipid synthesis. We found that GSH adducts inhibited SirT1 activity in Glrx−/− mice. Hepatic expression of nonoxidizable cysteine mutant SirT1 corrected hepatic lipids in Glrx−/− mice. Wild-type mice fed high-fat diet develop metabolic syndrome, diabetes, and NAFL within several months. Glrx deficiency accelerated high-fat-induced NAFL and progression to steatohepatitis, manifested by hepatic damage and inflammation. Innovation: These data suggest an essential role of hepatic Glrx in regulating SirT1, which controls protein glutathione adducts in the pathogenesis of hepatic steatosis. Conclusion: We provide a novel redox-dependent mechanism for regulation of hepatic lipid metabolism, and propose that upregulation of hepatic Glrx may be a beneficial strategy for NAFL. Antioxid. Redox Signal. 27, 313–327. PMID:27958883

  1. Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease.

    PubMed

    Chang, Xinxia; Wang, Zhe; Zhang, Jinlan; Yan, Hongmei; Bian, Hua; Xia, Mingfeng; Lin, Huandong; Jiang, Jiandong; Gao, Xin

    2016-09-15

    We recently demonstrated a positive effect of berberine on nonalcoholic fatty liver disease patients after 16 weeks of treatment by comparing mere lifestyle intervention in type 2 diabetes patients with berberine treatment, which decreased the content of hepatic fat. However, the potential mechanisms of the clinical effects are unclear. We used a lipidomic approach to characterize the state of lipid metabolism as reflected in the circulation of subjects with nonalcoholic fatty liver disease (NAFLD) before and after berberine treatment. Liquid chromatography-mass spectrometry evaluated the various lipid metabolites in serum samples obtained from the participants (41 patients in the berberine group and 39 patients in the mere lifestyle intervention group) before and after treatment. A total of 256 serum lipid molecular species were identified and quantified. Both treatments regulated various types of lipids in metabolic pathways, such as free fatty acids, phosphoglycerides and glycerides, in metabolic pathways, but berberine induced a substantially greater change in serum lipid species compared with mere lifestyle intervention after treatment. Berberine also caused obvious differences on ceramides. Berberine treatment markedly decreased serum levels of ceramide and ceramide-1-phosphate. Berberine altered circulating ceramides, which may underlie the improvement in fatty liver disease. ClinicalTrials.gov NCT00633282, Registered March 3, 2008.

  2. Medium and Long Chain Fatty Acids Differentially Modulate Apoptosis and Release of Inflammatory Cytokines in Human Liver Cells.

    PubMed

    Li, Lumin; Wang, Baogui; Yu, Ping; Wen, Xuefang; Gong, Deming; Zeng, Zheling

    2016-06-01

    Medium chain fatty acids (MCFA) can be more easily absorbed and supply energy more rapidly than long chain fatty acids (LCFA). However, little is known about the inflammatory response by the treatment of MCFA in human liver cells. Thus this study used human liver cells (LO2) to evaluate the effects of MCFA on apoptosis and inflammatory response. Tetrazolim-based colorimetric assay and lactate dehydrogenase assay were used to measure the viability of LO2 cells, isolated spleens and liver cells from BALB/C mice. Inverted fluorescence microscopy and flow cytometry were used to assess the cell apoptosis. Activity of superoxide dismutase and malondialdehyde level were measured to determine the oxidative damage. mRNA or protein levels of classical pro-inflammatory cytokines were analyzed by quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay and western blotting. The results showed that the liver cells treated with the fatty acids at 200 μM for 24 h exhibited good viability. Fatty acids induced inflammatory cytokines at transcriptional and translational levels to a lesser extent than lipopolysaccharide. LCFA (oleic acid) up-regulated tumor necrosis fator-α, monocyte chemoattractant-1 and interleukin-1β while down-regulated IL-6 and IL-8 secretion to a higher extent than MCFA in mRNA and protein levels. These findings suggested that MCFA may induce apoptosis to a less extent and exert more gentle inflammation than LCFA in human liver cells. © 2016 Institute of Food Technologists®

  3. Dolichos lablab Protects Against Nonalcoholic Fatty Liver Disease in Mice Fed High-Fat Diets.

    PubMed

    Im, A-Rang; Kim, Yun Hee; Kim, Young Hwa; Yang, Won-Kyung; Kim, Seung Hyung; Song, Kwang Hoon

    2017-12-01

    Hyacinth bean, Dolichos lablab or Lablab purpureus, has been used for centuries in India and China as an edible pod and animal forage, as well as to treat diarrhea and other gastrointestinal disease in traditional Korean medicine. Recently, we have demonstrated that D. lablab extract (DLL-Ex) prevented free fatty acid-induced lipid accumulation in an in vitro cellular nonalcoholic fatty liver disease (NAFLD) model. In this study, we, thus, aimed at clarifying the hepatoprotective effects of DLL-Ex in a high-fat diet-induced in vivo animal NAFLD model, as well as at elucidating underlying mechanisms of identified effects. Sixty, 6-week-old, male C57BL/6J mice were randomly divided into six groups: a control group fed a low-fat diet, four high-fat diet (HFD) groups, three receiving daily oral supplementation of DLL-Ex (25, 50, and 100 mg/kg/day), and one HFD group receiving daily oral supplementation of MILK (100 mg/kg/day). Effects of DLL-Ex supplementation were evaluated by histopathological and histochemical assessments. DLL-Ex supplementation inhibited HFD-induced increases in body weight and body fat mass and ameliorated increases in body weight, manifested as decreased liver function tests, lower serum triglycerides and cholesterol levels, and increased serum adiponectin levels. The expression of hepatic genes involved in lipid droplet accumulation and in fatty acid uptake was also decreased. We provide evidence of a protective effect of DLL-Ex against HFD-induced fatty liver disease in an animal model.

  4. Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease.

    PubMed

    Ganji, Shobha H; Kukes, Gary D; Lambrecht, Nils; Kashyap, Moti L; Kamanna, Vaijinath S

    2014-02-15

    Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver damage, comprises a spectrum of liver abnormalities including the early fat deposition in the liver (hepatic steatosis) and advanced nonalcoholic steatohepatitis. Niacin decreases plasma triglycerides, but its effect on hepatic steatosis is elusive. To examine the effect of niacin on steatosis, rats were fed either a rodent normal chow, chow containing high fat (HF), or HF containing 0.5% or 1.0% niacin in the diet for 4 wk. For regression studies, rats were first fed the HF diet for 6 wk to induce hepatic steatosis and were then treated with niacin (0.5% in the diet) while on the HF diet for 6 wk. The findings indicated that inclusion of niacin at 0.5% and 1.0% doses in the HF diet significantly decreased liver fat content, liver weight, hepatic oxidative products, and prevented hepatic steatosis. Niacin treatment to rats with preexisting hepatic steatosis induced by the HF diet significantly regressed steatosis. Niacin had no effect on the mRNA expression of fatty acid synthesis or oxidation genes (including sterol-regulatory element-binding protein 1, acetyl-CoA carboxylase 1, fatty acid synthase, and carnitine palmitoyltransferase 1) but significantly inhibited mRNA levels, protein expression, and activity of diacylglycerol acyltrasferase 2, a key enzyme in triglyceride synthesis. These novel findings suggest that niacin effectively prevents and causes the regression of experimental hepatic steatosis. Approved niacin formulation(s) for other indications or niacin analogs may offer a very cost-effective opportunity for the clinical development of niacin for treating NAFLD and fatty liver disease.

  5. Coffee and non-alcoholic fatty liver disease: brewing evidence for hepatoprotection?

    PubMed

    Chen, Shaohua; Teoh, Narci C; Chitturi, Shiv; Farrell, Geoffrey C

    2014-03-01

    Coffee is one of the most popular beverages in the world. Several studies consistently show that coffee drinkers with chronic liver disease have a reduced risk of cirrhosis and a lower incidence of hepatocellular carcinoma regardless of primary etiology. With the increasing prevalence of non-alcoholic fatty liver disease (NAFLD) worldwide, there is renewed interest in the effect of coffee intake on NAFLD severity and positive clinical outcomes. This review gives an overview of growing epidemiological and clinical evidence which indicate that coffee consumption reduces severity of NAFLD. These studies vary in methodology, and potential confounding factors have not always been completely excluded. However, it does appear that coffee, and particular components other than caffeine, reduce NAFLD prevalence and inflammation of non-alcoholic steatohepatitis. Several possible mechanisms underlying coffee's hepatoprotective effects in NAFLD include antioxidative, anti-inflammatory, and antifibrotic effects, while a chemopreventive effect against hepatocarcinogenesis seems likely. The so-far limited data supporting such effects will be discussed, and the need for further study is highlighted. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  6. Reducing Liver Fat by Low Carbohydrate Caloric Restriction Targets Hepatic Glucose Production in Non-Diabetic Obese Adults with Non-Alcoholic Fatty Liver Disease.

    PubMed

    Yu, Haoyong; Jia, Weiping; Guo, ZengKui

    2014-09-01

    Non-alcoholic fatty liver disease (NAFLD) impairs liver functions, the organ responsible for the regulation of endogenous glucose production and thus plays a key role in glycemic homeostasis. Therefore, interventions designed to normalize liver fat content are needed to improve glucose metabolism in patients affected by NAFLD such as obesity. this investigation is designed to determine the effects of caloric restriction on hepatic and peripheral glucose metabolism in obese humans with NAFLD. eight non-diabetic obese adults were restricted for daily energy intake (800 kcal) and low carbohydrate (<10%) for 8 weeks. Body compositions, liver fat and hepatic glucose production (HGP) and peripheral glucose disposal before and after the intervention were determined. the caloric restriction reduced liver fat content by 2/3 (p = 0.004). Abdominal subcutaneous and visceral fat, body weight, BMI, waist circumference and fasting plasma triglyceride and free fatty acid concentrations all significantly decreased (p < 0.05). The suppression of post-load HGP was improved by 22% (p = 0.002) whereas glucose disposal was not affected (p = 0.3). Fasting glucose remained unchanged and the changes in the 2-hour plasma glucose and insulin concentration were modest and statistically insignificant (p > 0.05). Liver fat is the only independent variable highly correlated to HGP after the removal of confounders. NAFLD impairs HGP but not peripheral glucose disposal; low carbohydrate caloric restriction effectively lowers liver fat which appears to directly correct the HGP impairment.

  7. Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals.

    PubMed

    Salgado, Ana Lúcia Farias de Azevedo; Carvalho, Luciana de; Oliveira, Ana Claudia; Santos, Virgínia Nascimento dos; Vieira, Jose Gilberto; Parise, Edison Roberto

    2010-01-01

    Due to its good correlation to glycemic clamp, HOMA-IR has been widely utilized as insulin resistance index in clinical and epidemiological studies involving non-alcoholic fatty liver disease carriers. However, values used for this parameter have shown large variability. To identify the HOMA-IR cut value that best distinguishes non-diabetic non-alcoholic fatty liver disease patients from a control group. One hundred sixteen non-alcoholic fatty liver disease patients were studied, diagnosed by clinical, biochemical, and liver image or biopsy criteria, and 88 healthy individuals, without any liver disease and testing for oral glucose tolerance within normality. These groups did not differ in age and gender. All were submitted to oral glucose tolerance test and blood samples were collected for glucose and insulin measurements by immunofluorometric method. HOMA-IR was calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5. NAFLD patients showed higher insulin, glycemia, and HOMA-IR values than control group, even when excluding glucose intolerant and diabetes mellitus patients by their glycemic curves. HOMA-IR 75th percentile for control group was 1.78 and the best area under the curve index was obtained for HOMA-IR values of 2.0 [AUC= 0.840 (0.781-0.899 CI 95%), sensitivity (Se): 85%, specificity (Sp): 83%] while value 2.5 showed best specificity without important loss in sensitivity [AUC=0,831 (0.773-0.888) Se = 72%, Sp = 94%]. HOMA-IR values above or equal to 2.0 or 2.5 show enhanced diagnostic value in distinguishing non-alcoholic fatty liver disease carriers from control group individuals.

  8. Oral Probiotic Microcapsule Formulation Ameliorates Non-Alcoholic Fatty Liver Disease in Bio F1B Golden Syrian Hamsters

    PubMed Central

    Bhathena, Jasmine; Martoni, Christopher; Kulamarva, Arun; Tomaro-Duchesneau, Catherine; Malhotra, Meenakshi; Paul, Arghya; Urbanska, Aleksandra Malgorzata; Prakash, Satya

    2013-01-01

    The beneficial effect of a microencapsulated feruloyl esterase producing Lactobacillus fermentum ATCC 11976 formulation for use in non-alcoholic fatty liver disease (NAFLD) was investigated. For which Bio F1B Golden Syrian hamsters were fed a methionine deficient/choline devoid diet to induce non-alcoholic fatty liver disease. Results, for the first time, show significant clinical benefits in experimental animals. Examination of lipids show that concentrations of hepatic free cholesterol, esterified cholesterol, triglycerides and phospholipids were significantly lowered in treated animals. In addition, serum total cholesterol, triglycerides, uric acid and insulin resistance were found to decrease in treated animals. Liver histology evaluations showed reduced fat deposits. Western blot analysis shows significant differences in expression levels of key liver enzymes in treated animals. In conclusion, these findings suggest the excellent potential of using an oral probiotic formulation to ameliorate NAFLD. PMID:23554890

  9. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease.

    PubMed

    Wieland, A; Frank, D N; Harnke, B; Bambha, K

    2015-11-01

    The human intestinal microbiota is a key regulator of host metabolic and immune functions and alterations in the microbiome ('dysbiosis') have been implicated in several human diseases. Because of the anatomical links between the intestines and the liver, dysbiosis may also disrupt hepatic function and thereby contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). To perform a comprehensive review of the medical literature investigating associations between intestinal dysbiosis and NAFLD, with a particular emphasis on studies that characterise the microbiome in NAFLD. We conducted a search of PubMed, Embase, and Web of Science using multiple search terms including: 'NAFLD, NASH, fatty liver, steatohepatitis' combined with 'metagenome, microbiom*, microbiota*, fecal flora, intestinal flora, gut bacteria'. Results were manually reviewed and studies selected based on relevance to intestinal microbiota and NAFLD. We also included studies that addressed potential mechanistic models of pathways linking the dysbiosis to NAFLD. Nine studies (five human and four animal models) were identified in our search that assessed associations between specific intestinal microbiota composition and NAFLD. We reviewed and summarised the results of additional investigations that more broadly addressed the mechanisms by which the microbiome may impact NAFLD pathogenesis. Investigations in humans and animals demonstrate associations between intestinal dysbiosis and NAFLD; however, causality has not been proven and mechanistic links require further delineation. As the field of microbiome research matures in techniques and study design, more detailed insights into NAFLD pathogenesis and its associations with the intestinal microbiota will be elucidated. © 2015 John Wiley & Sons Ltd.

  10. Drug metabolism alterations in nonalcoholic fatty liver disease

    PubMed Central

    Merrell, Matthew D.; Cherrington, Nathan J.

    2013-01-01

    Drug-metabolizing enzymes play a vital role in the elimination of the majority of therapeutic drugs. The major organ involved in drug metabolism is the liver. Chronic liver diseases have been identified as a potential source of significant interindividual variation in metabolism. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, affecting between 60 and 90 million Americans, yet the vast majority of NAFLD patients are undiagnosed. NAFLD encompasses a spectrum of pathologies, ranging from steatosis to nonalcoholic steatohepatitis and fibrosis. Numerous animal studies have investigated the effects of NAFLD on hepatic gene expression, observing significant alterations in mRNA, protein, and activity levels. Information on the effects of NAFLD in human patients is limited, though several significant investigations have recently been published. Significant alterations in the activity of drug-metabolizing enzymes may affect the clearance of therapeutic drugs, with the potential to result in adverse drug reactions. With the enormous prevalence of NAFLD, it is conceivable that every drug currently on the market is being given to patients with NAFLD. The current review is intended to present the results from both animal models and human patients, summarizing the observed alterations in the expression and activity of the phase I and II drug-metabolizing enzymes. PMID:21612324

  11. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease

    USDA-ARS?s Scientific Manuscript database

    Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by nonalcoholic fatty liver disease (NAFLD) leading to nonalcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been show...

  12. Investigating the role of cortisol and growth hormone in fatty liver development: fatty liver index in patients with pituitary adenomas.

    PubMed

    Auer, Matthias K; Stalla, Günter K; Stieg, Mareike R

    2016-10-01

    Non-alcoholic fatty liver disease (NAFLD) is a hallmark of the metabolic syndrome and has been shown to be an independent predictor of cardiovascular mortality. Although glucocorticoids and growth hormone are known to be implicated in its pathophysiology, it has only rarely been investigated in the context of patients with pituitary insufficiency or former cortisol excess. Case-control study in patients with biochemically controlled Cushing's disease (CD; N = 33) and non-functioning pituitary adenomas (NFPA; N = 79). NAFLD was estimated by calculating the fatty liver index (FLI) including BMI, waist circumference, GGT and triglyceride levels. Although there was no difference in FLI between patients with NFPA and CD, we identified average daily hydrocortisone (HC) intake in those with adrenal insufficiency to be an independent predictor of FLI (β = 1.124; p = 0.017), even after adjusting for BMI and waist circumference. In line, those with a FLI > 60 were also taking in average significantly more HC per day than those with a score <60 (21.05 mg ± 5.9 vs. 17.9 mg ± 4.4; p = 0.01). FLI was also the best independent predictor for HbA1c and fasting glucose levels (both p = 0.001). Growth hormone deficiency and replacement therapy were not associated with FLI in either group. While HC dosage affects FLI as an estimate of NFLD in patients with CD and NFPA, the benefit of GH replacement still needs to be determined. In contrast to reports in CD patients with active disease, NAFLD in those with biochemical control was not different from NFPA patients.

  13. [Non-alcoholic fatty liver disease, as a component of the metabolic syndrome, and its causal correlations with other extrahepatic diseases].

    PubMed

    Halmos, Tamás; Suba, Ilona

    2017-12-01

    Non-alcoholic fatty liver disease is the most common non-infectious chronic liver-disease in our age, and is a spectrum of all the diseases associated with increased fat accumulation in the hepatocytes. Its development is promoted by sedentary life-style, over-feeding, and certain genetic predisposition. Prevalence in the adult population, even in Hungary is ~30%. In a part of cases, this disease may pass into non-alcoholic steatohepatitis, later into fibrosis, rarely into primary hepatocellular cancer. Fatty liver is closely and bidirectionally related to the metabolic syndrome and type 2 diabetes, and nowadays there is a general consensus that fatty liver is the hepatic manifestation of the metabolic sycndrome. The importance of the fatty liver has been highly emphasized recently. In addition to the progression into steatohepatitis, its causal relationship with numerous extrahepatic disorders has been discovered. In our overview, we deal with the epidemiology, pathomechanism of the disease, discuss the possibilities of diagnosis, its relationship with the intestinal microbiota, its recently recognized correlations with bile acids and their receptors, and its supposed correlations with the circadian CLOCK system. Hereinafter, we overview those extrahepatic disorders, which have been shown to be causal link with the non-alcoholic fatty liver disease. Among these, we emphasize the metabolic syndrome/type 2 diabetes, cardiovascular disorders, chronic kidney disease, sleep apnea/hypoventilation syndrome, inflammatory bowel disease, Alzheimer's disease, osteoporosis, and psoriasis, as well. Based on the above, it can be stated, that high risk individuals with non-alcoholic fatty liver disease need systemic care, and require the detection of other components of this systemic pathological condition. While currently specific therapy for the disease is not yet known, life-style changes, adequate use of available medicines can prevent disease progression. Promising research

  14. Weight reduction for non-alcoholic fatty liver disease.

    PubMed

    Peng, Lijun; Wang, Jiyao; Li, Feng

    2011-06-15

    Non-alcoholic fatty liver disease (NAFLD) is becoming a wide spread liver disease. The present recommendations for treatment are not evidence-based. Some of them are various weight reduction measures with diet, exercise, drug, or surgical therapy. To assess the benefits and harms of intended weight reduction for patients with NAFLD. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, PubMed, EMBASE, Science Citation Index Expanded, Chinese Biomedicine Database, and ClinicalTrials.gov until February 2011. We included randomised clinical trials evaluating weight reduction with different measures versus no intervention or placebo in NAFLD patients. We extracted data independently. We calculated the odds ratio (OR) for dichotomous data and calculated the mean difference (MD) for continuous data, both with 95% confidence intervals (CI). The review includes seven trials; five on aspects of lifestyle changes (eg, diet, physical exercise) and two on treatment with a weight reduction drug 'orlistat'. In total, 373 participants were enrolled, and the duration of the trials ranged from 1 month to 1 year. Only one trial on lifestyle programme was judged to be of low risk of bias. We could not perform meta-analyses for the main outcomes as they were either not reported or there were insufficient number of trials for each outcome to be meta-analysed. We could meta-analyse the available data for body weight and body mass index only. Adverse events were poorly reported. The sparse data and high risk of bias preclude us from drawing any definite conclusion on lifestyle programme or orlistat for treatment of NAFLD. Further randomised clinical trials with low risk of bias are needed to test the beneficial and harmful effects of weight reduction for NAFLD patients. The long-term prognosis of development of fibrosis, mortality, and quality of life should be studied.

