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Sample records for nonalcoholic fatty liver

  1. Fatty liver - nonalcoholic

    MedlinePlus

    ... American Gastroenterological Association. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and ...

  2. Nonalcoholic fatty liver disease.

    PubMed

    Brunt, Elizabeth M; Wong, Vincent W-S; Nobili, Valerio; Day, Christopher P; Sookoian, Silvia; Maher, Jacquelyn J; Bugianesi, Elisabetta; Sirlin, Claude B; Neuschwander-Tetri, Brent A; Rinella, Mary E

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring. PMID:27188459

  3. Non-Alcoholic Fatty Liver Disease (NAFLD)

    MedlinePlus

    Non-Alcoholic Fatty Liver Disease What is Non-alcoholic fatty liver disease (NAFLD)? FAT N AFLD is a name that is given to a ... and under “Liver Health Information view ‘Nonalcoholic fatty liver Disease (NAFLD/NASH)’ IMPORTANT REMINDER: This information from the ...

  4. Nonalcoholic Fatty Liver Disease and Liver Transplantation.

    PubMed

    Pham, Tuan; Dick, Travis B; Charlton, Michael R

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is prevalent in the general population and a growing indication for liver transplant. Longer wait times and challenges with pretransplant survivorship are expected, underscoring the need for improved management of attendant comorbidities. Recognition with potential modification of obesity, sarcopenia, chronic kidney disease, and cardiovascular disease in patients with NAFLD may have important implications in the pretransplant and posttransplant periods. Although patients with NAFLD have generally favorable postoperative outcomes, they are at risk for developing recurrent disease in their allograft, driving the need for pharmacotherapies and dietary innovations appropriate for use in the posttransplant period. PMID:27063277

  5. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

    PubMed

    Brown, Gregory Thomas; Kleiner, David E

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is the liver injury most often associated with disorders of insulin resistance, including obesity, diabetes and the metabolic syndrome. The term encompasses several patterns of liver injury, including a relatively benign condition of steatosis without hepatocellular injury, nonalcoholic steatohepatitis (NASH), and a pattern of zone 1 steatosis, inflammation and fibrosis mainly observed in prepubertal children. Staging and grading systems have been developed to characterize the histological changes in NAFLD, mainly as a tool for clinical research. The histological features of NAFLD across these different manifestations and the scoring systems used to evaluate disease severity are discussed. PMID:26775559

  6. Pediatric Non-alcoholic Fatty Liver Disease.

    PubMed

    Uppal, Vikas; Mansoor, Sana; Furuya, Katryn N

    2016-05-01

    Childhood obesity has reached epidemic proportions, and by 2012, more than one third of American children were overweight or obese. As a result, increasingly, children are developing complications of obesity including liver disease. In fact, non-alcoholic fatty liver disease is the most common form of chronic liver disease seen in children today. Recently, there has been a burgeoning literature examining the pathogenesis, genetic markers, and role of the microbiome in this disease. On the clinical front, new modalities of diagnosing hepatic steatosis and hepatic fibrosis are being developed to provide non-invasive methods of surveillance in children. Lastly, the mainstay of treatment of pediatric non-alcoholic fatty liver disease (NAFLD) has been largely through lifestyle interventions, namely, dieting and exercise. Currently, there are a number of clinical trials examining novel lifestyle and drug therapies for NAFLD that are registered with the US National Institutes of Health ClinicalTrials.gov website. PMID:27086005

  7. 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. PMID:26898658

  8. Micronutrient Antioxidants and Nonalcoholic Fatty Liver Disease.

    PubMed

    Chen, Guanliang; Ni, Yinhua; Nagata, Naoto; Xu, Liang; Ota, Tsuguhito

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most important chronic liver diseases worldwide and has garnered increasing attention in recent decades. NAFLD is characterized by a wide range of liver changes, from simple steatosis to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. The blurred pathogenesis of NAFLD is very complicated and involves lipid accumulation, insulin resistance, inflammation, and fibrogenesis. NAFLD is closely associated with complications such as obesity, diabetes, steatohepatitis, and liver fibrosis. During the progression of NAFLD, reactive oxygen species (ROS) are activated and induce oxidative stress. Recent attempts at establishing effective NAFLD therapy have identified potential micronutrient antioxidants that may reduce the accumulation of ROS and finally ameliorate the disease. In this review, we present the molecular mechanisms involved in the pathogenesis of NAFLD and introduce some dietary antioxidants that may be used to prevent or cure NAFLD, such as vitamin D, E, and astaxanthin. PMID:27563875

  9. Histopathology of nonalcoholic fatty liver disease

    PubMed Central

    Brunt, Elizabeth M; Tiniakos, Dina G

    2010-01-01

    Histological analysis of liver biopsies remains a standard against which other methods of assessment for the presence and amount of hepatic injury due to nonalcoholic fatty liver disease (NAFLD) are measured. Histological evaluation remains the sole method of distinguishing steatosis from advanced forms of NAFLD, i.e. nonalcoholic steatohepatitis (NASH) and fibrosis. Included in the lesions of NAFLD are steatosis, lobular and portal inflammation, hepatocyte injury in the forms of ballooning and apoptosis, and fibrosis. However, patterns of these lesions are as distinguishing as the lesions themselves. Liver injury in adults and children due to NAFLD may have different histological patterns. In this review, the rationale for liver biopsy, as well as the histopathological lesions, the microscopically observable patterns of injury, and the differential diagnoses of NAFLD and NASH are discussed. PMID:21072891

  10. Managing non-alcoholic fatty liver disease.

    PubMed

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

    2016-07-01

    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

  11. 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

  12. Treatment Options for Nonalcoholic Fatty Liver Disease

    PubMed Central

    2008-01-01

    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. PMID:21180527

  13. Role of bioactive fatty acids in nonalcoholic fatty liver disease.

    PubMed

    Juárez-Hernández, Eva; Chávez-Tapia, Norberto C; Uribe, Misael; Barbero-Becerra, Varenka J

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by fat deposition in hepatocytes, and a strong association with nutritional factors. Dietary fatty acids are classified according to their biochemical properties, which confer their bioactive roles. Monounsaturated fatty acids have a dual role in various human and murine models. In contrast, polyunsaturated fatty acids exhibit antiobesity, anti steatosic and anti-inflammatory effects. The combination of these forms of fatty acids-according to dietary type, daily intake and the proportion of n-6 to n-3 fats-can compromise hepatic lipid metabolism. A chemosensory rather than a nutritional role makes bioactive fatty acids possible biomarkers for NAFLD. Bioactive fatty acids provide health benefits through modification of fatty acid composition and modulating the activity of liver cells during liver fibrosis. More and better evidence is necessary to elucidate the role of bioactive fatty acids in nutritional and clinical treatment strategies for patients with NAFLD. PMID:27485440