  15. The association of nonalcoholic fatty liver disease with central and peripheral blood pressure in adolescence: findings from a cross-sectional study

    PubMed Central

    Patel, Sumaiya; Lawlor, Debbie A.; Ferreira, Diana L.S.; Hughes, Alun D.; Chaturvedi, Nish; Callaway, Mark; Day, Chris; Sattar, Naveed; Fraser, Abigail

    2015-01-01

    Objectives: We aimed to determine the association of nonalcoholic fatty liver disease (NAFLD) with central and peripheral blood pressure (BP), in a general adolescent population and to examine whether associations are independent of adiposity. Methods: Using cross-sectional data from a subsample (N = 1904) of a UK birth cohort, we assessed markers of NAFLD including ultrasound scan (USS) determined fatty liver, shear velocity (marker of liver fibrosis), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) at a mean age of 17.8 years. These were related to BP [central and peripheral SBP and DBP and mean arterial pressure (MAP)]. Results: Fatty liver was positively associated with central and peripheral SBP, DBP and MAP in models adjusting for age, sex, social class, puberty and alcohol intake. These positive associations were attenuated to the null when fat mass was included. For example, in confounder-adjusted models, not including fat mass, mean central SBP was 3.74 mmHg [95% confidence interval (CI) 1.12 to 6.36] higher in adolescents with USS fatty liver than in those without; with additional adjustment for fat mass, the association attenuated to the null value (−0.37 mmHg; 95% CI –3.09 to 2.36). Similar patterns were found for associations of ALT and GGT with central and peripheral BP. There was no consistent evidence of associations of shear velocity or AST with BP measurements. Fatty liver was not consistently associated with central pulse pressure (PP), peripheral PP and Aix@75. Conclusion: NAFLD is not associated with higher central or peripheral BP in adolescents once confounding by adiposity is taken into account. PMID:25426570

  16. Novel associations of bile acid diarrhoea with fatty liver disease and gallstones: a cohort retrospective analysis.

    PubMed

    Appleby, Richard N; Nolan, Jonathan D; Johnston, Ian M; Pattni, Sanjeev S; Fox, Jessica; Walters, Julian Rf

    2017-01-01

    Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD. A cohort of patients with chronic diarrhoea who underwent 75 selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively. Additional clinical details available from the electronic patient record, including imaging, colonoscopy, chemistry and histopathology reports were used to calculate the prevalence of fatty liver disease, gallstones, colonic neoplasia and microscopic colitis, which was compared for BAD, the primary BAD subset and control patients with diarrhoea. Of 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (r s =-0.19, p<0.0001). Patients with BAD had an OR of 3.1 for an ALT >31 ng/mL with imaging showing fatty liver (p<0.001); similar figures occurred in the primary BAD group. FGF19 was not significantly related to fatty liver but low levels were predictive of ALT >40 IU/L. In 176 subjects with gallbladder imaging, 27% had gallstones, 7% had a prior cholecystectomy and 34% either of these. The median SeHCAT values were lower in those with gallstones (3.8%, p<0.0001), or gallstones/cholecystectomy (7.2%, p<0.001), compared with normal gallbladder imaging (14%). Overall, BAD had an OR of 2.0 for gallstones/cholecystectomy (p<0.05). BAD was not significantly associated with colonic adenoma/carcinoma or with microscopic colitis. The diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these associations require further investigation into

  17. Novel associations of bile acid diarrhoea with fatty liver disease and gallstones: a cohort retrospective analysis

    PubMed Central

    Appleby, Richard N; Nolan, Jonathan D; Johnston, Ian M; Pattni, Sanjeev S; Fox, Jessica; Walters, Julian RF

    2017-01-01

    Background Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD. Methods A cohort of patients with chronic diarrhoea who underwent 75selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively. Additional clinical details available from the electronic patient record, including imaging, colonoscopy, chemistry and histopathology reports were used to calculate the prevalence of fatty liver disease, gallstones, colonic neoplasia and microscopic colitis, which was compared for BAD, the primary BAD subset and control patients with diarrhoea. Findings Of 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (rs=−0.19, p<0.0001). Patients with BAD had an OR of 3.1 for an ALT >31 ng/mL with imaging showing fatty liver (p<0.001); similar figures occurred in the primary BAD group. FGF19 was not significantly related to fatty liver but low levels were predictive of ALT >40 IU/L. In 176 subjects with gallbladder imaging, 27% had gallstones, 7% had a prior cholecystectomy and 34% either of these. The median SeHCAT values were lower in those with gallstones (3.8%, p<0.0001), or gallstones/cholecystectomy (7.2%, p<0.001), compared with normal gallbladder imaging (14%). Overall, BAD had an OR of 2.0 for gallstones/cholecystectomy (p<0.05). BAD was not significantly associated with colonic adenoma/carcinoma or with microscopic colitis. Interpretation The diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these

  18. A comparative study of FDG PET/CT and enhanced multi-detector CT for detecting liver metastasis according to the size and location.

    PubMed

    Park, Jung Mi; Kim, Il Young; Kim, Sang Won; Lee, Sang Mi; Kim, Hyun Gi; Kim, Shin Young; Shin, Hyung Chul

    2013-04-01

    The aim of this study was to compare the diagnosability between (18)F-fluorodeoxyglucose (FDG) PET/CT and enhanced multi-detector CT (MDCT) for the detection of liver metastasis (LM) according to the size and location in liver and to evaluate standard maximum standardized uptake values (SUVmax) of all liver metastatic lesions. One hundred two consecutive patients with malignancy who underwent both FDG PET/CT and MDCT for LM evaluation were retrospectively reviewed. Among them, 56 patients with LM were enrolled in this study. LM was confirmed by follow-up imaging studies after at least 6 months or by histopathology. FDG PET/CT and MDCT images were visually analyzed using three-point scale by the consensus of two radiologists and two nuclear medicine physicians. The size and location (central vs. sub-capsular) of the all liver lesions were evaluated using MDCT images. Furthermore, SUVmax of all liver lesions on FDG PET/CT images were calculated. A total of 146 liver lesions were detected by FDG PET/CT and MDCT and 142 of the lesions were diagnosed as LM. The detection rates of MDCT and FDG PET/CT for LM by visual analysis were 77 and 78%, respectively. There was no significant difference of detection rate according to the overall location and size of the lesions. However, FDG PET/CT was more sensitive than MDCT for detecting small and sub-capsular LM. The detection rate of FDG PET/CT for LM was 68% by the cutoff SUVmax of 2.7. Although the diagnosabilities of MDCT and FDG PET/CT for detecting LM were comparable, FDG PET/CT is superior to MDCT for detecting small LM located in the sub-capsular portion of liver.

  19. Association between the Fatty Liver Index and Risk of Type 2 Diabetes in the EPIC-Potsdam Study

    PubMed Central

    Jäger, Susanne; Jacobs, Simone; Kröger, Janine; Stefan, Norbert; Fritsche, Andreas; Weikert, Cornelia; Boeing, Heiner; Schulze, Matthias B.

    2015-01-01

    The fatty liver index (FLI) predicts fatty liver by using BMI, waist circumference, γ-glutamyltransferase and triglycerides. We investigated the association between the FLI and the risk of type 2 diabetes and evaluated to what extent single FLI components contribute to the diabetes risk. We analysed a case-cohort study (random sub-cohort: 1922; incident cases: 563) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. The proportion of exposure effect (PEE) explained by single FLI components was evaluated and effect decomposition using inverse probability weighting (IPW) was applied. Women and men with a FLI ≥60 compared to those with a FLI <30 had a multivariable-adjusted Hazard Ratio (HR) of 17.6; 95% confidence interval (CI) 11.1-28.0 and HR: 10.9; 95% CI 6.22-19.2, respectively. Adjustment for BMI or waist circumference attenuated this association in men [PEEBMI (95% CI) = 53.8% (43.9%-65.8%); PEEwaist (95% CI) = 54.8% (44.2%-68.8%)]. In women, adjustment for waist circumference attenuated the association to a lesser degree than in men [PEEwaist (95% CI) = 31.1%; (21.9%-43.1%)] while BMI had no appreciable effect [PEEBMI (95% CI) = 11.0% (2.68%-21.0%)]. γ-glutamyltransferase and triglycerides showed only a small attenuation in women [PEEGGT(95% CI) = 3.11% (-0.72%-4.48%); PEETG (95% CI) = 6.36% (3.81%-9.92%)] and in men [PEEGGT = 0%; PEETG (95% CI) = 6.23% (2.03%-11.8%)]. In women, the total effect was decomposed into a direct effect and 4 indirect effects (HRBMI = 1.10; HRwaist = 1.28; HRGGT = 0.97 and HRTG = 1.03). In men, the 4 indirect effects were HRBMI = 1.25; HRwaist = 1.29; HRGGT = 0.97 and HRTG = 0.99. These data suggest that the FLI, as a proxy for fatty liver, is associated with risk of type 2 diabetes. This association is only partly explained by standard estimates of overall and abdominal body fatness, particularly among women. PMID:25902304

  20. Evaluation of fatty liver by using in-phase and opposed-phase MR images and in-vivo proton MR spectroscopy

    NASA Astrophysics Data System (ADS)

    Lee, Jae-Seung; Im, In-Chul; Goo, Eun-Hoe; Park, Hyong-Hu; Kwak, Byung-Joon

    2012-12-01

    The purpose of this study was to evaluate the necessity of in-phase and opposed-phase MR images and their correlations with weight, the aspartate aminotransferase/alanine aminotransferase (AST/ALT) value, and age. Magnetic resonance spectroscopy (MRS) was used as a reference in this study. We selected 68 people as subjects, among which 14 were volunteers with normal AST/ALT values ( <40/35 U/L) on a liver function study and 54 were non-alcoholic fatty liver patients for whom ultrasonic images had been obtained within 3 months of the study. In this study, the liver was more enhanced than the spleen or kidney. When the Eq. (3) formula was applied to normal volunteers, the difference between the in-phase and the opposed-phase images was -3.54 ± 12.56. The MRS study result showed a high sensitivity of 96.6% and a specificity of 100% ( p = 0.000) when the cutoff value was 20%. Furthermore, this result showed a high sensitivity of 94% and a specificity of 80% with a similar cutoff when the Eq. (2) formula was applied to non-alcoholic fatty liver patients ( p = 0.000). The MRS study revealed a strong correlation between normal volunteers and non-alcoholic fatty liver patients (r = 0.59, p = 0.04). The correlations between AST/ALT and Eq. (3) (r = 0.45, p = 0.004), age and Eq. (3) (r = 0.73, p = 0.03), and weight and Eq. (3) (r = 0.77, p = 0.000) values were all statistically significant. In the case of non-alcoholic liver disease, MRS was found to be significantly correlated with Eq. (1) (r = 0.39, p = 0.002), Eq. (2) (r = 0.68, p = 0.04), Eq. (3) (r = 0.67, p = 0.04), and AST/ALT (r = 0.77, p = 0.000). In conclusion, in-phase and opposed-phase images can help to distinguish a normal liver from a fatty liver in order to identify non-alcoholic fatty liver patients. The intensity difference between the in-phase and opposed-phase MR signals showed valuable correlations with respect to weight, AST/ALT value, and age, with all values being above the mild lipid value (r = 0.3).

  1. Stimulation by unsaturated fatty acid of squalene uptake in rat liver microsomes.

    PubMed

    Chin, J; Bloch, K

    1985-07-01

    Supernatant protein factor (SPF) and anionic phospholipids such as phosphatidylglycerol (PG) stimulate squalene epoxidase activity in rat liver microsomes by promoting [3H]squalene uptake as well as substrate translocation (Chin, J., and K. Bloch. 1984. J. Biol. Chem. 259: 11735-11738). This process is postulated to be membrane-mediated and not carrier-mediated. Here we show that treatment of PG with phospholipase A2 in the presence of bovine serum albumin abolishes the stimulatory effect of SPF on epoxidase activity. Disaturated fatty acyl-PGs are not as effective as egg yolk lecithin PG in the SPF effect. These findings suggest an important role for the unsaturated fatty acid moiety of PG. We also show that at submicellar concentrations, cis-unsaturated fatty acids stimulate microsomal epoxidase activity whereas saturated fatty acids do not. This effect is due to an increase in substrate uptake which in turn may facilitate substrate availability to the enzyme.

  2. Role of liver fatty acid binding protein in hepatocellular injury: effect of CrPic treatment.

    PubMed

    Fan, Weijiang; Chen, Kun; Zheng, Guoqiang; Wang, Wenhang; Teng, Anguo; Liu, Anjun; Ming, Dongfeng; Yan, Peng

    2013-07-01

    This study was designed to investigate the molecular mechanisms of chromium picolinate (CrPic, Fig. 1) hepatoprotective activity from alloxan-induced hepatic injury. Diabetes is induced by alloxan-treatment concurrently with the hepatic injury in mice. In this study, we investigate the protective effect of CrPic treatment in hepatic injury and the signal role of liver fatty acid binding protein in early hepatocellular injury diagnostics. In this study, alanine aminotransferase (ALT; EC 2.6.1.2) and aspartate aminotransferase (AST; EC 2.6.1.1) levels in the alloxan group were higher 71% and 50%, respectively, than those of the control group (ALT: 14.51±0.74; AST: 22.60±0.69). The AST and ALT levels in CrPic group were of minimal difference compared to the control groups. Here, CrPic exhibited amelioration alloxan induced oxidative stress in mouse livers. A significant increase in liver fatty acid-binding protein (L-FABP) was observed, which indicates increased fatty acid utilization in liver tissue [1]. In this study, the mRNA levels of L-FABP increased in both the control (1.1 fold) and CrPic (0.78 fold) groups compared the alloxan group. These findings suggest that hepatic injury may be prevented by CrPic, and is a potential target for use in the treatment of early hepatic injury. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values.

    PubMed

    Petta, Salvatore; Wong, Vincent Wai-Sun; Cammà, Calogero; Hiriart, Jean-Baptiste; Wong, Grace Lai-Hung; Marra, Fabio; Vergniol, Julien; Chan, Anthony Wing-Hung; Di Marco, Vito; Merrouche, Wassil; Chan, Henry Lik-Yuen; Barbara, Marco; Le-Bail, Brigitte; Arena, Umberto; Craxì, Antonio; de Ledinghen, Victor

    2017-04-01

    Liver stiffness measurement (LSM) frequently overestimates the severity of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Controlled attenuation parameter (CAP) is a new parameter provided by the same machine used for LSM and associated with both steatosis and body mass index, the two factors mostly affecting LSM performance in NAFLD. We aimed to determine whether prediction of liver fibrosis by LSM in NAFLD patients is affected by CAP values. Patients (n = 324) were assessed by clinical and histological (Kleiner score) features. LSM and CAP were performed using the M probe. CAP values were grouped by tertiles (lower 132-298, middle 299-338, higher 339-400 dB/m). Among patients with F0-F2 fibrosis, mean LSM values, expressed in kilopascals, increased according to CAP tertiles (6.8 versus 8.6 versus 9.4, P = 0.001), and along this line the area under the curve of LSM for the diagnosis of F3-F4 fibrosis was progressively reduced from lower to middle and further to higher CAP tertiles (0.915, 0.848-0.982; 0.830, 0.753-0.908; 0.806, 0.723-0.890). As a consequence, in subjects with F0-F2 fibrosis, the rates of false-positive LSM results for F3-F4 fibrosis increased according to CAP tertiles (7.2% in lower versus 16.6% in middle versus 18.1% in higher). Consistent with this, a decisional flowchart for predicting fibrosis was suggested by combining both LSM and CAP values. In patients with NAFLD, CAP values should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography. (Hepatology 2017;65:1145-1155). © 2016 by the American Association for the Study of Liver Diseases.

  4. Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Alwahsh, Salamah Mohammad; Gebhardt, Rolf

    2017-04-01

    Glucose is a major energy source for the entire body, while fructose metabolism occurs mainly in the liver. Fructose consumption has increased over the last decade globally and is suspected to contribute to the increased incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD is a manifestation of metabolic syndrome affecting about one-third of the population worldwide and has progressive pathological potential for liver cirrhosis and cancer through non-alcoholic steatohepatitis (NASH). Here we have reviewed the possible contribution of fructose to the pathophysiology of NAFLD. We critically summarize the current findings about several regulators, and their potential mechanisms, that have been studied in humans and animal models in response to fructose exposure. A novel hypothesis on fructose-dependent perturbation of liver regeneration and metabolism is advanced. Fructose intake could affect inflammatory and metabolic processes, liver function, gut microbiota, and portal endotoxin influx. The role of the brain in controlling fructose ingestion and the subsequent development of NAFLD is highlighted. Although the importance for fructose (over)consumption for NAFLD in humans is still debated and comprehensive intervention studies are invited, understanding of how fructose intake can favor these pathological processes is crucial for the development of appropriate noninvasive diagnostic and therapeutic approaches to detect and treat these metabolic effects. Still, lifestyle modification, to lessen the consumption of fructose-containing products, and physical exercise are major measures against NAFLD. Finally, promising drugs against fructose-induced insulin resistance and hepatic dysfunction that are emerging from studies in rodents are reviewed, but need further validation in human patients.

  5. Liver phospholipids fatty acids composition in response to different types of diets in rats of both sexes.

    PubMed

    Ranković, Slavica; Popović, Tamara; Martačić, Jasmina Debeljak; Petrović, Snježana; Tomić, Mirko; Ignjatović, Đurđica; Tovilović-Kovačević, Gordana; Glibetić, Maria

    2017-05-19

    Dietary intake influence changes in fatty acids (FA) profiles in liver which plays a central role in fatty acid metabolism, triacylglycerol synthesis and energy homeostasis. We investigated the effects of 4-weeks treatment with milk- and fish-based diet, on plasma biochemical parameters and FA composition of liver phospholipids (PL) in rats of both sexes. Adult, 4 months old, Wistar rats of both sexes, were fed with different types of diets: standard, milk-based and fish-based, during 4 weeks. Analytical characterization of different foods was done. Biochemical parameters in plasma were determined. Fatty acid composition was analyzed by gas-chromatography. Statistical significance of FA levels was tested with two-way analysis of variance (ANOVA) using the sex of animals and treatment (type of diet) as factors on logarithmic or trigonometric transformed data. Our results showed that both, milk- and fish-based diet, changed the composition and ratio of rat liver phospholipids FA, in gender-specific manner. Initially present sex differences appear to be dietary modulated. Although, applied diets changed the ratio of total saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), and effects were gender specific. Milk-based diet lowered SFA and elevated MUFA in males and increased PUFA in females vs. standard diet. The same diet decreased n-3, increased n-6 and n-6/n-3 ratio in males. Fish-based diet increased n-3, decreased n-6 and n-6/n-3 ratio vs. standard and milk-based diet in females. However, the ratio of individual FA in liver PL was also dietary-influenced, but with gender specific manner. While in females fish-based diet decreased AA (arachidonic acid) increased level of EPA (eicosapentaenoic acid), DPA (docosapentaenoic acid) and DHA (docosahexaenoic acid), the same diet elevated only DHA levels in males. Gender related variations in FA composition of rat liver PL were observed, and results have shown that

  6. The effect of feeding high corn oil on fatty-acid-binding-protein isolated from rat liver.

    PubMed

    Catalá, A

    1987-12-01

    Fatty-acid-binding-protein isolated from liver of rats receiving normal or high fat diet was studied by three different methods. The effect of high fat diet on the thermal stability of the protein was determined employing differential scanning calorimetry. Fatty acids have a stabilizing effect on the thermal stability of the protein. In order to determine the relative binding affinity of native and delipidated protein a Sephadex G-50 assay was employed using [1-14C] oleate as ligand. The delipidated protein exhibited greater binding of oleate than did the native material. Increases in the transfer of oleic acid from rat liver microsomes to egg lecithin liposomes in vitro were also observed when protein obtained from both sources were delipidated. The results suggest that high corn oil diet would modify the properties of fatty-acid-binding-protein in the uptake and cytosolic transport of long-chain fatty acids.

  7. Geraniol attenuates hydrogen peroxide-induced liver fatty acid alterations in male rats.

    PubMed

    Ozkaya, Ahmet; Sahin, Zafer; Gorgulu, Ahmet Orhan; Yuce, Abdurrauf; Celik, Sait

    2017-01-01

    Hydrogen peroxide (H 2 O 2 ) is an oxidant agent and this molecule naturally occurs in the body as a product of aerobic metabolism. Geraniol is a plant-derived natural antioxidant. The aim of this study was to determine the role of geraniol on hepatic fatty acids alterations following H 2 O 2 -induced oxidative stress in male rats. After randomization, male Wistar rats were divided into four groups ( n = 7 each group). Geraniol (50 mg/kg, dissolved in corn oil) and H 2 O 2 (16 mg/kg, dissolved in distilled water) were administered by an intraperitoneal injection. Administrations were performed during 30 days with 1-day interval. Administration of H 2 O 2 resulted with a significant increase in malondialdehyde (MDA) and a significant decrease in glutathione (GSH) peroxidase glutathione level; geraniol restored its effects on liver. However, hepatic catalase (CAT) activities were significantly higher in H 2 O 2 , geraniol, and geraniol+H 2 O 2 groups than control group. The ratio of hepatic total saturated fatty acids increased in H 2 O 2 -treated animals compared with control. In addition, hepatic total unsaturated fatty acids reduced in H 2 O 2 group compared with control. The percentages of both hepatic total saturated and unsaturated fatty acids were not different between geraniol+H 2 O 2 and control groups. H 2 O 2 -induced oxidative stress may affect fatty acid composition in liver and body. Geraniol can partly restore oxidative hepatic damage because it cannot completely reverse the H 2 O 2 -induced increase in hepatic CAT activities. Moreover, this natural compound can regulate hepatic total saturated and unsaturated fatty acids percentages against H 2 O 2 -induced alterations.

  8. Serum YKL-40 as a marker of liver fibrosis in patients with non-alcoholic fatty liver disease.

    PubMed

    Kumagai, Erina; Mano, Yohei; Yoshio, Sachiyo; Shoji, Hirotaka; Sugiyama, Masaya; Korenaga, Masaaki; Ishida, Tsuyoshi; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Hyogo, Hideyuki; Chayama, Kazuaki; Ohashi, Tomohiko; Ito, Kiyoaki; Yoneda, Masashi; Kawaguchi, Takumi; Torimura, Takuji; Nozaki, Yuichi; Watanabe, Sumio; Mizokami, Masashi; Kanto, Tatsuya

    2016-10-14

    Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. YKL-40, chitinase-like protein expressed in multiple tissues including liver, is involved in cell proliferation, inflammation and remodeling of the extracellular matrix. The aim of this study was to assess whether serum YKL-40 levels are associated with liver fibrosis in NAFLD patients. Serum YKL-40 levels were quantified in 111 NAFLD patients and 23 HCC patients with NAFLD. To identify the source of YKL-40, immunofluorescence staining of liver specimens from NAFLD patients was performed. Serum YKL-40 levels in NAFLD patients increased in accordance with the progression of liver fibrosis. Multivariate analysis revealed that YKL-40 was one of the independent factors significantly associated with severe fibrosis (F3-4). We established a new predictive model for fibrosis of NAFLD, using logistic regression analysis: YKL-40 based fibrosis score = -0.0545 + type IV collagen 7s * 0.3456 + YKL-40 * 0.0024. Serum YKL-40 levels of HCC patients with non-cirrhotic NAFLD were significantly higher than those without HCC. Immunofluorescence staining showed that YKL-40 was expressed by macrophages in liver tissue of NAFLD patients. In conclusion, macrophage-derived YKL-40 is a feasible biomarker of liver fibrosis in NAFLD patients.

  9. Prevalence of Fatty liver Disease and hepatic iron Overload in a northeastern german Population by Using Quantitative Mr imaging1

    PubMed Central

    Kühn, Jens-Peter; Meffert, Peter; Heske, Christian; Kromrey, Marie-Luise; Schmidt, Carsten O.; Mensel, Birger; Völzke, Henry; Lerch, Markus M.; Hernando, Diego; Mayerle, Julia; Reeder, Scott B.

    2017-01-01

    Purpose To quantify liver fat and liver iron content by measurement of confounder-corrected proton density fat fraction (PDFF) and R2* and to identify clinical associations for fatty liver disease and liver iron overload and their prevalence in a large-scale population-based study. Materials and Methods From 2008 to 2013, 2561 white participants (1336 women; median age, 52 years; 25th and 75th quartiles, 42 and 62 years) were prospectively recruited to the Study of Health in Pomerania (SHIP). Complex chemical shift–encoded magnetic resonance (MR) examination of the liver was performed, from which PDFF and R2* were assessed. On the basis of previous histopathologic calibration, participants were stratified according to their liver fat and iron content as follows: none (PDFF, ≤5.1%; R2*, ≤41.0 sec−1), mild (PDFF, >5.1%; R2*, >41 sec−1), moderate (PDFF, >14.1%; R2*, >62.5 sec−1), high (PDFF: >28.0%; R2*: >70.1 sec−1). Prevalence of fatty liver diseases and iron overload was calculated (weighted by probability of participation). Clinical associations were identified by using boosting for generalized linear models. Results Median PDFF was 3.9% (range, 0.6%–41.5%). Prevalence of fatty liver diseases was 42.2% (1082 of 2561 participants); mild, 28.5% (730 participants); moderate, 12.0% (307 participants); high content, 1.8% (45 participants). Median R2* was 34.4 sec−1 (range, 14.0–311.8 sec−1). Iron overload was observed in 17.4% (447 of 2561 participants; mild, 14.7% [376 participants]; moderate, 0.8% [20 participants]; high content, 2.0% [50 participants]). Liver fat content correlated with waist-to-height ratio, alanine transaminase, uric acid, serum triglycerides, and blood pressure. Liver iron content correlated with mean serum corpuscular hemoglobin, male sex, and age. Conclusion In a white German population, the prevalence of fatty liver diseases and liver iron overload is 42.2% (1082 of 2561) and 17.4% (447 of 2561). Whereas liver fat is

  10. Quality of life in patients with nonalcoholic fatty liver disease in combination with essential hypertension considering taste sensitivity to sodium chloride.

    PubMed

    Mashura, Hanna Y; Hanych, Taras M; Rishko, Alexander A

    2016-01-01

    Nonalcoholic fatty liver disease and hypertensive disease - is the most common combination of abnormalities that occur in people suffering from metabolic syndrome. Their combination not only causes concurrent damage of the liver and the heart, caused by common pathogenic beginning, and also mutually complicate the disease course of each other. The leading role in the development of nonalcoholic fatty liver disease belongs to abdominal obesity and insulin resistance, and is seen as a manifestation of liver disease in metabolic syndrome. Genetic predisposition, lifestyle, improper nutrition, including excessive use of sodium chloride, lead to excessive formation of visceral adipose tissue with development of abdominal obesity, which is a likely criterion of insulin resistance. The long course of nonalcoholic fatty liver disease in combination with essential hypertension in excessive consumption of sodium chloride may negatively affect their quality of life. The aim of the study is to find out the features of quality of life in patients with nonalcoholic fatty liver disease in combination with hypertensive disease with different taste sensitivity to sodium chloride. We have investigated the quality of life of 65 patients with nonalcoholic fatty liver disease in combination with hypertensive disease II stage with different taste sensitivity to sodium chloride. Salt taste sensitivity threshold to sodium chloride is determined by the method of R. Henkin. Assessment of quality of life was performed using the Ukrainian version of the questionnaire Medical Outcomes Study Short Form 36 (MO S SF-36). Was revealed that in patients with nonalcoholic fatty liver disease in combination with hypertensive disease II stage with high salt taste sensitivity threshold observed the decline in the quality of life that manifests as a decline in physical condition (especially of the physical functioning, physical role functioning and general health perceptions) and mental health

  11. Prevalence and severity of non-alcoholic fatty liver disease are underestimated in clinical practice: impact of a dedicated screening approach at a large university teaching hospital.

    PubMed

    Marjot, T; Sbardella, E; Moolla, A; Hazlehurst, J M; Tan, G D; Ainsworth, M; Cobbold, J F L; Tomlinson, J W

    2018-01-01

    To define the attitudes and current clinical practice of diabetes specialists with regard to non-alcoholic fatty liver disease and, based on the results, implement an evidenced-based pathway for non-alcoholic fatty liver disease assessment. An online survey was disseminated to diabetes specialists. Based on findings from this survey, we sought a local solution by launching an awareness campaign and implementing a screening algorithm across all diabetes clinics at a secondary/tertiary referral centre. A total of 133 diabetes specialists responded to the survey. Fewer than 5% of responders correctly assessed the prevalence and severity of advanced fibrotic non-alcoholic fatty liver disease in people with diabetes as 50-75%. Whilst most clinicians performed liver function tests, only 5.7% responded stating that they would use, or had used, a non-invasive algorithm to stage the severity of non-alcoholic fatty liver disease. Implementing a local non-alcoholic fatty liver disease awareness campaign and screening strategy using pre-printed blood request forms, we ensured that 100% (n=395) of all people with Type 1 and Type 2 diabetes mellitus attending secondary/tertiary care diabetes clinics over a 6-month period were appropriately screened for advanced fibrotic non-alcoholic fatty liver disease using the Fib-4 index; 17.9% required further investigation or assessment. The prevalence and severity of non-alcoholic fatty liver disease are underestimated among diabetes specialists. The Fib-4 index can easily be incorporated into clinical practice in secondary/tertiary care to identify those individuals at risk of advanced fibrosis who require further assessment and who may benefit from a dedicated multidisciplinary approach to their management. © 2017 Diabetes UK.

  12. Uric Acid Stimulates Fructokinase and Accelerates Fructose Metabolism in the Development of Fatty Liver

    PubMed Central

    Lanaspa, Miguel A.; Sanchez-Lozada, Laura G.; Cicerchi, Christina; Li, Nanxing; Roncal-Jimenez, Carlos A.; Ishimoto, Takuji; Le, Myphuong; Garcia, Gabriela E.; Thomas, Jeffrey B.; Rivard, Christopher J.; Andres-Hernando, Ana; Hunter, Brandi; Schreiner, George; Rodriguez-Iturbe, Bernardo; Sautin, Yuri Y.; Johnson, Richard J.

    2012-01-01

    Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver. PMID:23112875

  13. Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease.

    PubMed

    Jegatheesan, Prasanthi; Beutheu, Stéphanie; Ventura, Gabrielle; Sarfati, Gilles; Nubret, Esther; Kapel, Nathalie; Waligora-Dupriet, Anne-Judith; Bergheim, Ina; Cynober, Luc; De-Bandt, Jean-Pascal

    2016-02-01

    Fructose diets have been shown to induce insulin resistance and to alter liver metabolism and gut barrier function, ultimately leading to non-alcoholic fatty liver disease. Citrulline, Glutamine and Arginine may improve insulin sensitivity and have beneficial effects on gut trophicity. Our aim was to evaluate their effects on liver and gut functions in a rat model of fructose-induced non-alcoholic fatty liver disease. Male Sprague-Dawley rats (n = 58) received a 4-week fructose (60%) diet or standard chow with or without Citrulline (0.15 g/d) or an isomolar amount of Arginine or Glutamine. All diets were made isonitrogenous by addition of non-essential amino acids. At week 4, nutritional and metabolic status (plasma glucose, insulin, cholesterol, triglycerides and amino acids, net intestinal absorption) was determined; steatosis (hepatic triglycerides content, histological examination) and hepatic function (plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin) were assessed; and gut barrier integrity (myeloperoxidase activity, portal endotoxemia, tight junction protein expression and localization) and intestinal and hepatic inflammation were evaluated. We also assessed diets effects on caecal microbiota. In these experimental isonitrogenous fructose diet conditions, fructose led to steatosis with dyslipidemia but without altering glucose homeostasis, liver function or gut permeability. Fructose significantly decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia. Arginine and Glutamine supplements were ineffective but Citrulline supplementation prevented hypertriglyceridemia and attenuated liver fat accumulation. While nitrogen supply alone can attenuate fructose-induced non-alcoholic fatty liver disease, Citrulline appears to act directly on hepatic lipid metabolism by partially preventing hypertriglyceridemia and steatosis. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition

  14. A choline-deficient diet exacerbates fatty liver but attenuates insulin resistance and glucose intolerance in mice fed a high-fat diet.

    PubMed

    Raubenheimer, Peter J; Nyirenda, Moffat J; Walker, Brian R

    2006-07-01

    Liver fat accumulation is proposed to link obesity and insulin resistance. To dissect the role of liver fat in the insulin resistance of diet-induced obesity, we altered liver fat using a choline-deficient diet. C57Bl/6 mice were fed a low-fat (10% of calories) or high-fat (45% of calories) diet for 8 weeks; during the final 4 weeks, diets were either choline deficient or choline supplemented. In choline replete animals, high-fat feeding induced weight gain, elevated liver triglycerides (171%), hyperinsulinemia, and glucose intolerance. Choline deficiency did not affect body or adipose depot weights but amplified liver fat accumulation with high-fat diet (281%, P < 0.01). However, choline deficiency lowered fasting plasma insulin (from 983 +/- 175 to 433 +/- 36 pmol/l, P < 0.01) and improved glucose tolerance on a high-fat diet. In mice on 30% fat diet, choline deficiency increased liver mRNA levels of the rate-limiting enzyme in phosphatidylcholine synthesis and of enzymes involved in free fatty acid esterification, without affecting those of de novo lipogenesis or fatty acid oxidation. We conclude that liver fat accumulation per se does not cause insulin resistance during high-fat feeding and that choline deficiency may shunt potentially toxic free fatty acids toward innocuous storage triglyceride in the liver.

  15. The Effect of 10 Weeks Resistance Training on Cholesterol and Blood Triglyceride Levels of Patients with Fatty Liver Disease.

    PubMed

    Valizadeh, Rohollah; Hosseini Askarabadi, Siroos; Karampour, Sedigheh; Abdolhamid Tehrani, Mona

    2014-01-01

    The present study aims to consider the effect of 10 weeks resistance trainings on cholesterol and blood triglyceride (TG) levels of patients with having fatty liver, aged 50 to 60 in National Iranian South Oil Company (NISOC). This research is practical and its plan has been done experimentally with pretest and post-test on experimental and control groups. In this study, 20 samples from 100 patients who referred to sonography clinic in NISOC with distinction of fatty liver were selected randomly and divided into two groups of control (n = 10) and experimental (n = 10). Cholesterol and blood trigly-ceride were measured as pretest. Test of normality for TG was (p = 0/200) by Kolmogorov-Smirnov and (p = 0/070) for cholesterol by Shapiro-Wilk test. After 10 weeks resistance trainings, the analysis and resolution of data were done by computer and SPSS (16) software as well as the descriptive and statistical methods (t-test). Comparison between these two groups showed that 8 weeks resistance trainings with a ≤ 0.05 causes significant decrease in the amount of TG but did not any significant effect on cholesterol of fatty liver patients. How to cite this article: Valizadeh R, Askarabadi SH, Karampour S, Tehrani MA. The Effect of 10 Weeks Resistance Training on Cholesterol and Blood Triglyceride Levels of Patients with Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2014;4(1):64-65.

  16. Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease.

    PubMed

    Videla, Luis A; Rodrigo, Ramón; Araya, Julia; Poniachik, Jaime

    2006-12-01

    Non-alcoholic fatty liver disease (NAFLD) is emerging as a major cause of chronic liver disease in association with the rising prevalence of obesity and type 2 diabetes in the population. Oxidative stress and insulin resistance (IR) are major contributors in the pathogenesis of NAFLD and in the progression from steatosis to steatohepatitis. Recently, Houstis and colleagues reported that reactive oxygen species have a causal role in multiple forms of IR, a phenomenon that can further promote exacerbation of oxidative stress. The improvement of the knowledge of these interrelationships should contribute to elucidate pathogenic pathways and design effective treatments for NAFLD.

  17. Imaging evaluation of non-alcoholic fatty liver disease: focused on quantification.

    PubMed

    Lee, Dong Ho

    2017-12-01

    Non-alcoholic fatty liver disease (NAFLD) has been an emerging major health problem, and the most common cause of chronic liver disease in Western countries. Traditionally, liver biopsy has been gold standard method for quantification of hepatic steatosis. However, its invasive nature with potential complication as well as measurement variability are major problem. Thus, various imaging studies have been used for evaluation of hepatic steatosis. Ultrasonography provides fairly good accuracy to detect moderate-to-severe degree hepatic steatosis, but limited accuracy for mild steatosis. Operator-dependency and subjective/qualitative nature of examination are another major drawbacks of ultrasonography. Computed tomography can be considered as an unsuitable imaging modality for evaluation of NAFLD due to potential risk of radiation exposure and limited accuracy in detecting mild steatosis. Both magnetic resonance spectroscopy and magnetic resonance imaging using chemical shift technique provide highly accurate and reproducible diagnostic performance for evaluating NAFLD, and therefore, have been used in many clinical trials as a non-invasive reference of standard method.