  14. How to Diagnose Nonalcoholic Fatty Liver Disease.

    PubMed

    de Alwis, Nimantha M W; Anstee, Quentin M; Day, Christopher P

    2016-01-01

    Patients with nonalcoholic fatty liver disease (NAFLD) are asymptomatic and present with either unexplained abnormal liver blood tests or a bright liver on ultrasonography. Some patients will have normal liver blood tests raising the issue of whether patients with risk factors for NAFLD (diabetes and/or metabolic syndrome [MS]) should be screened for its presence with biomarkers, such as the fatty liver index (FLI). The diagnosis of NAFLD requires the exclusion of other causes of chronic liver disease and steatosis, especially heavy alcohol consumption and viral hepatitis particularly HCV genotype 3. Diagnostic work-up should include evaluation of family and personal history of components of the MS and assessment of liver tests, fasting blood glucose, triglycerides and HDL levels. A drug history is important due to a number being associated with steatosis. To confirm the diagnosis of NAFLD and quantify steatosis, ultrasound (US) and MRI-based techniques are available but none are in routine use outside clinical trials. Standard US is no more accurate than biomarkers such as FLI. The accurate staging of NAFLD requires liver biopsy; however, this is clearly impractical for such a prevalent disease. Accordingly, a number of imaging and blood-based biomarker tests have been evaluated. While none have proved reliable for the diagnosis of nonalcoholic steatohepatitis, several have proved accurate in diagnosing the presence of stage 3 or 4 fibrosis, including the NAFLD fibrosis score, fibrosis-4 and the enhanced liver fibrosis test. Of the imaging techniques, elastography has received the most attention and is being used in routine clinical practice. US acoustic radiation force impulse imaging, and MR-based elastography have recently been described but none are sufficiently accurate to replace liver biopsy for clinical trials as yet or are cost effective for use in routine clinical settings. PMID:27547937

  15. Natural History of Nonalcoholic Fatty Liver Disease.

    PubMed

    Goh, George Boon-Bee; McCullough, Arthur J

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) remains among the most common liver diseases worldwide, with increasing prevalence in concert with the obesity and metabolic syndrome epidemic. The evidence on the natural history, albeit with some ambiguity, suggests the potential for some subsets of NAFLD to progress to cirrhosis, liver-related complications and mortality with fibrosis being the most important predictor of hard long-term endpoints such as mortality and liver complications. In this setting, NAFLD proves to be a formidable disease entity, with considerable clinical burden, for both the present and the future. Our understanding of the natural history of NAFLD is constantly evolving, with nascent data challenging current dogma. Further clarification of the natural history is required with well-designed, well-defined studies using prospectively collected data. Identifying the predictors of long-term outcomes should be used to direct development of clinical trial endpoints in NAFLD. PMID:27003142

  16. Nonalcoholic fatty liver disease and hepatocellular carcinoma.

    PubMed

    Zoller, Heinz; Tilg, Herbert

    2016-08-01

    The fastest growing cause of cancer-related death is hepatocellular carcinoma (HCC), which is at least partly attributable to the rising prevalence of non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to malignant transformation into hepatocellular cancer. The estimated annual HCC incidence in the progressive form of NAFLD - non-alcoholic steatohepatitis (NASH) - is about 0.3%. The risk of HCC development is higher in men and increases with age, more advanced fibrosis, progressive obesity, insulin resistance and diabetes mellitus. Studies on the molecular mechanism of HCC development in NAFLD have shown that hepatocarcinogenesis is associated with complex changes at the immunometabolic interface. In line with these clinical risk factors, administration of a choline-deficient high-fat diet to mice over a prolonged period results in spontaneous HCC development in a high percentage of animals. The role of altered insulin signaling in tumorigenesis is further supported by the observation that components of the insulin-signaling cascade are frequently mutated in hepatocellular cancer cells. These changes further enhance insulin-mediated growth and cell division of hepatocytes. Furthermore, studies investigating nuclear factor kappa B (NF-κB) signaling and HCC development allowed dissection of the complex links between inflammation and carcinogenesis. To conclude, NAFLD reflects an important risk factor for HCC, develops also in non-cirrhotic livers and is a prototypic cancer involving inflammatory and metabolic pathways. STRENGTHS/WEAKNESSES AND SUMMARY OF THE TRANSLATIONAL POTENTIAL OF THE MESSAGES IN THE PAPER: The systematic review summarizes findings from unbiased clinical and translational studies on hepatocellular cancer in non-alcoholic fatty liver disease. This provides a concise overview on the epidemiology, risk factors and molecular

  17. Nutritional therapy for nonalcoholic fatty liver disease.

    PubMed

    Dongiovanni, Paola; Lanti, Claudia; Riso, Patrizia; Valenti, Luca

    2016-03-01

    Following the epidemics of obesity, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in western countries. NAFLD is the hepatic manifestation of metabolic syndrome and may progress to cirrhosis and hepatocellular carcinoma. To date, there are no approved drugs for the treatment of NAFLD, and the main clinical recommendation is lifestyle modification, including increase of physical activity and the adoption of a healthy eating behavior. In this regard, studies aimed to elucidate the effect of dietary interventions and the mechanisms of action of specific food bioactives are urgently needed. The present review tries to summarize the most recent data evidencing the effects of nutrients and dietary bioactive compounds intake (i.e., long-chain PUFA, Vitamin E, Vitamin D, minerals and polyphenols) on the modulation of molecular mechanisms leading to fat accumulation, oxidative stress, inflammation and liver fibrosis in NAFLD patients. PMID:26895659

  18. Treatment of nonalcoholic fatty liver disease

    PubMed Central

    Siebler, Juergen; Galle, Peter R

    2006-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause for elevated liver enzymes in the developed nations. Beyond prevention programs which are of particular interest because of the increasing number of overweight children, treatment should be focussed on the most important risk factors, obesity and insulin resistance. As a consequence of elucidating the pathomechanisms of NAFLD, the number of potential therapeutic options increased. However, many studies investigating the therapeutic effect show shortcomings in at least one of the following points: lack of a serial liver biopsy, short term of treatment and limited number of included patients. The second generation insulin sensitizer pioglitazone and rosiglitazone show the most promising improvements in NAFLD, but weight gain and potential hepatotoxicity calls for attention. In conclusion, a general recommendation for the application of specific drugs cannot be given. Besides controlled clinical trials, weight reduction and physical activity to improve insulin sensitivity in obese patients should be the priority objective. PMID:16610015

  19. Treatment options for nonalcoholic fatty liver disease

    PubMed Central

    Lam, Brian; Younossi, Zobair M.

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) has become increasingly recognized as the most common cause of abnormal liver enzymes in the last few decades and is among the most common forms of chronic liver disease in the Western world and across the globe. With the growing epidemic of obesity and diabetes, NAFLD is estimated to affect about one-quarter of the US population. Although most patients with NAFLD have nonprogressive bland steatosis, a minority of patients develop the histological subtype of nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, hepatocellular carcinoma, and liver-related death. This is especially true when NASH patients have type 2 diabetes. Treatment of NAFLD should therefore be directed towards patients with established NASH. Sustained weight loss seems to improve insulin resistance and associated NASH. In fact, weight loss with bariatric surgery leads to biochemical and histological improvement in morbidly obese patients with NASH. Several pharmacologic agents have been studied in an effort to improve insulin resistance and pro-inflammatory mediators potentially responsible for the development and progression of NASH. While some studies have shown initial promise, none has established long-term efficacy using randomized clinical trials. This paper briefly reviews the epidemiology, natural history, and pathophysiology of NAFLD and NASH and then focuses on the clinical trials of various therapeutic modalities for NAFLD. These include weight loss agents, bariatric surgery, insulin-sensitizing agents, lipid-lowering agents, antioxidants, probiotics, anti-tumor necrosis factor agents, cytoprotective and other novel agents. PMID:21180596

  20. Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome.

    PubMed

    Lonardo, Amedeo; Ballestri, Stefano; Marchesini, Giulio; Angulo, Paul; Loria, Paola

    2015-03-01

    The conventional paradigm of nonalcoholic fatty liver disease representing the "hepatic manifestation of the metabolic syndrome" is outdated. We identified and summarized longitudinal studies that, supporting the association of nonalcoholic fatty liver disease with either type 2 diabetes mellitus or metabolic syndrome, suggest that nonalcoholic fatty liver disease precedes the development of both conditions. Online Medical databases were searched, relevant articles were identified, their references were further assessed and tabulated data were checked. Although several cross-sectional studies linked nonalcoholic fatty liver disease to either diabetes and other components of the metabolic syndrome, we focused on 28 longitudinal studies which provided evidence for nonalcoholic fatty liver disease as a risk factor for the future development of diabetes. Moreover, additional 19 longitudinal reported that nonalcoholic fatty liver disease precedes and is a risk factor for the future development of the metabolic syndrome. Finally, molecular and genetic studies are discussed supporting the view that aetiology of steatosis and lipid intra-hepatocytic compartmentation are a major determinant of whether fatty liver is/is not associated with insulin resistance and metabolic syndrome. Data support the novel paradigm of nonalcoholic fatty liver disease as a strong determinant for the development of the metabolic syndrome, which has potentially relevant clinical implications for diagnosing, preventing and treating metabolic syndrome. PMID:25739820

  1. Herbal medicines and nonalcoholic fatty liver disease.

    PubMed

    Yao, Hong; Qiao, Yu-Jie; Zhao, Ya-Li; Tao, Xu-Feng; Xu, Li-Na; Yin, Lian-Hong; Qi, Yan; Peng, Jin-Yong

    2016-08-14

    Nonalcoholic fatty liver disease (NAFLD), which is characterized by excessive fat accumulation in the liver of patients who consume little or no alcohol, becomes increasingly common with rapid economic development. Long-term excess fat accumulation leads to NAFLD and represents a global health problem with no effective therapeutic approach. NAFLD is considered to be a series of complex, multifaceted pathological processes involving oxidative stress, inflammation, apoptosis, and metabolism. Over the past decades, herbal medicines have garnered growing attention as potential therapeutic agents to prevent and treat NAFLD, due to their high efficacy and low risk of side effects. In this review, we evaluate the use of herbal medicines (including traditional Chinese herbal formulas, crude extracts from medicinal plants, and pure natural products) to treat NAFLD. These herbal medicines are natural resources that can inform innovative drug research and the development of treatments for NAFLD in the future. PMID:27570425

  2. Herbal medicines and nonalcoholic fatty liver disease

    PubMed Central

    Yao, Hong; Qiao, Yu-Jie; Zhao, Ya-Li; Tao, Xu-Feng; Xu, Li-Na; Yin, Lian-Hong; Qi, Yan; Peng, Jin-Yong

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD), which is characterized by excessive fat accumulation in the liver of patients who consume little or no alcohol, becomes increasingly common with rapid economic development. Long-term excess fat accumulation leads to NAFLD and represents a global health problem with no effective therapeutic approach. NAFLD is considered to be a series of complex, multifaceted pathological processes involving oxidative stress, inflammation, apoptosis, and metabolism. Over the past decades, herbal medicines have garnered growing attention as potential therapeutic agents to prevent and treat NAFLD, due to their high efficacy and low risk of side effects. In this review, we evaluate the use of herbal medicines (including traditional Chinese herbal formulas, crude extracts from medicinal plants, and pure natural products) to treat NAFLD. These herbal medicines are natural resources that can inform innovative drug research and the development of treatments for NAFLD in the future. PMID:27570425

  3. Gut microbiome and nonalcoholic fatty liver diseases.

    PubMed

    Zhu, Lixin; Baker, Robert D; Baker, Susan S

    2015-01-01

    We review recent findings and hypotheses on the roles of gut microbiome in the pathogenesis of nonalcoholic fatty liver diseases (NAFLD). Microbial metabolites and cell components contribute to the development of hepatic steatosis and inflammation, key components of nonalcoholic steatohepatitis (NASH), the severe form of NAFLD. Altered gut microbiome can independently cause obesity, the most important risk factor for NAFLD. This capability is attributed to short-chain fatty acids (SCFAs), major gut microbial fermentation products. SCFAs account for a large portion of caloric intake of the host, and they enhance intestinal absorption by activating GLP-2 signaling. However, elevated SCFAs may be an adaptive measure to suppress colitis, which could be a higher priority than imbalanced calorie intake. The microbiome of NASH patients features an elevated capacity for alcohol production. The pathomechanisms for alcoholic steatohepatitis may apply to NASH. NAFLD/NASH is associated with elevated Gram-negative microbiome and endotoxemia. However, many NASH patients exhibited normal serum endotoxin indicating that endotoxemia is not required for the pathogenesis of NASH. These observations suggest that microbial intervention may benefit NAFLD/NASH patients. However, very limited effects were observed using traditional probiotic species. Novel probiotic therapy based on NAFLD/NASH specific microbial composition represents a promising future direction. PMID:25310763

  4. Pharmacological management of nonalcoholic fatty liver disease.

    PubMed

    Barb, Diana; Portillo-Sanchez, Paola; Cusi, Kenneth

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) affects one-third of the population and two-thirds of patients with obesity or type 2 diabetes (T2DM). Its more aggressive form is known as nonalcoholic steatohepatitis (NASH) and is characterized by hepatocyte necrosis, inflammation and often fibrosis. The presence of fibrosis indicates a more aggressive course and may lead to cirrhosis. Premature mortality in NASH is related to both hepatic (cirrhosis and hepatocellular carcinoma) and extra-hepatic complications, largely cardiovascular disease (CVD). Many therapeutic agents have been tested, but still none approved specifically for NASH. Treatment of NAFLD includes aggressive management of diabetes and cardiovascular risk factors, although the role of controlling hyperglycemia per se in patients with T2DM and NASH remains unknown. Agents tested with some success in non-diabetic patients with NASH include pioglitazone, liraglutide, vitamin E and to a lesser degree, pentoxiphylline. In patients with T2DM and NASH only pioglitazone has shown to significantly improve liver histology, with only a handful of patients with diabetes having been studied with other modalities. This review focuses on available agents for NASH to assist clinicians in the management of these complex patients. Many novel compounds are being studied and will likely make combination therapy for NASH a reality in the future. PMID:27301803

  5. 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

  6. Nuclear receptors and nonalcoholic fatty liver disease.

    PubMed

    Cave, Matthew C; Clair, Heather B; Hardesty, Josiah E; Falkner, K Cameron; Feng, Wenke; Clark, Barbara J; Sidey, Jennifer; Shi, Hongxue; Aqel, Bashar A; McClain, Craig J; Prough, Russell A

    2016-09-01

    Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic

  7. Nonalcoholic Fatty Liver Disease in Latinos.

    PubMed

    Saab, Sammy; Manne, Vignan; Nieto, Jose; Schwimmer, Jeffrey B; Chalasani, Naga P

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a serious public health concern that affects almost one third of the US population. The prevalence of NAFLD varies among ethnic/racial groups, with the Latin American population being affected disproportionately. The severity of NAFLD also may be greater in the Latino population. The increased prevalence and severity of NAFLD in Latino Americans likely is related to the interplay between issues such as genetic factors, access to health care, or the prevalence of chronic diseases such as metabolic syndrome or diabetes. In this review, we summarize the current literature on the prevalence and risk factors of NAFLD that are seen to be more common in the Latino population in the United States. Finally, we discuss available treatment options, medical and surgical, that are available for NAFLD and how they affect the Latino population. Health care providers need to address modifiable risk factors that impact the natural history as well as treatment outcomes for NAFLD among Latinos. Additional efforts are needed to improve awareness and health care utilization for Latinos. PMID:25976180