  18. Imaging evaluation of non-alcoholic fatty liver disease: focused on quantification

    PubMed Central

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) has been an emerging major health problem, and the most common cause of chronic liver disease in Western countries. Traditionally, liver biopsy has been gold standard method for quantification of hepatic steatosis. However, its invasive nature with potential complication as well as measurement variability are major problem. Thus, various imaging studies have been used for evaluation of hepatic steatosis. Ultrasonography provides fairly good accuracy to detect moderate-to-severe degree hepatic steatosis, but limited accuracy for mild steatosis. Operator-dependency and subjective/qualitative nature of examination are another major drawbacks of ultrasonography. Computed tomography can be considered as an unsuitable imaging modality for evaluation of NAFLD due to potential risk of radiation exposure and limited accuracy in detecting mild steatosis. Both magnetic resonance spectroscopy and magnetic resonance imaging using chemical shift technique provide highly accurate and reproducible diagnostic performance for evaluating NAFLD, and therefore, have been used in many clinical trials as a non-invasive reference of standard method. PMID:28994271

  19. Effects of Bariatric Surgery on Non-alcoholic Fatty Liver Disease: Magnetic Resonance Imaging Is an Effective, Non-invasive Method to Evaluate Changes in the Liver Fat Fraction.

    PubMed

    Hedderich, Dennis M; Hasenberg, Till; Haneder, Stefan; Schoenberg, Stefan O; Kücükoglu, Özlem; Canbay, Ali; Otto, Mirko

    2017-07-01

    Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease worldwide and is highly associated with obesity. The prevalences of both conditions have markedly increased in the Western civilization. Bariatric surgery is the most effective treatment for morbid obesity and its comorbidities such as NAFLD. Measure postoperative liver fat fraction (LFF) in bariatric patients by using in-opposed-phase MRI, a widely available clinical tool validated for the quantification of liver fat METHODS: Retrospective analyses of participants, who underwent laparoscopic Roux-Y-gastric-bypass (17) or laparoscopic sleeve gastrectomy (2) were performed using magnetic resonance imaging (MRI), bioelectrical impedance analysis (BIA), and anthropometric measurements 1 day before surgery, as well as 6, 12, and 24 weeks after surgery, LFF was calculated from fat-only and water-only MR images. Six months after surgery, a significant decrease of LFF and liver volume has been observed along with weight loss, decreased waist circumference, and parameters obtained by body fat measured by BIA. LFF significantly correlated with liver volume in the postoperative course. MRI including in-opposed-phase imaging of the liver can detect the quantitative decrease of fatty infiltration within the liver after bariatric surgery and thus could be a valuable tool to monitor NAFLD/NASH postoperatively.

  20. Effect of Jiangzhi tablet on serum indexes of mice with fatty liver induced by CCL4

    NASA Astrophysics Data System (ADS)

    Geng, Xiuli; Kong, Xuejun; Li, Chongxian; Hao, Shaojun; Wang, Hongyu; Chen, Weiliang; Zhang, Zhengchen

    2018-04-01

    To investigate the effect of Jiangzhi tablet on serum indexes of mice with fatty liver induced by CCL4, 60 mice were randomly divided into blank control group, model group, positive group, high, middle and low dose group. High fat diet fed mice for 2 weeks, in second the beginning of the weekend, each group of experimental animal except the blank group in the afternoon 1:00 subcutaneous injection of 40% CCl4 of edible oil (0.05 mL/10g, 2 times / week) for modeling; at the same time, 9:00 in the morning to lipid-lowering tablets LARGEMEDTUM and small dose group (0.1125g/ml, 0.05625g/ml, 0.02815g/ml) and Gantai tablet group (0.045g/ml) mice fed with corresponding drugs, the model group received the same volume of physiological saline. At the end of the fifth week, the eyeballs were collected and the serum was separated. The levels of serum triglyceride, high density lipoprotein, low density lipoprotein, serum AST, ALT and ALP were detected. Compared with the model group, Dongbao Gantai group, Jiangzhi tablets, high dose group had significantly decreased TG and LDL content in serum of mice (p<0.01), significantly increased the content of HDL (p<0.01); Jiangzhi tablets low dose group can significantly reduce TG and LDL content in serum (p<0.05), high HDL content increased significantly in the serum of mice (p<0.01). Dongbao Gantai group, Jiangzhi tablet high dose group and middle dose group could significantly reduce the content of ALT, ALP, AST in serum of mice (p<0.01), lipid-lowering tablets in small dose group can significantly reduce ALP and AST content in serum (p<0.01), decreased the content of ALT in serum of mice (p<0.05). The high, middle and low dose groups of Jiangzhi tablets have a better intervention effect on the mice model of fatty liver induced by small dose of carbon tetrachloride.

  1. Extra Virgin Olive Oil Reduced Polyunsaturated Fatty Acid and Cholesterol Oxidation in Rodent Liver: Is This Accounted for Hydroxytyrosol-Fatty Acid Conjugation?

    PubMed

    Lee, Yiu Yiu; Crauste, Céline; Wang, Hualin; Leung, Ho Hang; Vercauteren, Joseph; Galano, Jean-Marie; Oger, Camille; Durand, Thierry; Wan, Jennifer Man-Fan; Lee, Jetty Chung-Yung

    2016-10-17

    The effects of extra virgin olive oil (EVOO) and carbon tetrachloride (CCl 4 ) induced oxidative stress in rats were determined by the generation of isoprostanoids. These are known to be robust biomarkers to evaluate nonenzymatic and free radical related oxidation. Other oxidative stress biomarkers such as hydroxyeicosatetraenoic acid products (HETEs) and cholesterol oxidation products (COPs) were also determined. The rodents received a control diet, high-fat diet (20% w/w) composed of extra virgin olive oil (EVOO), corn oil (CO), or lard, and high-fat diets with CCl 4 insult throughout the experimental period. The EVOO diet was found to suppress the formation of isoprostanoids and COPs compared to that of the control. EVOO also had a high total phenolic content and antioxidant activity compared to those of CO and lard and may be contributed to by the hydroxytyrosol component conjugated to fatty acids (HT-FA). This is the first study to identify HT-FA in EVOO, and it was 4-fold higher than that of olive oil, whereas none was found in corn oil. Furthermore, the EVOO diet showed reduced liver lipid vesicles in CCl 4 treated rats compared to that of the control. However, liver toxicity measurements of AST (aspartate transaminase) and ALT (alanine transaminase) activities showed augmentation with CCl 4 treatment but were not alleviated by the diets given. Our findings suggest that EVOO is a daily functional food capable of enhancing the antioxidant system for liver protection; the effect is potentially attributed to the phenolic and lipophenolic (phenol conjugated by fatty acids) content.

  2. Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Griffett, Kristine; Burris, Thomas P., E-mail: burristp@slu.edu

    The liver X receptor (LXR) functions as a receptor for oxysterols and plays a critical role in the regulation of glucose and lipid metabolism. We recently described a synthetic LXR inverse agonist that displayed efficacy in treatment of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). This compound, SR9238, was designed to display liver specificity so as to avoid potential detrimental effects on reverse cholesterol transport in peripheral tissues. Here, we examined the effects of a LXR antagonist/inverse agonist, GSK2033, which displays systemic exposure. Although GSK2033 performed as expected in cell-based models as a LXR inversemore » agonist, it displayed unexpected activity in the mouse NAFLD model. The expression of lipogenic enzyme genes such as fatty acid synthase and sterol regulatory binding protein 1c were induced rather than suppressed and no effect on hepatic steatosis was found. Further characterization of the specificity of GSK2033 revealed that it displayed a significant degree of promiscuity, targeting a number of other nuclear receptors that could clearly alter hepatic gene expression. - Highlights: • The LXR antagonist GSK2033 suppresses the expression of lipogenic genes FASN and SREBF1 in HepG2 cells. • GSK2033 exhibits sufficient exposure to perform animal experiments targeting the liver. • GSK2033 has fails to suppress hepatic Fasn and Srebf1 expression in an animal model of non-alcoholic fatty liver disease. • GSK2033 may regulate the activity of several nuclear receptors.« less

  3. Topical Formulation Comprising Fatty Acid Extract from Cod Liver Oil: Development, Evaluation and Stability Studies.

    PubMed

    Ilievska, Biljana; Loftsson, Thorsteinn; Hjalmarsdottir, Martha Asdis; Asgrimsdottir, Gudrun Marta

    2016-06-01

    The purpose of this study was to develop a pharmaceutical formulation containing fatty acid extract rich in free omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid for topical use. Although the health benefits of cod liver oil and other fish oils taken orally as a dietary supplement have been acknowledged and exploited, it is clear that their use can be extended further to cover their antibacterial properties. In vitro evaluation showed that 20% (v/v) fatty acid extract exhibits good activity against strains of the Gram-positive bacteria Staphylococcus aureus, Enterococcus faecalis, Streptoccoccus pyogenes and Streptoccoccus pneumonia. Therefore, free polyunsaturated fatty acids from cod liver oil or other fish oils can be used as safe and natural antibacterial agents. In this study, ointment compositions containing free fatty acids as active antibacterial agents were prepared by using various natural waxes and characterized. The effects of different waxes, such as carnauba wax, ozokerite wax, laurel wax, beeswax, rice bran wax, candelilla wax and microcrystalline wax, in the concentration range of 1% to 5% (w/w) on the ointment texture, consistency and stability were evaluated. The results showed significant variations in texture, sensory and rheological profiles. This was attributed to the wax's nature and chain composition. Microcrystalline wax gave the best results but laurel wax, beeswax and rice bran wax exhibited excellent texturing, similar sensory profiles and well-balanced rheological properties.

  4. Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy.

    PubMed

    Cussons, Andrea J; Watts, Gerald F; Mori, Trevor A; Stuckey, Bronwyn G A

    2009-10-01

    There is an association between nonalcoholic fatty liver disease (NAFLD) and the polycystic ovary syndrome (PCOS). Marine-derived omega-3 fatty acids have favorable effects on cardiovascular risk and could reduce liver fat in NAFLD. The primary aim of this study was to examine the effects of omega-3 fatty acids on liver fat in PCOS. The secondary aim was to assess their effects on traditional cardiovascular risk factors. We conducted a randomized, crossover study at a tertiary cardiovascular research center. Twenty-five women with PCOS (mean age, 32.7 yr; mean body mass index, 34.8 kg/m(2)) participated in the study. We compared 4g/d of omega-3 fatty acids with placebo over 8 wk. The primary outcome measure was hepatic fat content quantified using proton magnetic resonance spectroscopy. Secondary outcome measures included fasting lipids and blood pressure. Omega-3 fatty acids significantly decreased liver fat content compared with placebo [10.2 (1.1) vs. 8.4 (0.9)%; P = 0.022]. There was also a reduction in triglycerides [1.19 (1.03-1.47) vs. 1.02 (0.93-1.18) mmol/liter; P = 0.002], systolic blood pressure [124.1 (12.1) vs. 122.3 (14.5) mm Hg; P = 0.018], and diastolic blood pressure [73.2 (8.4) vs. 69.7 (8.3) mm Hg; P = 0.005] with omega-3 fatty acids compared with placebo. Omega-3 fatty acids particularly decreased hepatic fat in women with hepatic steatosis, defined as liver fat percentage greater than 5% [18.2 (11.1) vs. 14.8 (9.3)%; P = 0.03]. Omega-3 fatty acid supplementation has a beneficial effect on liver fat content and other cardiovascular risk factors in women with PCOS, including those with hepatic steatosis. Whether this translates into a reduction in cardiometabolic events warrants further study.

  5. Role of the Gut Microbiome in Nonalcoholic Fatty Liver Disease.

    PubMed

    Aqel, Bashar; DiBaise, John K

    2015-12-01

    The incidence of nonalcoholic fatty liver disease (NAFLD) continues to increase with prevalence estimates ranging from 17%-33%, making it is the most common cause of chronic liver disease in North America. Its importance is due to not only its prevalence but also its association with increased cardiovascular morbidity and progression to cirrhosis in a subset of patients. NAFLD encompasses a pathologic spectrum of disease, from relatively benign accumulation of lipid (steatosis) to progressive nonalcoholic steatohepatitis associated with inflammation, fibrosis, and necrosis. Nonalcoholic steatohepatitis remains an important phenotypic state because this subgroup of patients is deemed at high risk for developing cirrhosis and progressing to liver failure requiring transplantation or to death. Gut microbiota has recently been identified as regulators of energy homeostasis and fat deposition, thereby implicating them in the development of obesity and associated metabolic diseases. The growing evidence that alteration in gut microbiota (dysbiosis) may affect liver pathology may allow for a better understanding of its role in the pathogenesis of NAFLD, help to identify patients at risk of progression, and expose a microbial target for prevention and therapeutic intervention. In this review, we discuss the growing evidence that highlights the relationship between gut microbiota and its association with NAFLD. © 2015 American Society for Parenteral and Enteral Nutrition.

  6. Association of Blood Fatty Acid Composition and Dietary Pattern with the Risk of Non-Alcoholic Fatty Liver Disease in Patients Who Underwent Cholecystectomy.

    PubMed

    Shim, Poyoung; Choi, Dongho; Park, Yongsoon

    2017-01-01

    The relationship between diet and non-alcoholic fatty liver disease (NAFLD) in patients with gallstone disease and in those who have a high risk for NAFLD has not been investigated. This study was conducted to investigate the association between the risk of NAFLD and dietary pattern in patients who underwent cholecystectomy. Additionally, we assessed the association between erythrocyte fatty acid composition, a marker for diet, and the risk of NAFLD. Patients (n = 139) underwent liver ultrasonography to determine the presence of NAFLD before laparoscopic cholecystectomy, reported dietary intake using food frequency questionnaire, and were assessed for blood fatty acid composition. Fifty-eight patients were diagnosed with NAFLD. The risk of NAFLD was negatively associated with 2 dietary patterns: consuming whole grain and legumes and consuming fish, vegetables, and fruit. NAFLD was positively associated with the consumption of refined grain, meat, processed meat, and fried foods. Additionally, the risk of NAFLD was positively associated with erythrocyte levels of 16:0 and 18:2t, while it was negatively associated with 20:5n3, 22:5n3, and Omega-3 Index. The risk of NAFLD was negatively associated with a healthy dietary pattern of consuming whole grains, legumes, vegetables, fish, and fruit and with an erythrocyte level of n-3 polyunsaturated fatty acids rich in fish. © 2017 S. Karger AG, Basel.

  7. Left Lobe Auxiliary Liver Transplantation for End-stage Hepatitis B Liver Cirrhosis.

    PubMed

    Wang, S-F; Chen, X-P; Chen, Z-S; Wei, L; Dong, S-L; Guo, H; Jiang, J-P; Teng, W-H; Huang, Z-Y; Zhang, W-G

    2017-06-01

    Auxiliary liver transplantation (ALT) for hepatitis B virus (HBV)-related liver cirrhosis previously showed poor results, because the native liver was a significant source of HBV recurrence and the graft could be rapidly destroyed by HBV infection in an immunosuppressive condition. Four patients with HBV-related liver cirrhosis were unable to undergo orthotopic liver transplantation because the only available grafts of left lobe were too small. Under entecavir-based anti-HBV treatment, they underwent ALT in which the recipient left liver was removed and the small left lobe graft was implanted in the corresponding space. The mean graft weight/recipient weight was 0.49% (range, 0.38%-0.55%). One year after transplantation, the graft sizes were increased to 273% and the remnant livers were decreased to 44%. Serum HBV DNA was persistently undetectable. Periodic graft biopsy showed no signs of tissue injury and negative immunostaining for hepatitis B surface antigen and hepatitis B core antigen. After a mean follow-up period of 21 months, all patients live well with normal graft function. Our study suggests that ALT for HBV-related liver cirrhosis is feasible under entecavir-based anti-HBV treatment. Successful application of small left livers in end-stage liver cirrhosis may significantly increase the pool of left liver grafts for adult patients. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  8. Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease

    PubMed Central

    Schwimmer, J B; Newton, K P; Awai, H I; Choi, L J; Garcia, M A; Ellis, L L; Vanderwall, K; Fontanesi, J

    2013-01-01

    Background Screening overweight and obese children for non-alcoholic fatty liver disease (NAFLD) is recommended by paediatric and endocrinology societies. However, gastroenterology societies have called for more data before making a formal recommendation. Aim To determine whether the detection of suspected NAFLD in overweight and obese children through screening in primary care and referral to paediatric gastroenterology resulted in a correct diagnosis of NAFLD. Methods Information generated in the clinical evaluation of 347 children identified with suspected NAFLD through screening in primary care and referral to paediatric gastroenterology was captured prospectively. Diagnostic outcomes were reported. The diagnostic performance of two times the upper limit of normal (ULN) for alanine aminotransferase (ALT) was assessed. Results Non-alcoholic fatty liver disease was diagnosed in 55% of children identified by screening and referral. Liver disease other than NAFLD was present in 18% of those referred. Autoimmune hepatitis was the most common alternative diagnosis. Children with NAFLD had significantly (P < 0.05) higher screening ALT (98 ± 95) than children with liver disease other than NAFLD (86 ± 74). Advanced fibrosis was present in 11% of children. For the diagnosis of NAFLD, screening ALT two times the clinical ULN had a sensitivity of 57% and a specificity of 71%. Conclusions Screening of overweight and obese children in primary care for NAFLD with referral to paediatric gastroenterology has the potential to identify clinically relevant liver pathology. Consensus is needed on how to value the risk and rewards of screening and referral, to identify children with liver disease in the most appropriate manner. PMID:24117728

  9. Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease.