  8. Adipokines in nonalcoholic fatty liver disease.

    PubMed

    Polyzos, Stergios A; Kountouras, Jannis; Mantzoros, Christos S

    2016-08-01

    Since the discovery of adipose tissue as a higly active endocrine tissue, adipokines, peptides produced by adipose tissue and exerting autocrine, paracrine and endocrine function, have gained increasing interest in various obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD). Data regarding the association between NAFLD and circulating leptin and adiponectin levels are generally well documented: leptin levels increase, whereas adiponectin levels decrease, by increasing the severity of NAFLD. Data regarding other adipokines in histologically confirmed NAFLD populations are inconclusive (e.g., resistin, visfatin, retinol-binding protein-4, chemerin) or limited (e.g., adipsin, obestatin, omentin, vaspin etc.). This review summarizes evidence on the association between adipokines and NAFLD. The first part of the review provides general consideration on the interplay between adipokines and NAFLD, and the second part provides evidence on specific adipokines possibly involved in NAFLD pathogenesis. A thorough insight into the pathophysiologic mechanisms linking adipokines with NAFLD may result in the design of studies investigating the combined adipokine use as noninvasive diagnostic markers of NAFLD and new clinical trials targeting the treatment of NAFLD. PMID:26725002

  9. Expression of fatty acid synthase in nonalcoholic fatty liver disease

    PubMed Central

    Dorn, Christoph; Riener, Marc-Oliver; Kirovski, Georgi; Saugspier, Michael; Steib, Kathrin; Weiss, Thomas S; Gäbele, Erwin; Kristiansen, Glen; Hartmann, Arndt; Hellerbrand, Claus

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which starts with simple hepatic steatosis and may progress toward inflammation (nonalcoholic steatohepatitis [NASH]). Fatty acid synthase (FASN) catalyzes the last step in fatty acid biosynthesis, and thus, it is believed to be a major determinant of the maximal hepatic capacity to generate fatty acids by de novo lipogenesis. The aim of this study was to analyze the correlation between hepatic steatosis and inflammation with FASN expression. In vitro incubation of primary human hepatocytes with fatty acids dose-dependently induced cellular lipid-accumulation and FASN expression, while stimulation with TNF did not affect FASN levels. Further, hepatic FASN expression was significantly increased in vivo in a murine model of hepatic steatosis without significant inflammation but not in a murine NASH model as compared to control mice. Also, FASN expression was not increased in mice subjected to bile duct ligation, an experimental model characterized by severe hepatocellular damage and inflammation. Furthermore, FASN expression was analyzed in 102 human control or NAFLD livers applying tissue micro array technology and immunohistochemistry, and correlated significantly with the degree of hepatic steatosis, but not with inflammation or ballooning of hepatocytes. Quantification of FASN mRNA expression in human liver samples confirmed significantly higher FASN levels in hepatic steatosis but not in NASH, and expression of SREBP1, which is the main transcriptional regulator of FASN, paralleled FASN expression levels in human and experimental NAFLD. In conclusion, the transcriptional induction of FASN expression in hepatic steatosis is impaired in NASH, while hepatic inflammation in the absence of steatosis does not affect FASN expression, suggesting that FASN may serve as a new diagnostic marker or therapeutic target for the progression of NAFLD. PMID:20606731

  10. Expression of fatty acid synthase in nonalcoholic fatty liver disease.

    PubMed

    Dorn, Christoph; Riener, Marc-Oliver; Kirovski, Georgi; Saugspier, Michael; Steib, Kathrin; Weiss, Thomas S; Gäbele, Erwin; Kristiansen, Glen; Hartmann, Arndt; Hellerbrand, Claus

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which starts with simple hepatic steatosis and may progress toward inflammation (nonalcoholic steatohepatitis [NASH]). Fatty acid synthase (FASN) catalyzes the last step in fatty acid biosynthesis, and thus, it is believed to be a major determinant of the maximal hepatic capacity to generate fatty acids by de novo lipogenesis. The aim of this study was to analyze the correlation between hepatic steatosis and inflammation with FASN expression. In vitro incubation of primary human hepatocytes with fatty acids dose-dependently induced cellular lipid-accumulation and FASN expression, while stimulation with TNF did not affect FASN levels. Further, hepatic FASN expression was significantly increased in vivo in a murine model of hepatic steatosis without significant inflammation but not in a murine NASH model as compared to control mice. Also, FASN expression was not increased in mice subjected to bile duct ligation, an experimental model characterized by severe hepatocellular damage and inflammation. Furthermore, FASN expression was analyzed in 102 human control or NAFLD livers applying tissue micro array technology and immunohistochemistry, and correlated significantly with the degree of hepatic steatosis, but not with inflammation or ballooning of hepatocytes. Quantification of FASN mRNA expression in human liver samples confirmed significantly higher FASN levels in hepatic steatosis but not in NASH, and expression of SREBP1, which is the main transcriptional regulator of FASN, paralleled FASN expression levels in human and experimental NAFLD. In conclusion, the transcriptional induction of FASN expression in hepatic steatosis is impaired in NASH, while hepatic inflammation in the absence of steatosis does not affect FASN expression, suggesting that FASN may serve as a new diagnostic marker or therapeutic target for the progression of NAFLD. PMID:20606731

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

    PubMed Central

    2013-01-01

    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. PMID:24133660

  12. NONALCOHOLIC FATTY LIVER DISEASE BRAZILIAN SOCIETY OF HEPATOLOGY CONSENSUS.

    PubMed

    Cotrim, Helma P; Parise, Edison R; Figueiredo-Mendes, Cláudio; Galizzi-Filho, João; Porta, Gilda; Oliveira, Claudia P

    2016-01-01

    The prevalence of obesity-related metabolic syndrome has rapidly increased in Brazil, resulting in a high frequency of nonalcoholic fatty liver disease, that didn't receive much attention in the past. However, it has received increased attention since this disease was identified to progress to end-stage liver diseases, such as cirrhosis and hepatocellular carcinoma. Clinical practice guidelines for the diagnosis and treatment of nonalcoholic fatty liver disease have not been established in Brazil. The Brazilian Society of Hepatology held an event with specialists' members from all over Brazil with the purpose of producing guideline for Nonalcoholic Fatty Liver Disease based on a systematic approach that reflects evidence-based medicine and expert opinions. The guideline discussed the following subjects: 1-Concepts and recommendations; 2-Diagnosis; 3-Non-medical treatment; 4-Medical treatment; 5-Pediatrics - Diagnosis; 6-Pediatrics - Non-medical treatment; 7-Pediatrics - Medical treatment; 8-Surgical treatment. PMID:27305420

  13. Relationship between non-alcoholic fatty liver disease and inflammation in patients with non-alcoholic fatty liver

    PubMed Central

    Foroughi, Mehdi; Maghsoudi, Zahra; Khayyatzadeh, Saeid; Ghiasvand, Reza; Askari, Gholamreza; Iraj, Bijan

    2016-01-01

    Background: Non-alcoholic fatty liver is the most chronic liver disease that eventually can become cirrhosis. One of the underlying assumptions for the fatty liver created by inflammation of the hepatocytes. We aimed to assess the association between non-alcoholic fatty liver disease (NAFLD) and sub-clinical inflammation. Materials and Methods: This is a cross-sectional study which was conducted on 55 patients over 30 years, with NAFLD. Fatty liver grade was assessed using liver ultrasound. Liver enzymes (alanine aminotransferase, aspartate aminotransferase), anthropometric characteristics and inflammatory marker C-reactive protein (CRP) were measured. Qualitative variables (sex and fatty liver grade) and quantitative variables such as were compared with independent t-test and Chi-square test. Relationship between fatty liver grade and inflammatory index was assessed with SPSS software (version 20; SPSS, Inc. Chicago, IL, USA). Results: Non-alcoholic fatty liver grades were associated with CRP level and this relationship remains in statistically significant level even after adjusting the effects of confounding variables such as age, sex and body mass index of participants (P = 0.016). Conclusion: In this cross-sectional study, presentation of NAFLD showed a significant correlation with sub-clinical systemic inflammation and CRP level. PMID:27014655

  14. [Non-alcoholic fatty liver disease and hepatocellular carcinoma - 2016].