    PubMed

    Schwimmer, J B; Newton, K P; Awai, H I; Choi, L J; Garcia, M A; Ellis, L L; Vanderwall, K; Fontanesi, J

    2013-11-01

    Screening overweight and obese children for non-alcoholic fatty liver disease (NAFLD) is recommended by paediatric and endocrinology societies. However, gastroenterology societies have called for more data before making a formal recommendation. To determine whether the detection of suspected NAFLD in overweight and obese children through screening in primary care and referral to paediatric gastroenterology resulted in a correct diagnosis of NAFLD. Information generated in the clinical evaluation of 347 children identified with suspected NAFLD through screening in primary care and referral to paediatric gastroenterology was captured prospectively. Diagnostic outcomes were reported. The diagnostic performance of two times the upper limit of normal (ULN) for alanine aminotransferase (ALT) was assessed. Non-alcoholic fatty liver disease was diagnosed in 55% of children identified by screening and referral. Liver disease other than NAFLD was present in 18% of those referred. Autoimmune hepatitis was the most common alternative diagnosis. Children with NAFLD had significantly (P < 0.05) higher screening ALT (98 ± 95) than children with liver disease other than NAFLD (86 ± 74). Advanced fibrosis was present in 11% of children. For the diagnosis of NAFLD, screening ALT two times the clinical ULN had a sensitivity of 57% and a specificity of 71%. Screening of overweight and obese children in primary care for NAFLD with referral to paediatric gastroenterology has the potential to identify clinically relevant liver pathology. Consensus is needed on how to value the risk and rewards of screening and referral, to identify children with liver disease in the most appropriate manner. © 2013 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

  10. Gut microbiota and host metabolism in liver cirrhosis

    PubMed Central

    Usami, Makoto; Miyoshi, Makoto; Yamashita, Hayato

    2015-01-01

    The gut microbiota has the capacity to produce a diverse range of compounds that play a major role in regulating the activity of distal organs and the liver is strategically positioned downstream of the gut. Gut microbiota linked compounds such as short chain fatty acids, bile acids, choline metabolites, indole derivatives, vitamins, polyamines, lipids, neurotransmitters and neuroactive compounds, and hypothalamic-pituitary-adrenal axis hormones have many biological functions. This review focuses on the gut microbiota and host metabolism in liver cirrhosis. Dysbiosis in liver cirrhosis causes serious complications, such as bacteremia and hepatic encephalopathy, accompanied by small intestinal bacterial overgrowth and increased intestinal permeability. Gut dysbiosis in cirrhosis and intervention with probiotics and synbiotics in a clinical setting is reviewed and evaluated. Recent studies have revealed the relationship between gut microbiota and host metabolism in chronic metabolic liver disease, especially, non-alcoholic fatty liver disease, alcoholic liver disease, and with the gut microbiota metabolic interactions in dysbiosis related metabolic diseases such as diabetes and obesity. Recently, our understanding of the relationship between the gut and liver and how this regulates systemic metabolic changes in liver cirrhosis has increased. The serum lipid levels of phospholipids, free fatty acids, polyunsaturated fatty acids, especially, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid have significant correlations with specific fecal flora in liver cirrhosis. Many clinical and experimental reports support the relationship between fatty acid metabolism and gut-microbiota. Various blood metabolome such as cytokines, amino acids, and vitamins are correlated with gut microbiota in probiotics-treated liver cirrhosis patients. The future evaluation of the gut-microbiota-liver metabolic network and the intervention of these relationships using probiotics

  11. Gut microbiota and host metabolism in liver cirrhosis.

    PubMed

    Usami, Makoto; Miyoshi, Makoto; Yamashita, Hayato

    2015-11-07

    The gut microbiota has the capacity to produce a diverse range of compounds that play a major role in regulating the activity of distal organs and the liver is strategically positioned downstream of the gut. Gut microbiota linked compounds such as short chain fatty acids, bile acids, choline metabolites, indole derivatives, vitamins, polyamines, lipids, neurotransmitters and neuroactive compounds, and hypothalamic-pituitary-adrenal axis hormones have many biological functions. This review focuses on the gut microbiota and host metabolism in liver cirrhosis. Dysbiosis in liver cirrhosis causes serious complications, such as bacteremia and hepatic encephalopathy, accompanied by small intestinal bacterial overgrowth and increased intestinal permeability. Gut dysbiosis in cirrhosis and intervention with probiotics and synbiotics in a clinical setting is reviewed and evaluated. Recent studies have revealed the relationship between gut microbiota and host metabolism in chronic metabolic liver disease, especially, non-alcoholic fatty liver disease, alcoholic liver disease, and with the gut microbiota metabolic interactions in dysbiosis related metabolic diseases such as diabetes and obesity. Recently, our understanding of the relationship between the gut and liver and how this regulates systemic metabolic changes in liver cirrhosis has increased. The serum lipid levels of phospholipids, free fatty acids, polyunsaturated fatty acids, especially, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid have significant correlations with specific fecal flora in liver cirrhosis. Many clinical and experimental reports support the relationship between fatty acid metabolism and gut-microbiota. Various blood metabolome such as cytokines, amino acids, and vitamins are correlated with gut microbiota in probiotics-treated liver cirrhosis patients. The future evaluation of the gut-microbiota-liver metabolic network and the intervention of these relationships using probiotics

  12. Radiographic liver size in Pekingese dogs versus other dog breeds.

    PubMed

    Choi, Jihye; Keh, Seoyeon; Kim, Hyunwook; Kim, Junyoung; Yoon, Junghee

    2013-01-01

    Differential diagnoses for canine liver disease are commonly based on radiographic estimates of liver size, however little has been published on breed variations. Aims of this study were to describe normal radiographic liver size in Pekingese dogs and to compare normal measurements for this breed with other dog breeds and Pekingese dogs with liver disease. Liver measurements were compared for clinically normal Pekingese (n = 61), normal non-Pekingese brachycephalic (n = 45), normal nonbrachycephalic (n = 71), and Pekingese breed dogs with liver disease (n = 22). For each dog, body weight, liver length, T11 vertebral length, thoracic depth, and thoracic width were measured on right lateral and ventrodorsal abdominal radiographs. Liver volume was calculated using a formula and ratios of liver length/T11 vertebral length and liver volume/body weight ratio were determined. Normal Pekingese dogs had a significantly smaller liver volume/body weight ratio (16.73 ± 5.67, P < 0.05) than normal non-Pekingese brachycephalic breed dogs (19.54 ± 5.03) and normal nonbrachycephalic breed dogs (18.72 ± 6.52). The liver length/T11 vertebral length ratio in normal Pekingese (4.64 ± 0.65) was significantly smaller than normal non-Pekingese brachycephalic breed dogs (5.16 ± 0.74) and normal nonbrachycephalic breed dogs (5.40 ± 0.74). Ratios of liver volume/body weight and liver length/T11 vertebral length in normal Pekingese were significantly different from Pekingese with liver diseases (P < 0.05). Findings supported our hypothesis that Pekingese dogs have a smaller normal radiographic liver size than other breeds. We recommend using 4.64× the length of the T11 vertebra as a radiographic criterion for normal liver length in Pekingese dogs. © 2012 Veterinary Radiology & Ultrasound.

  13. Variation in lipid classes and fatty acid composition of salmon shark (Lamna ditropis) liver with season and gender.

    PubMed

    Jayasinghe, Chamila; Gotoh, Naohiro; Wada, Shun

    2003-02-01

    The influence of season and gender on lipid content, lipid classes, and fatty acid compositions was assessed in livers of salmon shark (Lamna ditropis), caught in the Pacific Ocean. No significant difference in the hepatosomatic index was noted with season, though the lipid content was significantly higher (P<0.05) in winter. Triacylglycerol (TAG) was identified as the predominant lipid class (78.5-82.0%), followed by sterol esters (5.7-9.1%) and hydrocarbons (3.4-5.4%). No significant differences were observed in TAG composition with respect to the season or gender. However, diacylglyceryl ether contents were significantly higher (P<0.05) in winter (3.8-5.3%) than those obtained in summer (1.3-1.1%). Polyunsaturated fatty acids constituted the major fatty acid class of salmon shark total liver lipid and docosahexaenoic acid (C22:6n-3) (22.7-28.4%) was the most abundant fatty acid which was significantly lower (P<0.05) in winter. These results suggested that lipid characteristics of salmon shark liver were influenced by season, but not by gender.

  14. Assessment of Portal Venous and Hepatic Artery Haemodynamic Variation in Non-Alcoholic Fatty Liver Disease (NAFLD) Patients.

    PubMed

    Balasubramanian, Padhmini; Boopathy, Vinoth; Govindasamy, Ezhumalai; Venkatesh, Basavaiya Prabhu

    2016-08-01

    Non-Alcoholic Fatty Liver Disease (NAFLD) has various spectrums of liver diseases like isolated fatty liver, steatohepatitis and cirrhosis usually progressing in a linear fashion. In this process they are known to cause certain haemodynamic changes in the portal flow and hepatic artery flow. The aim of the study was to study these haemodynamic changes in patients with NAFLD and to correlate it with the disease severity. Ninety patients diagnosed to have NAFLD based on ultrasound abdomen (30 each in grade1, grade2 and grade3 NAFLD) and 30 controls (Normal liver on ultrasound abdomen) were subjected to portal vein and hepatic artery Doppler study. Peak maximum velocity (Vmax), Peak minimum velocity (Vmin), Mean flow velocity (MFV), and Vein pulsality index (VPI) of the portal vein and hepatic artery resistivity index (HARI) of the hepatic artery were the doppler parameters which were assessed. Liver span was also assessed both for the fatty liver and controls. The mean Vmax, Vmin, MFV and VPI of the portal vein in patients with NAFLD was 12.23±1.74cm/sec, 9.31±1.45cm/sec, 10.76±1.48cm/sec, and 0.24±0.04 as compared to 14.05±2.43cm/sec, 10.01±2.27cm/sec, 12.23±2.47cm/sec, 0.3±0.08 in controls respectively. All these differences were statistically significant except for Vmin. The Mean HARI in patients with fatty liver was 0.65±0.06 when compared to controls of 0.75±0.06 (p=0.001). HARI (r-value of -0.517) had a better negative correlation followed by VPI (r-value of -0.44) and Vmax (r-value of -0.293) with the severity of NAFLD. MFV had a very weak negative correlation (r-value of -0.182) with the severity of NAFLD. The Vmax, MFV, VPI and HARI were significantly less when compared to controls suggesting a reduced portal flow and an increased hepatic arterial flow in patients with NAFLD. Among the parameters, HARI correlated better with the severity of NAFLD followed by VPI.

  15. Trophic niches of sympatric tropical tuna in the Western Indian Ocean inferred by stable isotopes and neutral fatty acids

    NASA Astrophysics Data System (ADS)

    Sardenne, Fany; Bodin, Nathalie; Chassot, Emmanuel; Amiel, Aurélien; Fouché, Edwin; Degroote, Maxime; Hollanda, Stéphanie; Pethybridge, Heidi; Lebreton, Benoit; Guillou, Gaël; Ménard, Frédéric

    2016-08-01

    This study examined the trophic ecology of three sympatric tropical tuna species (bigeye BET, skipjack SKJ, and yellowfin YFT) sampled in the Western Indian Ocean throughout 2013. Specifically we explored inter-specific resource partitioning and ontogenetic variability using neutral fatty acids and stable isotope analysis of liver and muscle from small (⩽100 cm fork length, FL) and large (>100 cm FL) tuna collected in mixed schools at the surface by purse-seine. Both biochemical tracers were used to calculate trophic niche indices that collectively revealed high potential for resource overlap, especially among small tuna. Resource overlap appeared strongest between BET and YFT, with SKJ tissues having high carbon isotope (δ13C) values (-17 ± 0.3‰), lower nitrogen isotope (δ15N) values (11.4 ± 0.6‰), and higher relative proportion of poly-unsaturated fatty acids (PUFA) than the two other species, indicating a different diet. Size was found to be a strong predictor for most biochemical tracers in the three species with δ13C, δ15N and total lipid content in the liver. In the larger species (YFT and BET), proportions of mono-unsaturated fatty acids typically increased with size, while quantities of PUFA decreased. In addition to ontogenetic variability, trophic markers were shown to vary between sampling area and season: higher lipid reserves and δ15N values, and lower δ13C values occurred during monsoon periods around Seychelles than in the Mozambique Channel (parted from about 1500 km). Our multi-tracer approach reveals the magnitude of potential competitive interactions in mixed tropical tuna schools at both small and large sizes and demonstrates that ontogenetic niche differentiation acts as a major factor of coexistence in tropical tuna.

  16. Hepatic microvascular dysfunction and increased advanced glycation end products are components of non-alcoholic fatty liver disease.

    PubMed

    Pereira, Evelyn Nunes Goulart da Silva; Silvares, Raquel Rangel; Flores, Edgar Eduardo Ilaquita; Rodrigues, Karine Lino; Ramos, Isalira Peroba; da Silva, Igor José; Machado, Marcelo Pelajo; Miranda, Rosiane Aparecida; Pazos-Moura, Carmen Cabanelas; Gonçalves-de-Albuquerque, Cassiano F; Faria-Neto, Hugo Caire de Castro; Tibiriça, Eduardo; Daliry, Anissa

    2017-01-01

    This study aimed to investigate the pathophysiology of hepatic microcirculatory dysfunction in non-alcoholic fatty liver disease (NAFLD). In Wistar rats, NAFLD model was induced by 20 weeks of high-fat diet (HFD) feeding. Rolling and adhesion of leukocytes and tissue perfusion in hepatic microcirculation were examined using in vivo microscopic and laser speckle contrast imaging (LSCI), respectively. Oxidative stress and inflamatory parameters were analysed by TBARs, catalase enzyme activity, RT-PCR and ELISA. The participation of advanced glycation end-products (AGE) and its receptor RAGE was evaluated by the measurement of gene and protein expression of RAGE by RT-PCR and Western-blot, respectively and by liver and serum quantification of fluorescent AGEs. Wistar rats fed high-fat diet (HFD) showed increase in epididymal and abdominal fat content, systolic arterial blood pressure, fasting blood glucose levels, hepatic triglycerides and cholesterol, and impairment of glucose and insulin metabolisms. Liver histology confirmed the presence of steatosis and ultrasound analysis revealed increased liver size and parenchymal echogenicity in HFD-fed rats. HFD causes significant increases in leukocyte rolling and adhesion on hepatic microcirculation and decrease in liver microvascular blood flow. Liver tissue presented increase in oxidative stress and inflammtion. At 20 weeks, there was a significantly increase in AGE content in the liver and serum of HFD-fed rats and an increase in RAGE gene expression in the liver. The increase in liver AGE levels and microcirculatory disturbances could play a role in the pathogenesis of liver injury and are key components of NAFLD.

  17. Recent insights into the biological functions of liver fatty acid binding protein 1

    PubMed Central

    Wang, GuQi; Bonkovsky, Herbert L.; de Lemos, Andrew; Burczynski, Frank J.

    2015-01-01

    Over four decades have passed since liver fatty acid binding protein (FABP)1 was first isolated. There are few protein families for which most of the complete tertiary structures, binding properties, and tissue occurrences are described in such detail and yet new functions are being uncovered for this protein. FABP1 is known to be critical for fatty acid uptake and intracellular transport and also has an important role in regulating lipid metabolism and cellular signaling pathways. FABP1 is an important endogenous cytoprotectant, minimizing hepatocyte oxidative damage and interfering with ischemia-reperfusion and other hepatic injuries. The protein may be targeted for metabolic activation through the cross-talk among many transcriptional factors and their activating ligands. Deficiency or malfunction of FABP1 has been reported in several diseases. FABP1 also influences cell proliferation during liver regeneration and may be considered as a prognostic factor for hepatic surgery. FABP1 binds and modulates the action of many molecules such as fatty acids, heme, and other metalloporphyrins. The ability to bind heme is another cytoprotective property and one that deserves closer investigation. The role of FABP1 in substrate availability and in protection from oxidative stress suggests that FABP1 plays a pivotal role during intracellular bacterial/viral infections by reducing inflammation and the adverse effects of starvation (energy deficiency). PMID:26443794

  18. Surgically-Induced Weight Loss Significantly Improves Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome

    PubMed Central

    Mattar, Samer G.; Velcu, Laura M.; Rabinovitz, Mordechai; Demetris, A J.; Krasinskas, A M.; Barinas-Mitchell, Emma; Eid, George M.; Ramanathan, Ramesh; Taylor, Debra S.; Schauer, Philip R.

    2005-01-01

    Objective: To evaluate the effects of surgical weight loss on fatty liver disease in severely obese patients. Summary Background Data: Nonalcoholic fatty liver disease (NAFLD), a spectrum that extends to liver fibrosis and cirrhosis, is rising at an alarming rate. This increase is occurring in conjunction with the rise of severe obesity and is probably mediated in part by metabolic syndrome (MS). Surgical weight loss operations, probably by reversing MS, have been shown to result in improvement in liver histology. Methods: Patients who underwent laparoscopic surgical weight loss operations from March 1999 through August 2004, and who agreed to have an intraoperative liver biopsy followed by at least one postoperative liver biopsy, were included. Results: There were 70 patients who were eligible. All patients underwent laparoscopic operations, the majority being laparoscopic Roux-en-Y gastric bypass. The mean excess body weight loss at time of second biopsy was 59% ± 22% and the time interval between biopsies was 15 ± 9 months. There was a reduction in prevalence of metabolic syndrome, from 70% to 14% (P < 0.001), and a marked improvement in liver steatosis (from 88% to 8%), inflammation (from 23% to 2%), and fibrosis (from 31% to 13%; all P < 0.001). Inflammation and fibrosis resolved in 37% and 20% of patients, respectively, corresponding to improvement of 82% (P < 0.001) in grade and 39% (P < 0.001) in stage of liver disease. Conclusion: Surgical weight loss results in significant improvement of liver morphology in severely obese patients. These beneficial changes may be associated with a significant reduction in the prevalence of the metabolic syndrome. PMID:16192822

  19. Characterization of fat metabolism in the fatty liver caused by a high-fat, low-carbohydrate diet: A study under equal energy conditions.

    PubMed

    Kurosaka, Yuka; Shiroya, Yoko; Yamauchi, Hideki; Kitamura, Hiromi; Minato, Kumiko

    2017-05-20

    The pathology of fatty liver due to increased percentage of calories derived from fat without increased overall caloric intake is largely unclear. In this study, we aimed to characterize fat metabolism in rats with fatty liver resulting from consumption of a high-fat, low-carbohydrate (HFLC) diet without increased caloric intake. Four-week-old male Sprague-Dawley rats were randomly assigned to the control (Con) and HFLC groups, and rats were fed the corresponding diets ad libitum. Significant decreases in food intake per gram body weight were observed in the HFLC group compared with that in the Con group. Thus, there were no significant differences in body weights or caloric intake per gram body weight between the two groups. Marked progressive fat accumulation was observed in the livers of rats in the HFLC group, accompanied by suppression of de novo lipogenesis (DNL)-related proteins in the liver and increased leptin concentrations in the blood. In addition, electron microscopic observations revealed that many lipid droplets had accumulated within the hepatocytes, and mitochondrial numbers were reduced in the hepatocytes of rats in the HFLC group. Our findings confirmed that consumption of the HFLC diet induced fatty liver, even without increased caloric intake. Furthermore, DNL was not likely to be a crucial factor inducing fatty liver with standard energy intake. Instead, ultrastructural abnormalities found in mitochondria, which may cause a decline in β-oxidation, could contribute to the development of fatty liver. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Protective Effects of Vitamin E Analogs against Carbon Tetrachloride-Induced Fatty Liver in Rats

    PubMed Central

    Yachi, Rieko; Igarashi, Osamu; Kiyose, Chikako

    2010-01-01

    Recently, it has been reported that α-tocopherol (α-Toc) is effective for amelioration of liver damage. However, it is unknown whether other vitamin E analogs are effective. In this study, we investigated the effects of γ-tocopherol (γ-Toc) and tocotrienols (T3) in rats with fatty liver. Rats fed a vitamin E-deficient diet for four weeks were divided into eight groups: Control, carbon tetrachloride (CCl4), α-Toc, α-Toc + CCl4, γ-Toc, γ-Toc + CCl4, T3 mix, T3 mix + CCl4. After a 24 h fast, the rats were administered 20 mg of each of the vitamin E analogs, respectively. Moreover, the CCl4 group were given 0.5 ml/kg body weight corn oil preparation containing CCl4 6 h after vitamin E administration. We measured the activities of aspartate aminotransferase and alanine aminotransferase (ALT) in plasma, and the contents of triglyceride (TG), total cholesterol (T-Chol) and vitamin E analogs in the liver. Also, we determined the hepatic expression of mRNA for inflammatory cytokines. The liver TG content in the γ-Toc + CCl4 and T3 mix + CCl4 groups was decreased in comparison with the CCl4 group. Moreover, ALT activity in the T3 mix + CCl4 group was significantly lower than CCl4 group. These findings suggest that γ-Toc and T3 are effective for amelioration of fatty liver. PMID:20838570

  1. Antrodia cinnamomea Prevents Obesity, Dyslipidemia, and the Derived Fatty Liver via Regulating AMPK and SREBP Signaling.

    PubMed

    Peng, Chiung-Huei; Yang, Mon-Yuan; Yang, Yi-Sun; Yu, Chieh-Chou; Wang, Chau-Jong

    2017-01-01

    Antrodia cinnamomea (AC), a protogenic fungus that only grows on the heartwood of endemic Cinnamomum kanehirae Hayata in Taiwan, is used to treat a variety of illness including liver disease. However, little is known about the benefit of AC against obesity and the related hepatic disorder. Using high-fat-diet (HFD) feed mice, we aimed to investigate whether the extract of AC (ACE) could reduce excessive weight, body fat, and serum lipids and prevent the development of non-alcoholic fatty liver (NAFLD). C57BL/6 mice were divided into five groups fed with different diets: control, HFD, and HFD with 0.5%, 1%, or 2% of ACE, respectively. After 10 weeks the animals were sacrificed, with serum and liver collected. HFD-induced elevation of body weight gain, body fat deposition, and serum free fatty acid (FFA), triacylglycerol (TGs), total cholesterol, and ratio of LDL cholesterol (LDL-C)/HDL cholesterol (HDL-C), were significantly restored by ACE. ACE reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hepatic lipid deposits increased by HFD. ACE increased p-AMP activated protein kinase (pAMPK) but decreased Sterol regulatory element binding protein (SREBP), fatty acid synthase (FAS), 1-acylglycerol-3-phosphate acyltransferase (AGPAT), and 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase. The chemical analysis reveals ACE is full of triterpenes, the most abundant of which is Antcin K, followed by sulphurenic acid, eburicoic acid, antcin C, dehydrosulphurenic acid, antcin B, and propanoic acid. In conclusion, ACE should be used to prevent obesity and derived fatty liver. The applicability of ACE on NAFLD deserves further investigation.