    PubMed

    Pár, Alajos; Pár, Gabriella

    2016-06-19

    In the past decade non-alcoholic liver disease became the most frequently diagnosed liver disease in developed countries. At the same time, the dramatic rise in the incidence of hepatocellular carcinoma is attributed to this common metabolic disorder, and mainly to its severe form, non-alcoholic steatohepatitis. The risk factors of these associated diseases are genetic predisposition, obesity and diabetes as well as chronic low grade necro-infammation, which often leads to liver fibrosis. Free fatty acids, cytokines, lipotoxicity, insulin resistance, microRNS dysregulation and alteration in intestinal microbiota play a pivotal role in the pathogenesis. Treatment of non-alcoholic fatty liver disease - weight reduction and physical exercise in obesity, metformin in diabetes, statins in dyslipidemia and, as a new option, obeticholic acid - may diminish the risk of the hepatocellular carcinoma related to this metabolic disease. PMID:27287838

  15. [Use of Legalon in non-alcoholic fatty liver disease].

    PubMed

    Buturova, L I; Tsybizova, T A; Kalinin, A V

    2010-01-01

    The article presents the current understanding of the etiology, pathogenesis of nonalcoholic fatty liver disease, its basic forms, risk factors, prevalence and clinical course. Shows the data of research on the effectiveness of purely herbal product Legalon, in the treatment of non-alcoholic fatty liver disease. The 2-month course of treatment was underwent in the research team, on that background there was noted positive dynamics: cropped asthenic syndrome, pain and heaviness in the right hypochondrium, dyspepsia. In assessing of the biochemical parameters was shown a significant decrease in serum transaminases, gamma-glyutamiltransaminazy level. PMID:20734480

  16. Non-alcoholic fatty liver disease and liver transplantation.

    PubMed

    Khan, Reenam S; Newsome, Philip N

    2016-08-01

    Cirrhosis secondary to non-alcoholic steatohepatitis (NASH) is a common indication for liver transplant. In comparison to other cirrhotic patients, patients with NASH cirrhosis are more likely to be older and have the metabolic syndrome. Pre-transplant, patients require careful evaluation of cardiovascular risk. As the incidence of non-alcoholic fatty liver disease (NAFLD) is rising, a greater proportion of donor grafts have steatosis greater than 30%, which is associated with poor outcomes. Grafts with steatosis greater than 60% are unsuitable for transplant. Overall, post-transplant survival outcomes for patients with NASH cirrhosis are similar to those with cirrhosis without NASH. However, NASH cirrhosis is associated with a higher 30-day mortality, predominantly from an increase in cardiovascular events and infections. Following liver transplant, there is a significant risk of NASH recurrence, although this seldom results in allograft loss. Furthermore, a significant number of patients who had a liver transplant for other reasons develop NASH de novo. When patients with NASH cirrhosis are considered for transplant, one of the major challenges lies in identifying which patients are too high risk for surgery. This review aims to provide information to aid this decision making process, and to provide guidance on the peri-operative care strategies that can modify risk. PMID:26997540

  17. Therapeutic potential of green tea in nonalcoholic fatty liver disease.

    PubMed

    Masterjohn, Christopher; Bruno, Richard S

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a constellation of progressive liver disorders that are closely related to obesity, diabetes, and insulin resistance and may afflict over 70 million Americans. NAFLD may occur as relatively benign, nonprogressive liver steatosis, but in many individuals it may progress in severity to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and liver failure or hepatocellular carcinoma. No validated treatments currently exist for NAFLD except for weight loss, which has a poor long-term success rate. Thus, dietary strategies that prevent the development of liver steatosis or its progression to nonalcoholic steatohepatitis are critically needed. Green tea is rich in polyphenolic catechins that have hypolipidemic, thermogenic, antioxidant, and anti-inflammatory activities that may mitigate the occurrence and progression of NAFLD. This review presents the experimental evidence demonstrating the hepatoprotective properties of green tea and its catechins and the proposed mechanisms by which these targeted dietary agents protect against NAFLD. PMID:22221215

  18. Current treatment options for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

    PubMed Central

    Beaton, Melanie D

    2012-01-01

    Nonalcoholic fatty liver disease is the leading cause of liver disease in western society. It is a cause of end-stage liver disease, with increased mortality secondary to cirrhosis and its complications. It is also recognized that cardiovascular disease is a significant cause of death in these patients. Significant work evaluating various treatments has been performed in recent years; however, to date, no ideal therapy exists. Lifestyle modification remains the cornerstone of management. The present article reviews the current status of various treatment modalities evaluated in nonalcoholic fatty liver disease. PMID:22720278

  19. Mechanisms of disease progression in nonalcoholic fatty liver disease.

    PubMed

    Jou, Janice; Choi, Steve S; Diehl, Anna Mae

    2008-11-01

    Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic pathology, ranging from simple steatosis (also called nonalcoholic fatty liver or NAFL) in its most benign form, to cirrhosis in its most advanced form. Nonalcoholic steatohepatitis (NASH) is an intermediate level of hepatic pathology. Hepatocyte accumulation of triglyceride is a hallmark of NAFL and NASH, but this sometimes subsides once cirrhosis has developed. Triglyceride storage per se is not hepatotoxic. Rather, it is a marker of increased exposure of hepatocytes to potentially toxic fatty acids. NAFL progresses to NASH when adaptive mechanisms that protect hepatocytes from fatty acid-mediated lipotoxicity become overwhelmed and rates of hepatocyte death begin to outstrip mechanisms that normally regenerate dead hepatocytes. This triggers repair responses that involve activation of hepatic stellate cells to myofibroblasts. The myofibroblasts generate excessive matrix and produce factors that stimulate expansion of liver progenitor populations. The progenitor cells produce chemokines to attract various kinds of inflammatory cells to the liver. They also differentiate to replace the dead hepatocytes. The intensity of these repair responses generally parallel the degree of hepatocyte death, resulting in variable distortion of the hepatic architecture with fibrosis, infiltrating immune cells, and regenerating epithelial nodules. As in other types of chronic liver injury, cirrhosis ensues in patients with NAFLD when repair is extreme and sustained, but ultimately unsuccessful, at reconstituting healthy hepatic epithelia. PMID:18956293

  20. Non-Alcoholic Fatty Liver Disease in Children

    PubMed Central

    SINGER, CRISTINA; STANCU, POLIXENIA; COŞOVEANU, SIMONA; BOTU, ALINA

    2014-01-01

    In the last years, there has been extremely much information which reveals an alarming increase of obesity in children and, at the same time, an increase of the incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD implies a wide range of affections starting from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH); the latter can evolve to cirrhosis and hepatic carcinoma. All these affections were noticed in children, too. The article presents data on the epidemiology, pathogeny, clinical and paraclinical findings, and treatment of NAFLD in children. PMID:25729601

  1. Current Pharmacologic Therapy for Nonalcoholic Fatty Liver Disease.

    PubMed

    Ganesh, Swaytha; Rustgi, Vinod K

    2016-05-01

    Weight loss, regular exercise, and diet composition modification seem to improve biochemical and histologic abnormalities. Other therapies directed at insulin resistance, oxidative stress, cytoprotection, and fibrosis may also offer benefits. Insulin sensitizers and vitamin E seem to be the most promising; however, they cause side effects. A multifaceted approach of lifestyle modifications, weight loss, and pharmacotherapy can be used in combination, but no single treatment approach has proved universally applicable to the general population with nonalcoholic steatohepatitis (NASH). Continuous clinical and preclinical studies on existing and potential drugs are needed to improve treatment of nonalcoholic fatty liver disease/NASH. PMID:27063274