  2. Bone morphogenetic protein-binding endothelial regulator of liver sinusoidal endothelial cells induces iron overload in a fatty liver mouse model.

    PubMed

    Hasebe, Takumu; Tanaka, Hiroki; Sawada, Koji; Nakajima, Shunsuke; Ohtake, Takaaki; Fujiya, Mikihiro; Kohgo, Yutaka

    2017-03-01

    Non-alcoholic fatty liver disease (NAFLD) is frequently accompanied by iron overload. However, because of the complex hepcidin-regulating molecules, the molecular mechanism underlying iron overload remains unknown. To identify the key molecule involved in NAFLD-associated iron dysregulation, we performed whole-RNA sequencing on the livers of obese mice. Male C57BL/6 mice were fed a regular or high-fat diet for 16 or 48 weeks. Internal iron was evaluated by plasma iron, ferritin or hepatic iron content. Whole-RNA sequencing was performed by transcriptome analysis using semiconductor high-throughput sequencer. Mouse liver tissues or isolated hepatocytes and sinusoidal endothelial cells were used to assess the expression of iron-regulating molecules. Mice fed a high-fat diet for 16 weeks showed excess iron accumulation. Longer exposure to a high-fat diet increased hepatic fibrosis and intrahepatic iron accumulation. A pathway analysis of the sequencing data showed that several inflammatory pathways, including bone morphogenetic protein (BMP)-SMAD signaling, were significantly affected. Sequencing analysis showed 2314 altered genes, including decreased mRNA expression of the hepcidin-coding gene Hamp. Hepcidin protein expression and SMAD phosphorylation, which induces Hamp, were found to be reduced. The expression of BMP-binding endothelial regulator (BMPER), which inhibits BMP-SMAD signaling by binding BMP extracellularly, was up-regulated in fatty livers. In addition, immunohistochemical and cell isolation analyses showed that BMPER was primarily expressed in the liver sinusoidal endothelial cells (LSECs) rather than hepatocytes. BMPER secretion by LSECs inhibits BMP-SMAD signaling in hepatocytes and further reduces hepcidin protein expression. These intrahepatic molecular interactions suggest a novel molecular basis of iron overload in NAFLD.

  3. Non-alcoholic fatty liver disease is not associated with a lower health perception.

    PubMed

    Mlynarsky, Liat; Schlesinger, Dalit; Lotan, Roni; Webb, Muriel; Halpern, Zamir; Santo, Erwin; Shibolet, Oren; Zelber-Sagi, Shira

    2016-05-07

    To examine the association between non-alcoholic fatty liver disease (NAFLD) and general health perception. This cross sectional and prospective follow-up study was performed on a cohort of a sub-sample of the first Israeli national health and nutrition examination survey, with no secondary liver disease or history of alcohol abuse. On the first survey, in 2003-2004, 349 participants were included. In 2009-2010 participants from the baseline survey were invited to participate in a follow-up survey. On both baseline and follow-up surveys the data collected included: self-reported general health perception, physical activity habits, frequency of physician's visits, fatigue impact scale and abdominal ultrasound. Fatty liver was diagnosed by abdominal ultrasonography using standardized criteria and the ratio between the median brightness level of the liver and the right kidney was calculated to determine the Hepato-Renal Index. Out of 349 eligible participants in the first survey, 213 volunteers participated in the follow-up cohort and were included in the current analysis, NAFLD was diagnosed in 70/213 (32.9%). The prevalence of "very good" self-reported health perception was lower among participants diagnosed with NAFLD compared to those without NAFLD. However, adjustment for BMI attenuated the association (OR = 0.73, 95%CI: 0.36-1.50, P = 0.392). Similar results were observed for the hepato-renal index; it was inversely associated with "very good" health perception but adjustment for BMI attenuated the association. In a full model of multivariate analysis, that included all potential predictors for health perception, NAFLD was not associated with the self-reported general health perception (OR = 0.86, 95%CI: 0.40-1.86, P = 0.704). The odds for "very good" self-reported general health perception (compared to "else") increased among men (OR = 2.42, 95%CI: 1.26-4.66, P = 0.008) and those with higher performance of leisure time physical activity (OR = 1.01, 95%CI: 1

  4. Prediction of Nonalcoholic Fatty Liver Disease Via a Novel Panel of Serum Adipokines

    PubMed Central

    Jamali, Raika; Arj, Abbas; Razavizade, Mohsen; Aarabi, Mohammad Hossein

    2016-01-01

    Abstract Considering limitations of liver biopsy for diagnosis of nonalcoholic liver disease (NAFLD), biomarkers’ panels were proposed. The aims of this study were to establish models based on serum adipokines for discriminating NAFLD from healthy individuals and nonalcoholic steatohepatitis (NASH) from simple steatosis. This case-control study was conducted in patients with persistent elevated serum aminotransferase levels and fatty liver on ultrasound. Individuals with evidence of alcohol consumption, hepatotoxic medication, viral hepatitis, and known liver disease were excluded. Liver biopsy was performed in the remaining patients to distinguish NAFLD/NASH. Histologic findings were interpreted using “nonalcoholic fatty liver activity score.” Control group consisted of healthy volunteers with normal physical examination, liver function tests, and liver ultrasound. Binary logistic regression analysis was applied to ascertain the effects of independent variables on the likelihood that participants have NAFLD/NASH. Decreased serum adiponectin and elevated serum visfatin, IL-6, TNF-a were associated with an increased likelihood of exhibiting NAFLD. NAFLD discriminant score was developed as the following: [(−0.298 × adiponectin) + (0.022 × TNF-a) + (1.021 × Log visfatin) + (0.709 × Log IL-6) + 1.154]. In NAFLD discriminant score, 86.4% of original grouped cases were correctly classified. Discriminant score threshold value of (−0.29) yielded a sensitivity and specificity of 91% and 83% respectively, for discriminating NAFLD from healthy controls. Decreased serum adiponectin and elevated serum visfatin, IL-8, TNF-a were correlated with an increased probability of NASH. NASH discriminant score was proposed as the following: [(−0.091 × adiponectin) + (0.044 × TNF-a) + (1.017 × Log visfatin) + (0.028 × Log IL-8) − 1.787] In NASH model, 84% of original cases were correctly classified. Discriminant score threshold value of (−0.22) yielded a

  5. Fatty liver hemorrhagic syndrome in the backyard chicken: a retrospective histopathologic case series.

    PubMed

    Trott, K A; Giannitti, F; Rimoldi, G; Hill, A; Woods, L; Barr, B; Anderson, M; Mete, A

    2014-07-01

    Fatty liver hemorrhagic syndrome, characterized by sudden death in overconditioned hens due to hepatic rupture and hemorrhage, is one of the leading noninfectious idiopathic causes of mortality in backyard chickens. Nutritional, genetic, environmental, and hormonal factors, or combinations of these, have been proposed yet not proven as the underlying cause. In an attempt to characterize the hepatic changes leading to the syndrome, this retrospective case study examined 76 backyard chickens that were diagnosed with fatty liver hemorrhagic syndrome between January 2007 and September 2012 and presented for necropsy to the diagnostic laboratory of the California Animal Health and Food Safety Laboratory System. A majority of the birds were female (99%), obese (97.5%), and in active lay (69.7%). Livers were examined histologically, and the degree of hepatocellular vacuolation (lipidosis), the reticular stromal architecture, the presence of collagenous connective tissue, and vascular wall changes were evaluated and graded using hematoxylin and eosin, Gomori's reticulin, oil red O, Masson's trichrome, and Verhoeff-Van Gieson stains. Interestingly, there was no correlation between lipidosis and reticulin grades; hepatocellular lipidosis was absent in 22% of the cases and mild in 26% of the cases. Additionally, there was evidence of repeated bouts of intraparenchymal hemorrhage before the acute "bleed-out" in 35.5% of the cases. These data are not supportive of the previously proposed causes and provide a framework for future studies to elucidate the pathogenesis of this condition. Furthermore, the data shown in this study support hemorrhagic liver syndrome as a more accurate name, as hepatic lipidosis is absent in a significant proportion of ruptured livers. © The Author(s) 2013.

  6. Rutin suppresses palmitic acids-triggered inflammation in macrophages and blocks high fat diet-induced obesity and fatty liver in mice.

    PubMed

    Gao, Mingming; Ma, Yongjie; Liu, Dexi

    2013-11-01

    To elucidate the mechanism of rutin in blocking macrophage-mediated inflammation and high fat diet-induced obesity and fatty liver. Both in vitro and in vivo approaches were taken in evaluating the effects of rutin on palmitic acids-triggered inflammation in cultured macrophages, and on weight gain and development of fatty liver of mice fed a high fat diet. Palmitic acids increase mRNA levels of pro-inflammatory cytokines, and elevate the production of TNFα in cultured macrophages. Pre-exposure of rutin to cells greatly suppressed these elevations. The suppressed inflammation by rutin was correlated with a decrease in transcription of genes responsible for ER stress and production of reactive oxygen species. In vivo, rutin protects mice from high fat diet-induced obesity, fatty liver and insulin resistance. The protective effects were associated with lack of hypertrophy and crown-like structures in the white adipose tissue, decreased mRNA levels of marker genes for macrophages including F4/80, Cd11c and Cd68, and repressed transcription of genes involved in chronic inflammation such as Mcp1 and Tnfα in white adipose tissue. In addition, rutin increases the expression of genes responsible for energy expenditure in brown adipose tissue including Pgc1α and Dio2. Furthermore, rutin suppresses transcription of Srebp1c and Cd36 in the liver, leading to a blockade of fatty liver development. These results suggest that supplementation of rutin is a promising strategy for blocking macrophage-mediated inflammation and inflammation-induced obesity and its associated complications.

  7. Serum aminotransferases in nonalcoholic fatty liver disease are a signature of liver metabolic perturbations at the amino acid and Krebs cycle level.

    PubMed

    Sookoian, Silvia; Castaño, Gustavo O; Scian, Romina; Fernández Gianotti, Tomas; Dopazo, Hernán; Rohr, Cristian; Gaj, Graciela; San Martino, Julio; Sevic, Ina; Flichman, Diego; Pirola, Carlos J

    2016-02-01

    Extensive epidemiologic studies have shown that cardiovascular disease and the metabolic syndrome (MetS) are associated with serum concentrations of liver enzymes; however, fundamental characteristics of this relation are currently unknown. We aimed to explore the role of liver aminotransferases in nonalcoholic fatty liver disease (NAFLD) and MetS. Liver gene- and protein-expression changes of aminotransferases, including their corresponding isoforms, were evaluated in a case-control study of patients with NAFLD (n = 42), which was proven through a biopsy (control subjects: n = 10). We also carried out a serum targeted metabolite profiling to the glycolysis, gluconeogenesis, and Krebs cycle (n = 48) and an exploration by the next-generation sequencing of aminotransferase genes (n = 96). An in vitro study to provide a biological explanation of changes in the transcriptional level and enzymatic activity of aminotransferases was included. Fatty liver was associated with a deregulated liver expression of aminotransferases, which was unrelated to the disease severity. Metabolite profiling showed that serum aminotransferase concentrations are a signature of liver metabolic perturbations, particularly at the amino acid metabolism and Krebs cycle level. A significant and positive association between systolic hypertension and liver expression levels of glutamic-oxaloacetic transaminase 2 (GOT2) messenger RNA (Spearman R = 0.42, P = 0.03) was observed. The rs6993 located in the 3' untranslated region of the GOT2 locus was significantly associated with features of the MetS, including arterial hypertension [P = 0.028; OR: 2.285 (95% CI: 1.024, 5.09); adjusted by NAFLD severity] and plasma lipid concentrations. In the context of an abnormal hepatic triglyceride accumulation, circulating aminotransferases rise as a consequence of the need for increased reactions of transamination to cope with the liver metabolic derangement that is associated with greater gluconeogenesis and

  8. Fatty liver disease, an emerging etiology of hepatocellular carcinoma in Argentina.

    PubMed

    Piñero, Federico; Pages, Josefina; Marciano, Sebastián; Fernández, Nora; Silva, Jorge; Anders, Margarita; Zerega, Alina; Ridruejo, Ezequiel; Ameigeiras, Beatriz; D'Amico, Claudia; Gaite, Luis; Bermúdez, Carla; Cobos, Manuel; Rosales, Carlos; Romero, Gustavo; McCormack, Lucas; Reggiardo, Virginia; Colombato, Luis; Gadano, Adrián; Silva, Marcelo

    2018-01-27

    To investigate any changing trends in the etiologies of hepatocellular carcinoma (HCC) in Argentina during the last years. A longitudinal cohort study was conducted by 14 regional hospitals starting in 2009 through 2016. All adult patients with newly diagnosed HCC either with pathology or imaging criteria were included. Patients were classified as presenting non-alcoholic fatty liver disease (NAFLD) either by histology or clinically, provided that all other etiologies of liver disease were ruled out, fatty liver was present on abdominal ultrasound and alcohol consumption was excluded. Complete follow-up was assessed in all included subjects since the date of HCC diagnosis until death or last medical visit. A total of 708 consecutive adults with HCC were included. Six out of 14 hospitals were liver transplant centers ( n = 484). The prevalence of diabetes mellitus was 27.7%. Overall, HCV was the main cause of liver disease related with HCC (37%) including cirrhotic and non-cirrhotic patients, followed by alcoholic liver disease 20.8%, NAFLD 11.4%, cryptogenic 9.6%, HBV 5.4% infection, cholestatic disease and autoimmune hepatitis 2.2%, and other causes 9.9%. A 6-fold increase in the percentage corresponding to NAFLD-HCC was detected when the starting year, i.e ., 2009 was compared to the last one, i.e ., 2015 (4.3% vs 25.6%; P < 0.0001). Accordingly, a higher prevalence of diabetes mellitus was present in NAFLD-HCC group 61.7% when compared to other than NAFLD-HCC 23.3% ( P < 0.0001). Lower median AFP values at HCC diagnosis were observed between NAFLD-HCC and non-NAFLD groups (6.6 ng/mL vs 26 ng/mL; P = 0.02). Neither NAFLD nor other HCC etiologies were associated with higher mortality. The growing incidence of NAFLD-HCC documented in the United States and Europe is also observed in Argentina, a confirmation with important Public Health implications.

  9. The utility of Xenon-133 liver scan in the diagnosis and management of nonalcoholic fatty liver disease.

    PubMed

    Al-Busafi, Said A; Ghali, Peter; Wong, Philip; Novales-Diaz, Javier A; Deschênes, Marc

    2012-03-01

    Nonalcoholic fatty liver disease (NAFLD) is an important and common condition affecting approximately 20% of the general population. Given the limitation of radiological investigations, diagnosis often requires a liver biopsy. To compare Xenon-133 (Xe-133) liver scanning with ultrasonography in the diagnosis of NAFLD. From January 2003 to February 2007, 258 consecutive patients with suspected NAFLD underwent Xe-133 liver scanning at Royal Victoria Hospital (Montreal, Quebec). Of these, 43 patients underwent ultrasonography and liver biopsy for the evaluation of NAFLD. Patients with other liver diseases and significant alcohol consumption were excluded. Two nuclear medicine physicians assessed liver Xe-133 uptake and measured the grade of steatosis using a standardized protocol. The degree of steatosis was determined from biopsy specimens assessed by two hepatopathologists. NAFLD was identified by liver biopsy in 35 of 43 patients (81.4%). Xe-133 scan demonstrated 94.3% sensitivity (95% CI 81.4% to 98.4%) and 87.5% specificity (95% CI 52.9% to 99.4%) for the presence of NAFLD. The positive and negative predictive values for detection of steatosis by Xe-133 scan were 97.1% (95% CI 85.1% to 99.8%) and 77.8% (95% CI 45.3% to 93.7%), respectively. The positive and negative likelihood ratios were 7.54 (95% CI 1.20 to 47.26) and 0.07 (95% CI 0.02 to 0.26), respectively. Two patients with NAFLD (5.7%) who had a negative Xe-133 scan result had histologically mild steatosis (<10%). The grade of steatosis on liver biopsy was highly correlated with the results of the Xe-133 scan (r=0.87; P<0.001). The sensitivity and specificity of ultrasound in diagnosing steatosis were 62.9% and 75%, respectively. Xe-133 liver scan proved to be a safe, reliable, noninvasive method for diagnosing and quantifying hepatic steatosis, and was superior to ultrasound.