  2. Olive oil consumption and non-alcoholic fatty liver disease

    PubMed Central

    Assy, Nimer; Nassar, Faris; Nasser, Gattas; Grosovski, Maria

    2009-01-01

    The clinical implications of non-alcoholic fatty liver diseases (NAFLD) derive from their potential to progress to fibrosis and cirrhosis. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress results in increased free fatty acid delivery to the liver and increased hepatic triglyceride (TG) accumulation. An olive oil-rich diet decreases accumulation of TGs in the liver, improves postprandial TGs, glucose and glucagon-like peptide-1 responses in insulin-resistant subjects, and upregulates glucose transporter-2 expression in the liver. The principal mechanisms include: decreased nuclear factor-kappaB activation, decreased low-density lipoprotein oxidation, and improved insulin resistance by reduced production of inflammatory cytokines (tumor necrosis factor, interleukin-6) and improvement of jun N-terminal kinase-mediated phosphorylation of insulin receptor substrate-1. The beneficial effect of the Mediterranean diet is derived from monounsaturated fatty acids, mainly from olive oil. In this review, we describe the dietary sources of the monounsaturated fatty acids, the composition of olive oil, dietary fats and their relationship to insulin resistance and postprandial lipid and glucose responses in non-alcoholic steatohepatitis, clinical and experimental studies that assess the relationship between olive oil and NAFLD, and the mechanism by which olive oil ameliorates fatty liver, and we discuss future perspectives. PMID:19370776

  3. Nonalcoholic Fatty Liver Disease and the Gut Microbiome.

    PubMed

    Boursier, Jerome; Diehl, Anna Mae

    2016-05-01

    Recent progress has allowed a more comprehensive study of the gut microbiota. Gut microbiota helps in health maintenance and gut dysbiosis associates with chronic metabolic diseases. Modulation of short-chain fatty acids and choline bioavailability, lipoprotein lipase induction, alteration of bile acid profile, endogenous alcohol production, or liver inflammation secondary to endotoxemia result from gut dysbiosis. Modulation of the gut microbiota by pre/probiotics gives promising results in animal, but needs to be evaluated in human before use in clinical practice. Gut microbiota adds complexity to the pathophysiology of nonalcoholic fatty liver disease but represents an opportunity to discover new therapeutic targets. PMID:27063268

  4. Management of non-alcoholic fatty liver disease in 2015

    PubMed Central

    Malhotra, Neel; Beaton, Melanie D

    2015-01-01

    There is no single pharmacologic therapy that has been approved to treat nonalcoholic fatty liver disease in the general population. The backbone of therapy currently includes intensive lifestyle modification with established targets for diet and weight loss. The use of unsweetened, unfiltered coffee along with limiting high fructose corn syrup have emerged as beneficial dietary recommendations. The use of empiric oral hypoglycemic agents and vitamin E, however, has not been widely accepted. Developing bariatric surgical techniques are promising, but additional studies with long-term follow up are needed before it can be widely recommended. Finally, liver transplantation is an increasingly frequent consideration once complications of end-stage disease have developed. The future treatment of those with nonalcoholic fatty liver disease will likely involve a personalized approach. The importance of the gut microbiome in mediating hepatocyte inflammation and intestinal permeability is emerging and may offer avenues for novel treatment. The study of anti-fibrotic agents such as pentoxifylline and FXR agonists hold promise and new pathways, such as hepatocyte cannabinoid receptor antagonists are being studied. With the incidence of obesity and the metabolic syndrome increasing throughout the developed world, the future will continue to focus on finding novel agents and new applications of existing therapies to help prevent and to mediate the progression of nonalcoholic fatty liver disease. PMID:26730275

  5. Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum.

    PubMed

    Hardy, Timothy; Oakley, Fiona; Anstee, Quentin M; Day, Christopher P

    2016-05-23

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction in the Western world and is increasing owing to its close association with obesity and insulin resistance. NAFLD represents a spectrum of liver disease that, in a minority of patients, can lead to progressive nonalcoholic steatohepatitis (NASH), fibrosis, and ultimately hepatocellular carcinoma and liver failure. NAFLD is a complex trait resulting from the interaction between environmental exposure and a susceptible polygenic background and comprising multiple independent modifiers of risk, such as the microbiome. The molecular mechanisms that combine to define the transition to NASH and progressive disease are complex, and consequently, no pharmacological therapy currently exists to treat NASH. A better understanding of the pathogenesis of NAFLD is critical if new treatments are to be discovered. PMID:26980160

  6. Nonalcoholic fatty liver disease as a multi-systemic disease

    PubMed Central

    Fotbolcu, Hakan; Zorlu, Elçin

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD includes a wide spectrum of liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis and advanced hepatic fibrosis. NAFLD has been recognized as a hepatic manifestation of metabolic syndrome linked with insulin resistance. NAFLD should be considered not only a liver specific disease but also an early mediator of systemic diseases. Therefore, NAFLD is usually associated with cardiovascular disease, chronic kidney disease, type 2 diabetes, obesity, and dyslipidemia. NAFLD is highly prevalent in the general population and is associated with increased cardiovascular morbidity and mortality. The underlying mechanisms and pathogenesis of NAFLD with regard to other medical disorders are not yet fully understood. This review focuses on pathogenesis of NAFLD and its relation with other systemic diseases. PMID:27122660

  7. Histology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in Adults and Children.

    PubMed

    Kleiner, David E; Makhlouf, Hala R

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the liver disease associated with obesity, diabetes, and the metabolic syndrome. Although steatosis is a key histologic feature, liver biopsies of patients with NAFLD can show a wide range of findings. Nonalcoholic steatohepatitis (NASH) is a progressive subtype of NAFLD first defined by analogy to alcoholic hepatitis. Young children may have an alternate pattern of progressive NAFLD characterized by a zone 1 distribution of steatosis, inflammation, and fibrosis. Several grading and staging systems exist, but all require adequate biopsies. Although NASH generally shows fibrosis progression over time, some patients show regression of disease. PMID:27063270

  8. 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. PMID:26620035

  9. 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. PMID:27237577

  10. 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

  11. Nonalcoholic Fatty Liver Disease: Lipids and Insulin Resistance.

    PubMed

    Berk, Paul D; Verna, Elizabeth C

    2016-05-01

    Obesity and its major comorbidities, including type 2 diabetes mellitus, nonalcoholic fatty liver disease (NAFLD), obesity cardiomyopathy, and certain cancers, have caused life expectancy in the United States to decline in recent years. Obesity is the increased accumulation of triglycerides (TG), which are synthesized from glycerol and long-chain fatty acids (LCFA) throughout the body. LCFA enter adipocytes, hepatocytes, and cardiomyocytes via specific, facilitated transport processes. Metabolism of increased cellular TG content in obesity may lead to comorbidities such as NAFLD and cardiomyopathy. Better understanding of LCFA transport processes may lead to successful treatment of obesity and NAFLD. PMID:27063267