  10. Relationship of Tear Size and Location to Fatty Degeneration of the Rotator Cuff

    PubMed Central

    Kim, H. Mike; Dahiya, Nirvikar; Teefey, Sharlene A.; Keener, Jay D.; Galatz, Leesa M.; Yamaguchi, Ken

    2010-01-01

    Background: Fatty degeneration of the rotator cuff muscles may have detrimental effects on both anatomical and functional outcomes following shoulder surgery. The purpose of this study was to investigate the relationship between tear geometry and muscle fatty degeneration in shoulders with a deficient rotator cuff. Methods: Ultrasonograms of both shoulders of 262 patients were reviewed to assess the type of rotator cuff tear and fatty degeneration in the supraspinatus and infraspinatus muscles. The 251 shoulders with a full-thickness tear underwent further evaluation for tear size and location. The relationship of tear size and location to fatty degeneration of the supraspinatus and infraspinatus muscles was investigated with use of statistical comparisons and regression models. Results: Fatty degeneration was found almost exclusively in shoulders with a full-thickness rotator cuff tear. Of the 251 shoulders with a full-thickness tear, eighty-seven (34.7%) had fatty degeneration in either the supraspinatus or infraspinatus, or both. Eighty-two (32.7%) of the 251 full-thickness tears had a distance of 0 mm between the biceps tendon and anterior margin of the tear. Ninety percent of the full-thickness tears with fatty degeneration in both muscles had a distance of 0 mm posterior from the biceps, whereas only 9% of those without fatty degeneration had a distance of 0 mm. Tears with fatty degeneration had significantly greater width and length than those without fatty degeneration (p < 0.0001). Tears with fatty degeneration had a significantly shorter distance posterior from the biceps than those without fatty degeneration (p < 0.0001). The distance posterior from the biceps was found to be the most important predictor for supraspinatus fatty degeneration, whereas tear width and length were found to be the most important predictors for infraspinatus fatty degeneration. Conclusions: Fatty degeneration of the rotator cuff muscles is closely associated with tear size and

  11. PNPLA3 Expression Is Related to Liver Steatosis in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Aragonès, Gemma; Auguet, Teresa; Armengol, Sandra; Berlanga, Alba; Guiu-Jurado, Esther; Aguilar, Carmen; Martínez, Salomé; Sabench, Fátima; Porras, José Antonio; Ruiz, Maikel Daniel; Hernández, Mercé; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

    2016-01-01

    Recent reports suggest a role for the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) in the pathology of non-alcoholic fatty liver disease (NAFLD). Lipid deposition in the liver seems to be a critical process in the pathogenesis of NAFLD. The aim of the present work was to evaluate the association between the liver PNPLA3 expression, key genes of lipid metabolism, and the presence of NAFLD in morbidly obese women. We used real-time polymerase chain reaction (PCR) analysis to analyze the hepatic expression of PNPLA3 and lipid metabolism-related genes in 55 morbidly obese subjects with normal liver histology (NL, n = 18), simple steatosis (SS, n = 20), and non-alcoholic steatohepatitis (NASH, n = 17). Liver biopsies were collected during bariatric surgery. We observed that liver PNPLA3 expression was increased in NAFLD than in NL. It was also upregulated in SS than in NL. Interestingly, we found that the expression of PNPLA3 was significantly higher in severe than mild SS group. In addition, the expression of the transcription factors LXRα, PPARα, and SREBP2 was positively correlated with PNPLA3 liver expression. Regarding rs738409 polymorphism, GG genotype was positive correlated with the presence of NASH. In conclusion, our results show that PNPLA3 could be related to lipid accumulation in liver, mainly in the development and progression of simple steatosis. PMID:27128907

  12. PNPLA3 Expression Is Related to Liver Steatosis in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease.

    PubMed

    Aragonès, Gemma; Auguet, Teresa; Armengol, Sandra; Berlanga, Alba; Guiu-Jurado, Esther; Aguilar, Carmen; Martínez, Salomé; Sabench, Fátima; Porras, José Antonio; Ruiz, Maikel Daniel; Hernández, Mercé; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

    2016-04-27

    Recent reports suggest a role for the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) in the pathology of non-alcoholic fatty liver disease (NAFLD). Lipid deposition in the liver seems to be a critical process in the pathogenesis of NAFLD. The aim of the present work was to evaluate the association between the liver PNPLA3 expression, key genes of lipid metabolism, and the presence of NAFLD in morbidly obese women. We used real-time polymerase chain reaction (PCR) analysis to analyze the hepatic expression of PNPLA3 and lipid metabolism-related genes in 55 morbidly obese subjects with normal liver histology (NL, n = 18), simple steatosis (SS, n = 20), and non-alcoholic steatohepatitis (NASH, n = 17). Liver biopsies were collected during bariatric surgery. We observed that liver PNPLA3 expression was increased in NAFLD than in NL. It was also upregulated in SS than in NL. Interestingly, we found that the expression of PNPLA3 was significantly higher in severe than mild SS group. In addition, the expression of the transcription factors LXRα, PPARα, and SREBP2 was positively correlated with PNPLA3 liver expression. Regarding rs738409 polymorphism, GG genotype was positive correlated with the presence of NASH. In conclusion, our results show that PNPLA3 could be related to lipid accumulation in liver, mainly in the development and progression of simple steatosis.

  13. Ursolic Acid Increases Skeletal Muscle and Brown Fat and Decreases Diet-Induced Obesity, Glucose Intolerance and Fatty Liver Disease

    PubMed Central

    Kunkel, Steven D.; Elmore, Christopher J.; Bongers, Kale S.; Ebert, Scott M.; Fox, Daniel K.; Dyle, Michael C.; Bullard, Steven A.; Adams, Christopher M.

    2012-01-01

    Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness. PMID:22745735

  14. [Effects of total glucosides of paeony on enhancing insulin sensitivity and antagonizing nonalcoholic fatty liver in rats].

    PubMed

    Zheng, Lin-Ying; Pan, Jing-Qiang; Lv, Jun-Hua

    2008-10-01

    To study the pathological changes of blood glucose, serum lipid, insulin resistance, liver function, liver cell denaturalization of total glucosides of paeony on nonalcoholic fatty liver rats caused by insulin resistance and discuss the acting mechanism. Adult SD rats were maintained on high-fat-sugar-salt diet for 56 days. In the 57th day, their fasting blood glucose (FBG) and 2-hours blood glucose after oral glucose tolerance test (OGTT-2 hBG) were mensurated, according to which and the weight the rats were divided randomly into nonalcoholic fatty liver model group, metformin group (0.2 g x kg(-1)) and total glucosides of paeony group (high dosage 0.15 g x kg(-1), low dosage 0.05 g x kg(-1)). All the rats were still administered the same diet and given different drugs by intragastric administration for 28 days. In the 29th day, all of them were killed and the blood was sampled to measure the levels of blood glucose [FBG, OGTT-2 hBG, fasting insulin (Fins)] and serum lipid [free fatty acids (FFA), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)], then the HOMA insulin resistance index (HOMA-IRI, fasting glucosexinsulin) and insulin sensitivity index (ISI) were counted. The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholinesterase (ChE), superoxide dismutase (SOD) and the contents of malondialdehyde (MDA) were measured also. Livers were weighed and collected to be observed the pathological changes. Compared with normal group, in nonalcoholic fatty liver model group the levels of Fins and IRI were increased obviously (P < 0.01), ISI were decreased (P < 0.01), FFA, TG, TC, LDL-C were increased (P < 0.01), HDL-C were decreased (P < 0.05); the content of MDA were increased (P < 0.05), the activities of SOD were decreased (P < 0.01); AST, ALT and ChE were increased (P < 0.05, or P < 0.01), the pathological changes of liver fat were severe (P < 0

  15. Effects of Stigmasterol and β-Sitosterol on Nonalcoholic Fatty Liver Disease in a Mouse Model: A Lipidomic Analysis.

    PubMed

    Feng, Simin; Gan, Ling; Yang, Chung S; Liu, Anna B; Lu, Wenyun; Shao, Ping; Dai, Zhuqing; Sun, Peilong; Luo, Zisheng

    2018-04-04

    To study the effects of stigmasterol and β-sitosterol on high-fat Western diet (HFWD)-induced nonalcoholic fatty liver disease (NAFLD), lipidomic analyses were conducted in liver samples collected after 33 weeks of the treatment. Principal component analysis showed these phytosterols were effective in protecting against HFWD-induced NAFLD. Orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and S-plots showed that triacylglycerols (TGs), phosphatidylcholines, cholesteryl esters, diacylglycerols, and free fatty acids (FFAs) were the major lipid species contributing to these discriminations. The alleviation of NAFLD is mainly associated with decreases in hepatic cholesterol, TGs with polyunsaturated fatty acids, and alterations of free hepatic FFA. In conclusion, phytosterols, at a dose comparable to that suggested for humans by the FDA for the reduction of plasma cholesterol levels, are shown to protect against NAFLD in this long-term (33-week) study.

  16. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver

    PubMed Central

    Aigner, Elmar; Weiss, Günter; Datz, Christian

    2015-01-01

    Elevated iron stores as indicated by hyperferritinemia with normal or mildly elevated transferrin saturation and mostly mild hepatic iron deposition are a characteristic finding in subjects with non-alcoholic fatty liver disease (NAFLD). Excess iron is observed in approximately one third of NAFLD patients and is commonly referred to as the “dysmetabolic iron overload syndrome”. Clinical evidence suggests that elevated body iron stores aggravate the clinical course of NAFLD with regard to liver-related and extrahepatic disease complications which relates to the fact that excess iron catalyses the formation of toxic hydroxyl-radicals subsequently resulting in cellular damage. Iron removal improves insulin sensitivity, delays the onset of type 2 diabetes mellitus, improves pathologic liver function tests and likewise ameliorates NAFLD histology. Several mechanisms contribute to pathologic iron accumulation in NAFLD. These include impaired iron export from hepatocytes and mesenchymal Kupffer cells as a consequence of imbalances in the concentrations of iron regulatory factors, such as hepcidin, cytokines, copper or other dietary factors. This review summarizes the knowledge about iron homeostasis in NAFLD and the rationale for its therapeutic implications. PMID:25729473

  17. Impact of miR-140 Deficiency on Non-Alcoholic Fatty Liver Disease.

    PubMed

    Wolfson, Benjamin; Lo, Pang-Kuo; Yao, Yuan; Li, Linhao; Wang, Hongbing; Zhou, Qun

    2018-04-27

    Loss of miR-140 has a pro-fibrotic effect in the mammary gland. This study aimed to investigate whether miR-140 loss and obesity act synergistically to promote non-alcoholic fatty liver disease, and to identify the underlying mechanisms. Liver tissues were isolated from lean-fat diet and high-fat diet fed wild-type and miR-140 knockout mice. Using molecular staining and immunohistochemistry techniques we identified increased development of non-alcoholic fatty liver disease (NAFLD) and fibrotic indicators in miR-140 knockout mice. Utilizing an in vitro model system, we demonstrated that miR-140 targets TLR-4, and that miR-140 overexpression is sufficient to inhibit palmitic acid signaling through the TLR-4/NFκB pathway. Our findings demonstrate that loss of miR-140 results in increased expression of TLR-4, sensitizing cells to palmitic acid signaling and resulting in increased inflammatory activity through the TLR4/NFκB pathway. This signaling axis promotes NAFLD development in a high-fat diet context and indicates the potential utility of miR-140 rescue as a therapeutic strategy in NAFLD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  18. Serum bile acid level and fatty acid composition in Chinese children with non-alcoholic fatty liver disease.

    PubMed

    Lu, Li Ping; Wan, Yan Ping; Xun, Peng Cheng; Zhou, Ke Jun; Chen, Cheng; Cheng, Si Yang; Zhang, Min Zhong; Wu, Chun Hua; Lin, Wei Wei; Jiang, Ying; Feng, Hai Xia; Wang, Jia Lu; He, Ka; Cai, Wei

    2017-08-01

    To determine serum bile acid (BA) and fatty acid (FA) profiles in Chinese children with non-alcoholic fatty liver disease (NAFLD). A total 76 children aged 4-17 years were categorized into three groups according to the presence and absence of as well as the severity of NAFLD, that is, non-NAFLD (control), mild and moderate to severe NAFLD groups, respectively, based on their liver ultrasonography findings. Serum BA and FA profiles were quantified separately by mass spectrometry and gas chromatography. General linear models were performed to assess the differences among the groups. After adjusted for potential confounders, children with NAFLD had higher levels of chenodeoxycholic acid (CDCA), unconjugated primary BAs (CDCA + cholic acid) but lower levels of deoxycholic acid (DCA), taurodeoxycholic acid (TDCA), glycodeoxycholic acid (GDCA), total DCA (DCA + TDCA + GDCA), glycolithocholic acid (GLCA) and total lithocholic acid (GLCA + taurolithocholic acid) than children without NAFLD. As for FAs, children with mild and moderate to severe NAFLD had higher levels of n-7 monounsaturated FA. Circulating BA and FA profiles may change in children with NAFLD. Further studies are needed to determine their associations and to understand the underlying mechanism of action. © 2017 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

  19. APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice.

    PubMed

    Cheng, Xiaoyun; Yamauchi, Jun; Lee, Sojin; Zhang, Ting; Gong, Zhenwei; Muzumdar, Radhika; Qu, Shen; Dong, H Henry

    2017-03-03

    Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 (APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretion versus fatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and non-esterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro- and anti-inflammatory cytokines. APOC3 neither exacerbated diet-induced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Nonalcoholic fatty liver disease: for better or worse, blame the gut microbiota?

    PubMed

    Li, Ding-You; Yang, Min; Edwards, Sarah; Ye, Shui-Qing

    2013-11-01

    Nonalcoholic fatty liver disease (NAFLD) is a major clinical consequence for people with obesity and metabolic syndrome and is also associated with enteral and parenteral nutrition. Early studies suggested that altered gut microbiota might contribute to obesity by affecting energy harvest from the diet and energy storage in the host. Recent evidence in humans as well as in animal models has linked gut microbiota to the development of NAFLD through the gut-liver axis. With bacterial overgrowth and increased intestinal permeability observed in patients with NAFLD and in animal models, gut-derived bacterial products such as endotoxin (lipopolysaccharide) and bacterial DNA are being delivered to the liver through the portal vein and then activate Toll-like receptors (TLRs), mainly TLR4 and TLR9, and their downstream cytokines and chemokines, leading to the development and progression of NAFLD. Given the limited data in humans, the role of gut microbiota in the pathogenesis of NAFLD is still open to discussion. Prebiotics and probiotics have been attempted to modify the microbiota as preventive or therapeutic strategies on this pathological condition. Their beneficial effects on NALFD have been demonstrated in animal models and limited human studies. However, prospective, appropriately powered, randomized, controlled clinical trials are needed to determine whether prebiotics and probiotics and other integrated strategies to modify intestinal microbiota are efficacious therapeutic modalities to treat NALFD.

  1. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease.

    PubMed

    Ronis, Martin J J; Baumgardner, January N; Sharma, Neha; Vantrease, Jamie; Ferguson, Matthew; Tong, Yudong; Wu, Xianli; Cleves, Mario A; Badger, Thomas M

    2013-02-01

    Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by non-alcoholic fatty liver disease (NAFLD) leading to non-alcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been shown to protect against steatosis and alcoholic liver injury. The current study was designed to determine if a similar beneficial effect of MCT occurs in a rat model of NAFLD. Groups of male rats were isocalorically overfed diets containing 10%, 35% or 70% total energy as corn oil or a 70% fat diet in which corn oil was replaced with increasing concentrations of saturated fat (18:82, beef tallow:MCT oil) from 20% to 65% for 21 days using total enteral nutrition (TEN). As dietary content of corn oil increased, hepatic steatosis and serum alanine amino transferases were elevated (P < 0.05). This was accompanied by greater expression of cytochrome P450 enzyme CYP2E1 (P < 0.05) and higher concentrations of polyunsaturated 18:2 and 20:4 fatty acids (FA) in the hepatic lipid fractions (P < 0.05). Keeping the total dietary fat at 70%, but increasing the proportion of MCT-enriched saturated fat resulted in a dose-dependent reduction in steatosis and necrosis without affecting CYP2E1 induction. There was no incorporation of C8-C10 FAs into liver lipids, but increasing the ratio of MCT to corn oil: reduced liver lipid 18:2 and 20:4 concentrations; reduced membrane susceptibility to radical attack; stimulated FA β- and ω-oxidation as a result of activation of peroxisomal proliferator activated receptor (PPAR)α, and appeared to increase mitochondrial respiration through complex III. These data suggest that replacing unsaturated fats like corn oil with MCT oil in the diet could be utilized as a potential treatment for NAFLD.

  2. Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

    PubMed

    Suzuki-Kemuriyama, Noriko; Matsuzaka, Takashi; Kuba, Motoko; Ohno, Hiroshi; Han, Song-Iee; Takeuchi, Yoshinori; Isaka, Masaaki; Kobayashi, Kazuto; Iwasaki, Hitoshi; Yatoh, Shigeru; Suzuki, Hiroaki; Miyajima, Katsuhiro; Nakae, Dai; Yahagi, Naoya; Nakagawa, Yoshimi; Sone, Hirohito; Yamada, Nobuhiro; Shimano, Hitoshi

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

  3. Non-alcoholic fatty liver disease, diet and gut microbiota

    PubMed Central

    Finelli, Carmine; Tarantino, Giovanni

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may advantageously affect host metabolism. Large-scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high-risk populations, are fervently awaited. PMID:26417275

  4. Impact of graft-to-recipient weight ratio on small-for-size syndrome following living donor liver transplantation.

    PubMed

    Bell, Richard; Pandanaboyana, Sanjay; Upasani, Vivek; Prasad, Raj

    2018-05-01

    This meta-analysis aimed to compare living donor liver transplantation (LDLT) grafts with a graft-to-recipient weight ratio (GRWR) of <0.8 to grafts with a GRWR ≥0.8 with regards to small-for-size syndrome (SFSS) and short and longer term outcomes. An electronic search was performed of the MEDLINE, EMBASE and PubMed databases until December 2016 using both subject headings (MeSH) and free text. Pooled odds ratios and hazard ratios were calculated using fixed- and random-effects models for meta-analysis. Eight studies including 1833 patients met the inclusion criteria. The rate of SFSS was 10% in the <0.8 group and 5% in the ≥0.8 group (odds ratio: 1.69 (1.09, 2.61) (P = 0.020)). No significant difference was noted between the two groups with regards to graft survival up to 5 years (hazard ratio: 1.31 (0.88, 1.94) (P = 0.190)). Similarly, no significant difference was noted in overall complications (P = 0.06), biliary (P = 0.290) or vascular complications (P = 0.190), perioperative haemorrhage (P = 0.150), post-operative mortality (P = 0.810) and rejection (P = 0.160). The incidence of SFSS in grafts with a GRWR <0.8 is more than in GRWR ≥0.8; however, the low GRWR does not appear to impact perioperative outcomes or graft survival. © 2018 Royal Australasian College of Surgeons.

  5. PNPLA3, the triacylglycerol synthesis/hydrolysis/storage dilemma, and nonalcoholic fatty liver disease

    PubMed Central

    Sookoian, Silvia; Pirola, Carlos J

    2012-01-01

    Genome-wide and candidate gene association studies have identified several variants that predispose individuals to developing nonalcoholic fatty liver disease (NAFLD). However, the gene that has been consistently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain containing 3 (PNPLA3, also known as adiponutrin). A nonsynonymous single nucleotide polymorphism in PNPLA3 (rs738409 C/G, a coding variant that encodes an amino acid substitution  I148M) is significantly associated with fatty liver and histological disease severity, not only in adults but also in children. Nevertheless, how PNPLA3 influences the biology of fatty liver disease is still an open question. A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the  I148M variant promotes hepatic lipid synthesis due to a gain of function. We revise here the published data about the role of the  I148M variant in lipogenesis/lipolysis, and suggest putative areas of future research. For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation, and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3’UTR region (hsa-miR-769-3p and hsa-miR-516a-3p). In addition, interesting unanswered questions remain to be explored. For example, PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity, and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element, corroborated by the DNase I hypersensitivity site peak. Finally, an interaction between PNPLA3 and glycerol-3-phosphate acyltransferase 2 is suggested by data miming. PMID:23155331

  6. Topical Formulation Comprising Fatty Acid Extract from Cod Liver Oil: Development, Evaluation and Stability Studies

    PubMed Central

    Ilievska, Biljana; Loftsson, Thorsteinn; Hjalmarsdottir, Martha Asdis; Asgrimsdottir, Gudrun Marta

    2016-01-01

    The purpose of this study was to develop a pharmaceutical formulation containing fatty acid extract rich in free omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid for topical use. Although the health benefits of cod liver oil and other fish oils taken orally as a dietary supplement have been acknowledged and exploited, it is clear that their use can be extended further to cover their antibacterial properties. In vitro evaluation showed that 20% (v/v) fatty acid extract exhibits good activity against strains of the Gram-positive bacteria Staphylococcus aureus, Enterococcus faecalis, Streptoccoccus pyogenes and Streptoccoccus pneumonia. Therefore, free polyunsaturated fatty acids from cod liver oil or other fish oils can be used as safe and natural antibacterial agents. In this study, ointment compositions containing free fatty acids as active antibacterial agents were prepared by using various natural waxes and characterized. The effects of different waxes, such as carnauba wax, ozokerite wax, laurel wax, beeswax, rice bran wax, candelilla wax and microcrystalline wax, in the concentration range of 1% to 5% (w/w) on the ointment texture, consistency and stability were evaluated. The results showed significant variations in texture, sensory and rheological profiles. This was attributed to the wax’s nature and chain composition. Microcrystalline wax gave the best results but laurel wax, beeswax and rice bran wax exhibited excellent texturing, similar sensory profiles and well-balanced rheological properties. PMID:27258290

  7. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease.