  12. Dietary recommendations for patients with nonalcoholic fatty liver disease

    PubMed Central

    Stankowiak-Kulpa, Hanna; Grzymisławski, Marian

    2014-01-01

    Changes to patients’ lifestyle, especially a modified dietary approach, play a key role in the treatment of nonalcoholic fatty liver disease (NAFLD). A balanced, limiting and individually tailored nutritional scheme enables weight loss and an improvement in the clinical picture of NAFLD. According to nutritional recommendations for patients with NAFLD, carbohydrates should comprise 40–50% of total dietary energy. It is advisable to increase the amount of complex carbohydrates rich in dietary fibre. A major role in the aetiology of NAFLD is played by excessive intake of fructose, which is related to the rise in consumption of nonalcoholic beverages among subjects in developed countries. Fat intake should comprise < 30% of daily calories. It is essential to increase consumption of food products rich in mono- and polyunsaturated fatty acids. Ingestion of protein should constitute 15–20% of total energy. PMID:24868294

  13. Role of Mitochondria in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Nassir, Fatiha; Ibdah, Jamal A.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) affects about 30% of the general population in the United States and includes a spectrum of disease that includes simple steatosis, non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Significant insight has been gained into our understanding of the pathogenesis of NALFD; however the key metabolic aberrations underlying lipid accumulation in hepatocytes and the progression of NAFLD remain to be elucidated. Accumulating and emerging evidence indicate that hepatic mitochondria play a critical role in the development and pathogenesis of steatosis and NAFLD. Here, we review studies that document a link between the pathogenesis of NAFLD and hepatic mitochondrial dysfunction with particular focus on new insights into the role of impaired fatty acid oxidation, the transcription factor peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and sirtuins in development and progression of NAFLD. PMID:24837835

  14. Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis

    PubMed Central

    Le, Thuy-Anh; Loomba, Rohit

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver enzymes and chronic liver disease in the US with expected rise in incidence paralleling the epidemic of obesity. A subset of patients with NAFLD have the progressive form of NAFLD that is termed non-alcoholic steatohepatitis (NASH), which is characterized by specific features on liver histology including hepatocellular ballooning degeneration, lobular inflammation, and zone-3 steatosis with or without peri-sinusoidal fibrosis. Non-alcoholic steatohepatitis can progress to cirrhosis and result in liver-related death. Insulin resistance is commonly seen in patients with NASH and often co-exists with other features of the metabolic syndrome including hypertension, hyperlipidemia, and obesity. Although weight loss through lifestyle modifications including dietary changes and increased physical exercise remains the backbone of management of NASH, it has proved challenging for patients to achieve and maintain weight loss goals. Thus, it is often necessary to couple lifestyle changes with another pharmacologic treatment for NASH. Insulin sensitizers including the biguanides (metformin), thiazolidinediones (pioglitazone and rosiglitazone), and glucagon-like peptide-1 receptor agonists (exenatide) are large groups of medications that have been studied for the treatment of NASH. Other agents with anti-inflammatory, anti-apoptotic, or anti-fibrotic properties which have been studied in NASH include vitamin E, pentoxifylline, betaine, and ursodeoxycholic acid. This review will provide a detailed summary on the clinical data behind the full spectrum of treatments that exist for NASH and suggest management recommendations. PMID:25755424

  15. Treatment of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Scherer, Antonia; Dufour, Jean-François

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions from steatosis to cirrhosis and hepatocellular carcinoma. Steatosis is a benign reversible condition, which does not need treatment. Cirrhosis and hepatocellular carcinoma are the end stages of any chronic liver disease and do not have etiology-specific treatments. In this chapter, we will review treatment options for non-alcoholic steatohepatitis, which is the progressive form of NAFLD. Basically there are 2 strategies, the first of which is to address lifestyle and the second to use medication. The first approach is the most physiologic, the least expensive, but is also the most difficult to implement. The second approach, which should help patients who failed the first approach, is at the advanced clinical research stage. PMID:27548081

  16. Vitamin E reduces liver stiffness in nonalcoholic fatty liver disease

    PubMed Central

    Fukui, Aiko; Kawabe, Naoto; Hashimoto, Senju; Murao, Michihito; Nakano, Takuji; Shimazaki, Hiroaki; Kan, Toshiki; Nakaoka, Kazunori; Ohki, Masashi; Takagawa, Yuka; Takamura, Tomoki; Kamei, Hiroyuki; Yoshioka, Kentaro

    2015-01-01

    AIM: To evaluate the efficacy of vitamin E treatment on liver stiffness in nonalcoholic fatty liver disease (NAFLD). METHODS: Thirty-eight NAFLD patients were administered vitamin E for > 1 year. The doses of vitamin E were 150, 300, or 600 mg; three times per day after each meal. Responses were assessed by liver enzyme levels [aspartate aminotransferase (AST), alanine aminotranferease (ALT), and γ-glutamyl transpeptidase (γ-GTP)], noninvasive scoring systems of hepatic fibrosis-4 [FIB-4 index and aspartate aminotransferase-to-platelet index (APRI)], and liver stiffness [velocity of shear wave (Vs)] measured by acoustic radiation force impulse elastography. Vs measurements were performed at baseline and 12 mo after baseline. The patients were genotyped for the patatin-like phospholipase domain containing 3 (PNPLA3) polymorphisms and then divided into either the CC/CG or GG group to examine each group’s responses to vitamin E treatment. RESULTS: We found marked differences in the platelet count, serum albumin levels, alkaline phosphatase levels, FIB-4 index, APRI, and Vs at baseline depending on the PNPLA3 polymorphism. AST, ALT, and γ-GTP levels (all P < 0.001); FIB-4 index (P = 0.035); APRI (P < 0.001); and Vs (P < 0.001) significantly decreased from baseline to 12 mo in the analysis of all patients. In the subset analyses of PNPLA3 genotypes, AST levels (P = 0.011), ALT levels (P < 0.001), γ-GTP levels (P = 0.005), APRI (P = 0.036), and Vs (P = 0.029) in genotype GG patients significantly improved, and AST and ALT levels (both P < 0.001), γ-GTP levels (P = 0.003), FIB-4 index (P = 0.017), and APRI (P < 0.001) in genotype CC/CG patients. CONCLUSION: One year of vitamin E treatment improved noninvasive fibrosis scores and liver stiffness in NAFLD patients. The responses were similar between different PNPLA3 genotypes. PMID:26644818

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

    PubMed

    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

  18. 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

  19. Non-alcoholic fatty liver disease in 2015

    PubMed Central

    Ahmed, Monjur

    2015-01-01

    There is worldwide epidemic of non-alcoholic fatty liver disease (NAFLD). NAFLD is a clinical entity related to metabolic syndrome. Majority of the patients are obese but the disease can affect non-obese individuals as well. Metabolic factors and genetics play important roles in the pathogenesis of this disorder. The spectrum of disorders included in NAFLD are benign macrovesicular hepatic steatosis, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis of liver and hepatocellular carcinoma. Although the disease remains asymptomatic most of the time, it can slowly progress to end stage liver disease. It will be the most common indication of liver transplantation in the future. It is diagnosed by abnormal liver chemistry, imaging studies and liver biopsy. As there are risks of potential complications during liver biopsy, many patients do not opt for liver biopsy. There are some noninvasive scoring systems to find out whether patients have advanced hepatic fibrosis. At the present time, there are limited treatment options which include lifestyle modification to loose weight, vitamin E and thioglitazones. Different therapeutic agents are being investigated for optimal management of this entity. There are some studies done on incretin based therapies in patients with NAFLD. Other potential agents will be silent information regulator protein Sirtuin and antifibrotic monoclonal antibody Simtuzumab against lysyl oxidase like molecule 2. But they are still in the investigational phase. PMID:26085906

  20. Carotenoids and non-alcoholic fatty liver disease

    PubMed Central

    Yilmaz, Bahiddin; Sahin, Kazim; Bilen, Hande; Bahcecioglu, Ibrahim H.; Bilir, Birdal; Ashraf, Sara; Halazun, Karim J.