    PubMed

    Luukkonen, Panu K; Zhou, You; Sädevirta, Sanja; Leivonen, Marja; Arola, Johanna; Orešič, Matej; Hyötyläinen, Tuulia; Yki-Järvinen, Hannele

    2016-05-01

    Recent data in mice have identified de novo ceramide synthesis as the key mediator of hepatic insulin resistance (IR) that in humans characterizes increases in liver fat due to IR ('Metabolic NAFLD' but not that due to the I148M gene variant in PNPLA3 ('PNPLA3 NAFLD'). We determined which bioactive lipids co-segregate with IR in the human liver. Liver lipidome was profiled in liver biopsies from 125 subjects that were divided into equally sized groups based on median HOMA-IR ('High and Low HOMA-IR', n=62 and n=63) or PNPLA3 genotype (PNPLA3(148MM/MI), n=61 vs. PNPLA3(148II), n=64). The subjects were also divided into 4 groups who had either IR, the I148M gene variant, both of the risk factors or neither. Steatosis and NASH prevalence were similarly increased in 'High HOMA-IR' and PNPLA3(148MM/MI) groups compared to their respective control groups. The 'High HOMA-IR' but not the PNPLA3(148MM/MI) group had features of IR. The liver in 'High HOMA-IR' vs. 'Low HOMA-IR' was markedly enriched in saturated and monounsaturated triacylglycerols and free fatty acids, dihydroceramides (markers of de novo ceramide synthesis) and ceramides. Markers of other ceramide synthetic pathways were unchanged. In PNPLA3(148MM/MI)vs. PNPLA3(148II), the increase in liver fat was due to polyunsaturated triacylglycerols while other lipids were unchanged. Similar changes were observed when data were analyzed using the 4 subgroups. Similar increases in liver fat and NASH are associated with a metabolically harmful saturated, ceramide-enriched liver lipidome in 'Metabolic NAFLD' but not in 'PNPLA3 NAFLD'. This difference may explain why metabolic but not PNPLA3 NAFLD increases the risk of type 2 diabetes and cardiovascular disease. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  8. Rodent Models of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

    PubMed Central

    Imajo, Kento; Yoneda, Masato; Kessoku, Takaomi; Ogawa, Yuji; Maeda, Shin; Sumida, Yoshio; Hyogo, Hideyuki; Eguchi, Yuichiro; Wada, Koichiro; Nakajima, Atsushi

    2013-01-01

    Research in nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), has been limited by the availability of suitable models for this disease. A number of rodent models have been described in which the relevant liver pathology develops in an appropriate metabolic context. These models are promising tools for researchers investigating one of the key issues of NASH: not so much why steatosis occurs, but what causes the transition from simple steatosis to the inflammatory, progressive fibrosing condition of steatohepatitis. The different rodent models can be classified into two large groups. The first includes models in which the disease is acquired after dietary or pharmacological manipulation, and the second, genetically modified models in which liver disease develops spontaneously. To date, no single rodent model has encompassed the full spectrum of human disease progression, but individual models can imitate particular characteristics of human disease. Therefore, it is important that researchers choose the appropriate rodent models. The purpose of the present review is to discuss the metabolic abnormalities present in the currently available rodent models of NAFLD, summarizing the strengths and weaknesses of the established models and the key findings that have furthered our understanding of the disease’s pathogenesis. PMID:24192824

  9. Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease

    PubMed Central

    Shoji, Hirotaka; Yoshio, Sachiyo; Mano, Yohei; Kumagai, Erina; Sugiyama, Masaya; Korenaga, Masaaki; Arai, Taeang; Itokawa, Norio; Atsukawa, Masanori; Aikata, Hiroshi; Hyogo, Hideyuki; Chayama, Kazuaki; Ohashi, Tomohiko; Ito, Kiyoaki; Yoneda, Masashi; Nozaki, Yuichi; Kawaguchi, Takumi; Torimura, Takuji; Abe, Masanori; Hiasa, Yoichi; Fukai, Moto; Kamiyama, Toshiya; Taketomi, Akinobu; Mizokami, Masashi; Kanto, Tatsuya

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. Activation of macrophages and hepatic stellate cells is a critical step that promotes liver fibrosis. We aimed to explore the feasibility of interleukin-34 (IL-34), a key regulator of macrophages, as a fibrosis marker in patients with NAFLD. We enrolled 197 liver biopsy-proven NAFLD patients. We evaluated the serum levels of IL-34, macrophage-colony stimulating factor (M-CSF), soluble CD163 (sCD163), 40 cytokines/chemokines, hyaluronic acid, type IV collagen 7s, and clinically-approved fibrosis scores. IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis. Immunostaining experiments, using resected liver specimens from NAFLD patients, revealed that IL-34 was mainly expressed on liver fibroblasts. IL-34 based fibrosis score (0.0387*IL-34 (pg/ml) + 0.3623*type IV collagen 7s (ng/ml) + 0.0184*age (year)–1.1850) was a practical predictive model of liver fibrosis. Using receiver-operating characteristic analyses, the area under the curve, sensitivity, and specificity of IL-34 based fibrosis score were superior or comparable to the other fibrosis biomarkers and scores. In conclusion, the IL-34 based fibrosis score, including serum IL-34, type IV collagen 7s and age, is a feasible diagnostic marker of liver fibrosis in NAFLD patients. PMID:27363523

  10. MicroRNA biomarker identification in serum for fish oil-induced fatty liver development in Wistar Kyoto rats

    EPA Science Inventory

    Hepatic steatosis (also known as fatty liver) is present in 25-30% of the US population and can increase susceptibility to the toxic effects of chemical exposures. There is need to develop biomarkers of hepatic steatosis that can be used in screening, experimental models, and hum...

  11. APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice*

    PubMed Central

    Cheng, Xiaoyun; Yamauchi, Jun; Lee, Sojin; Zhang, Ting; Gong, Zhenwei; Muzumdar, Radhika; Qu, Shen; Dong, H. Henry

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 (APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretion versus fatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and non-esterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro- and anti-inflammatory cytokines. APOC3 neither exacerbated diet-induced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity. PMID:28115523

  12. Risk factors for biopsy-proven advanced non-alcoholic fatty liver disease in the Veterans Health Administration.

    PubMed

    Patel, Y A; Gifford, E J; Glass, L M; McNeil, R; Turner, M J; Han, B; Provenzale, D; Choi, S S; Moylan, C A; Hunt, C M

    2018-01-01

    With its increasing incidence, nonalcoholic fatty liver disease (NAFLD) is of particular concern in the Veterans Health Administration (VHA). To evaluate risk factors for advanced fibrosis in biopsy-proven NAFLD in the VHA, to identify patients at risk for adverse outcomes. In randomly selected cases from VHA databases (2005-2015), we performed a retrospective case-control study in adults with biopsy-defined NAFLD or normal liver. Of 2091 patients reviewed, 399 met inclusion criteria. Normal controls (n = 65) had normal liver function. The four NAFLD cohorts included: NAFL steatosis (n = 76), nonalcoholic steatohepatitis (NASH) without fibrosis (n = 68), NAFLD/NASH stage 1-3 fibrosis (n = 82), and NAFLD/NASH cirrhosis (n = 70). NAFLD with hepatocellular carcinoma (HCC) was separately identified (n = 38). Most patients were older White men. NAFLD patients with any fibrosis were on average severely obese (BMI>35 kg/m 2 ). Diabetes (54.4%-79.6%) and hypertension (85.8%-100%) were more common in NAFLD with fibrosis or HCC. Across NAFLD, 12.3%-19.5% were enrolled in diet/exercise programs and 0%-2.6% had bariatric surgery. Hispanics exhibited higher rates of NASH (20.6%), while Blacks had low NAFLD rates (1.4%-11.8%), particularly NAFLD cirrhosis and HCC (1.4%-2.6%). Diabetes (OR 11.8, P < .001) and BMI (OR 1.4, P < .001) were the most significant predictors of advanced fibrosis. In the VHA, diabetes and severe obesity increased risk for advanced fibrosis in NAFLD. Of these patients, only a small proportion (~20%) had enrolled in diet/exercise programs or had bariatric surgery (~2%). These results suggest that providers should focus/tailor interventions to improve outcomes, particularly in those with diabetes and severe obesity. © 2017 John Wiley & Sons Ltd.

  13. Liver disease

    MedlinePlus

    ... Coccidioidomycosis Delta agent (hepatitis D) Drug-induced cholestasis Fatty liver disease Hemochromatosis Hepatitis A Hepatitis B Hepatitis C ... abscess Reye syndrome Sclerosing cholangitis Wilson disease Images Fatty liver, CT scan Liver with disproportional fattening, CT scan ...

  14. Analysis of focal spared areas in fatty liver using color Doppler imaging and contrast-enhanced microvessel display sonography.

    PubMed

    Liu, Li-Ping; Dong, Bao-Wei; Yu, Xiao-Ling; Zhang, Da-Kun; Li, Xin; Li, Hua

    2008-03-01

    The purpose of this study was to investigate whether focal fatty sparing (FFS) formation in the liver relates to aberrant blood flow. Sixty-three FFSs of the liver in 52 patients were examined by color Doppler flow imaging and contrast-enhanced microvessel display sonography. The 63 FFSs included 16 FFSs in the porta hepatis, 14 FFSs around the gallbladder fossa, and 33 other FFSs. The control group included patients with a diagnosis of fatty liver but no FFSs or focal lesions near the porta hepatis. Fourteen of 16 FFSs in the porta hepatis showed venous blood toward those areas that were differentiated from the portal and hepatic veins. Focal fatty sparings in the hilus hepatis correlated with aberrant veins, having a statistical significance compared with the control group (P < .0001). Seven of 14 FFSs around the gallbladder fossa contained blood vessels, 5 of them veins and the remaining 2 arteries. Two FFSs were located around hemangiomas. Three FFSs were located around maldeveloped vessels. The blood supply to an FFS in the porta hepatis may be correlated with aberrant veins. Focal fatty sparings around the gallbladder fossa may be associated with aberrant blood flow.

  15. Protective effects of glycyrrhizic acid against non-alcoholic fatty liver disease in mice.

    PubMed

    Sun, Xue; Duan, Xingping; Wang, Changyuan; Liu, Zhihao; Sun, Pengyuan; Huo, Xiaokui; Ma, Xiaodong; Sun, Huijun; Liu, Kexin; Meng, Qiang

    2017-07-05

    Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. The purpose of the present study is to investigate the protective effect of glycyrrhizic acid (GA), a natural triterpene glycoside, on NAFLD induced by a high-fat diet (HFD) in mice, and further to elucidate the mechanisms underlying GA protection. GA treatment significantly reduced the relative liver weight, serum ALT, AST activities, levels of serum lipid, blood glucose and insulin. GA suppressed lipid accumulation in liver. Further mechanism investigation indicated that GA reduced hepatic lipogenesis via downregulating SREBP-1c, FAS and SCD1 expression, increased fatty acids β-oxidation via an increase in PPARα, CPT1α and ACADS, and promoted triglyceride metabolism through inducing LPL activity. Furthermore, GA reduced gluconeogenesis through repressing PEPCK and G6Pase, and increased glycogen synthesis through an induction in gene expression of PDase and GSK3β. In addition, GA increased insulin sensitivity through upregulating phosphorylation of IRS-1 and IRS-2. In conclusion, GA produces protective effect against NAFLD, due to regulation of genes involved in lipid, glucose homeostasis and insulin sensitivity. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Theacrine protects against nonalcoholic fatty liver disease by regulating acylcarnitine metabolism.

    PubMed

    Wang, Guo-En; Li, Yi-Fang; Zhai, Yu-Jia; Gong, Lian; Tian, Jing-Yu; Hong, Mo; Yao, Nan; Wu, Yan-Ping; Kurihara, Hiroshi; He, Rong-Rong

    2018-05-01

    Acylcarnitine metabolism disorder contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). There are, however, few ideal medications for NAFLD, which work by targeting acylcarnitine metabolism. The aim of this study was to investigate the protective effects of theacrine, a rare purine alkaloid isolated from Camellia assamica var. kucha, against acylcarnitine metabolism disorder in NAFLD. The pharmacological activities of theacrine were studied using high-fat diet (HFD)-fed ApoE-/- and C57BL/6 J mice models. Oleate-treated HepG2 and L-02 cells were used to investigate the molecular mechanism of theacrine on acylcarnitine metabolism. The target of theacrine was confirmed in vitro as the blockade of sirtuin 3 (SIRT3) and protein kinase A. Theacrine inhibits hepatic steatosis and liver inflammation and improves energy expenditure in HFD-fed mice. Theacrine ameliorates acylcarnitine metabolism disorder in HFD-fed mice and oleate-treated hepatocytes by improving fatty acid oxidation. The underlying mechanism involves theacrine's activation of the mitochondrial deacetylase SIRT3 and consequently, the increased activity of long-chain acyl coenzyme A dehydrogenase (LCAD) through deacetylation. Theacrine promotes acylcarnitine metabolism in NAFLD through the SIRT3/LCAD signaling pathway. The target of theacrine's activities on NAFLD is identified as SIRT3. Copyright © 2018. Published by Elsevier Inc.

  17. The proportions of different lecithins in the livers of rats deficient in essential fatty acids

    PubMed Central

    Collins, F. D.

    1966-01-01

    1. Lecithin was prepared from the livers of rats deficient in essential fatty acids and analysed by means of countercurrent distribution. Thin-layer chromatography showed that only lecithin was present. 2. The distributions of phosphorus and the fatty acids at the 3 and 2 positions were determined. 3. It has been shown that 26% of the fatty acids in the 3 position were unsaturated and that most of the Δ5,8,11-eicosatrienoic acid and the arachidonic acids occur as the stearoyl or oleoyl lecithins. PMID:5965328

  18. Magnetic resonance imaging and liver histology as biomarkers of hepatic steatosis in children with nonalcoholic fatty liver disease.

    PubMed

    Schwimmer, Jeffrey B; Middleton, Michael S; Behling, Cynthia; Newton, Kimberly P; Awai, Hannah I; Paiz, Melissa N; Lam, Jessica; Hooker, Jonathan C; Hamilton, Gavin; Fontanesi, John; Sirlin, Claude B

    2015-06-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. In order to advance the field of NAFLD, noninvasive imaging methods for measuring liver fat are needed. Advanced magnetic resonance imaging (MRI) has shown great promise for the quantitative assessment of hepatic steatosis but has not been validated in children. Therefore, this study was designed to evaluate the correlation and diagnostic accuracy of MRI-estimated liver proton density fat fraction (PDFF), a biomarker for hepatic steatosis, compared to histologic steatosis grade in children. The study included 174 children with a mean age of 14.0 years. Liver PDFF estimated by MRI was significantly (P < 0.01) correlated (0.725) with steatosis grade. The correlation of MRI-estimated liver PDFF and steatosis grade was influenced by both sex and fibrosis stage. The correlation was significantly (P < 0.01) stronger in girls (0.86) than in boys (0.70). The correlation was significantly (P < 0.01) weaker in children with stage 2-4 fibrosis (0.61) than children with no fibrosis (0.76) or stage 1 fibrosis (0.78). The diagnostic accuracy of commonly used threshold values to distinguish between no steatosis and mild steatosis ranged from 0.69 to 0.82. The overall accuracy of predicting the histologic steatosis grade from MRI-estimated liver PDFF was 56%. No single threshold had sufficient sensitivity and specificity to be considered diagnostic for an individual child. Advanced magnitude-based MRI can be used to estimate liver PDFF in children, and those PDFF values correlate well with steatosis grade by liver histology. Thus, magnitude-based MRI has the potential for clinical utility in the evaluation of NAFLD, but at this time no single threshold value has sufficient accuracy to be considered diagnostic for an individual child. © 2015 by the American Association for the Study of Liver Diseases.

  19. Omega-3 Fatty Acid Deficiency Increases Stearoyl-CoA Desaturase Expression and Activity Indices in Rat Liver: Positive Association with Non-Fasting Plasma Triglyceride Levels

    PubMed Central

    Hofacer, Rylon; Magrisso, I. Jack; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Benoit, Stephen C.; McNamara, Robert K.

    2011-01-01

    Although omega-3 (n-3) fatty acids negatively regulate triglyceride biosynthesis, the mechanisms mediating this effect are poorly understood, and emerging evidence suggests that stearoyl-CoA desaturase (Scd1) is required for de novo triglyceride biosynthesis. To investigate this mechanism, we determined the effects of perinatal n-3 deficiency and postnatal repletion on rat liver Scd1 mRNA expression and activity indices (liver 16:1/16:0 & 18:1/18:0 ratios), and determined relationships with postprandial (non-fasting) plasma triglyceride levels. Rats were fed conventional diets with or without the n-3 fatty acid precursor α-linolenic acid (ALA, 18:3n-3) during perinatal development (E0-P100), and a subset of rats fed the ALA− diet were switched to the ALA+ diet post-weaning (P21-P100, repletion). Compared with controls, rats fed the ALA− diet exhibited significantly lower liver long-chain n-3 fatty acid compositions and elevations in monounsaturated fatty acid composition, both of which were normalized in repleted rats. Liver Scd1 mRNA expression and activity indices (16:1/16:0 & 18:1/18:0 ratios) were significantly greater in n-3 deficient rats compared with controls and repleted rats. Among all rats, liver Scd1 mRNA expression was positively correlated with liver 18:1/18:0 and 16:1/16:0 ratios. Plasma triglyceride levels, but not glucose or insulin levels, were significantly greater in n-3 deficient rats compared with controls and repleted rats. Liver Scd1 mRNA expression and activity indices were positively correlated with plasma triglyceride levels. These preclinical findings demonstrate that n-3 fatty acid status is an important determinant of liver Scd1 mRNA expression and activity, and suggest that down-regulation of Scd1 is a mechanism by which n-3 fatty acids repress constitutive triglyceride biosynthesis. PMID:22047910

  20. Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease.

    PubMed

    Tang, Y; Bian, Z; Zhao, L; Liu, Y; Liang, S; Wang, Q; Han, X; Peng, Y; Chen, X; Shen, L; Qiu, D; Li, Z; Ma, X

    2011-11-01

    Mechanisms associated with the progression of simple steatosis to non-alcoholic fatty liver disease (NAFLD) remain undefined. Regulatory T cells (T(regs)) play a critical role in regulating inflammatory processes in non-alcoholic steatohepatitis (NASH) and because T helper type 17 (Th17) functionally oppose T(reg)-mediated responses, this study focused on characterizing the role of Th17 cells using a NAFLD mouse model. C57BL/6 mice were fed either a normal diet (ND) or high fat (HF) diet for 8 weeks. Mice in the HF group had a significantly higher frequency of liver Th17 cells compared to ND-fed mice. Neutralization of interleukin (IL)-17 in HF mice ameliorated lipopolysaccharide (LPS)-induced liver injury reflected by decreased serum alanine aminotransferase (ALT) levels and reduced inflammatory cell infiltrates in the liver. In vitro, HepG2 cells cultured in the presence of free fatty acids (FFA; oleic acid and palmitic acid) for 24 h and IL-17 developed steatosis via insulin-signalling pathway interference. IL-17 and FFAs synergized to induce IL-6 production by HepG2 cells and murine primary hepatocytes which, in combination with transforming growth factor (TGF-β), expanded Th17 cells. It is likely that a similar process occurs in NASH patients, as there were significant levels of IL-17(+) cell infiltrates in NASH patient livers. The hepatic expression of Th17 cell-related genes [retinoid-related orphan receptor gamma (ROR)γt, IL-17, IL-21 and IL-23] was also increased significantly in NASH patients compared to healthy controls. Th17 cells and IL-17 were associated with hepatic steatosis and proinflammatory response in NAFLD and facilitated the transition from simple steatosis to steatohepatitis. Strategies designed to alter the balance between Th17 cells and T(regs) should be explored as a means of preventing progression to NASH and advanced liver diseases in NAFLD patients. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for