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a growing health problem around the world, especially in developed countries. NAFLD includes all cases of fatty liver disease from simple steatosis to cirrhosis, without excessive alcohol intake, use of steatogenic medication or hereditary disorders. Pathogenesis is associated with dietary high fat intake, decreased free fatty acid (FFA) oxidation, increased hepatic lipogenesis and lipolysis from the adipose tissue. These metabolic alterations contribute to the hepatic fat accumulation. Consequently, stimulated oxidative stress and inflammation play a major role in hepatocellular damage. Therefore, antioxidant and anti-inflammatory agents may have a role in the prevention of this disease. Carotenoids are potent antioxidant and anti-inflammatory micronutrients, which have been investigated in the prevention and treatment of NAFLD. The main sources of the carotenoids are fruits and vegetables. In this article we review the potential role and possible molecular mechanism of carotenoids in NAFLD. PMID:26151056

  1. Transcriptional networks implicated in human nonalcoholic fatty liver disease.

    PubMed

    Ye, Hua; Liu, Wei

    2015-10-01

    The transcriptome of nonalcoholic fatty liver disease (NAFLD) was investigated in several studies. However, the implications of transcriptional networks in progressive NAFLD are not clear and mechanisms inducing transition from nonalcoholic simple fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) are still elusive. The aims of this study were to (1) construct networks for progressive NAFLD, (2) identify hub genes and functional modules in these networks and (3) infer potential linkages among hub genes, transcription factors and microRNAs (miRNA) for NAFLD progression. A systems biology approach by combining differential expression analysis and weighted gene co-expression network analysis (WGCNA) was utilized to dissect transcriptional profiles in 19 normal, 10 NAFL and 16 NASH patients. Based on this framework, 3 modules related to chromosome organization, proteasomal ubiquitin-dependent protein degradation and immune response were identified in NASH network. Furthermore, 9 modules of co-expressed genes associated with NAFL/NASH transition were found. Further characterization of these modules defined 13 highly connected hub genes in NAFLD progression network. Interestingly, 11 significantly changed miRNAs were predicted to target 10 of the 13 hub genes. Characterization of modules and hub genes that may be regulated by miRNAs could facilitate the identification of candidate genes and pathways responsible for NAFL/NASH transition and lead to a better understanding of NAFLD pathogenesis. The identified modules and hub genes may point to potential targets for therapeutic interventions. PMID:25851235

  2. Dietary approach in the treatment of nonalcoholic fatty liver disease

    PubMed Central

    Ferolla, Silvia Marinho; Silva, Luciana Costa; Ferrari, Maria de Lourdes Abreu; da Cunha, Aloísio Sales; Martins, Flaviano dos Santos; Couto, Cláudia Alves; Ferrari, Teresa Cristina Abreu

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) has been identified as one of the most prevalent chronic liver disease in adults and children populations. NAFLD is usually associated with the metabolic syndrome (MS), which is chiefly related to insulin resistance and its consequences. Insulin resistance has a crucial role in the pathogenesis of hepatic steatosis and potentially nonalcoholic steatohepatitis (NASH). Because of the contemporary epidemics of MS and obesity, the burden of NAFLD is also expected to rise. Unhealthy diets, such as the so-called western diet, are enriched in fructose, trans-fatty acids and saturated fat and seem to be associated with the development of NAFLD. In human studies, certain dietary sugars, particularly fructose, are used as a substrate for lipogenesis leading to hepatic fatty infiltration, inflammation, and possibly fibrosis. Other investigations have shown that fat consumption especially cholesterol and trans/saturated fatty acids are also steatogenic and seem to increase visceral adiposity. The identification of specific dietary components that favor the development of NASH could be important for the management of this disorder. This review focuses on the effects of different dietary approaches to prevent and treat NAFLD emphasizing the macronutrients and energy composition. PMID:26523205

  3. Dietary approach in the treatment of nonalcoholic fatty liver disease.

    PubMed

    Ferolla, Silvia Marinho; Silva, Luciana Costa; Ferrari, Maria de Lourdes Abreu; da Cunha, Aloísio Sales; Martins, Flaviano Dos Santos; Couto, Cláudia Alves; Ferrari, Teresa Cristina Abreu

    2015-10-28

    Nonalcoholic fatty liver disease (NAFLD) has been identified as one of the most prevalent chronic liver disease in adults and children populations. NAFLD is usually associated with the metabolic syndrome (MS), which is chiefly related to insulin resistance and its consequences. Insulin resistance has a crucial role in the pathogenesis of hepatic steatosis and potentially nonalcoholic steatohepatitis (NASH). Because of the contemporary epidemics of MS and obesity, the burden of NAFLD is also expected to rise. Unhealthy diets, such as the so-called western diet, are enriched in fructose, trans-fatty acids and saturated fat and seem to be associated with the development of NAFLD. In human studies, certain dietary sugars, particularly fructose, are used as a substrate for lipogenesis leading to hepatic fatty infiltration, inflammation, and possibly fibrosis. Other investigations have shown that fat consumption especially cholesterol and trans/saturated fatty acids are also steatogenic and seem to increase visceral adiposity. The identification of specific dietary components that favor the development of NASH could be important for the management of this disorder. This review focuses on the effects of different dietary approaches to prevent and treat NAFLD emphasizing the macronutrients and energy composition. PMID:26523205

  4. Translational approaches: From fatty liver to non-alcoholic steatohepatitis

    PubMed Central

    Rosso, Natalia; Chavez-Tapia, Norberto C; Tiribelli, Claudio; Bellentani, Stefano

    2014-01-01

    Over the past few decades, non-alcoholic fatty liver disease (NAFLD) has become one, if not the most common, cause of chronic liver disease affecting both adults and children. The increasing number of cases at an early age is the most worrying aspect of this pathology, since it provides more time for its evolution. The spectrum of this disease ranges from liver steatosis to steatohepatitis, fibrosis and in some cases, hepatocellular carcinoma. NAFLD may not always be considered a benign disease and hepatologists must be cautious in the presence of fatty liver. This should prompt the use of the available experimental models to understand better the pathogenesis and to develop a rational treatment of a disease that is dangerously increasing. In spite of the growing efforts, the pathogenesis of NAFLD is still poorly understood. In the present article we review the most relevant hypotheses and evidence that account for the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis. The available in vitro and in vivo experimental models of NASH are discussed and revised in terms of their validity in translational studies. These studies must be aimed at the discovery of the still unknown triggers or mediators that induce the progression of hepatic inflammation, apoptosis and fibrosis. PMID:25083077

  5. 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. PMID:27017224

  6. Update on Berberine in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Liu, Yang; Zhang, Li; Song, Haiyan

    2013-01-01

    Berberine (BBR), an active ingredient from nature plants, has demonstrated multiple biological activities and pharmacological effects in a series of metabolic diseases including nonalcoholic fatty liver disease (NAFLD). The recent literature points out that BBR may be a potential drug for NAFLD in both experimental models and clinical trials. This review highlights important discoveries of BBR in this increasing disease and addresses the relevant targets of BBR on NAFLD which links to insulin pathway, adenosine monophosphate-activated protein kinase (AMPK) signaling, gut environment, hepatic lipid transportation, among others. Developing nuanced understanding of the mechanisms will help to optimize more targeted and effective clinical application of BBR for NAFLD. PMID:23843872

  7. 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

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

    PubMed

    Agrawal, Swastik; Duseja, Ajay K

    2012-06-01

    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

  9. Gender and racial differences in nonalcoholic fatty liver disease

    PubMed Central

    Pan, Jen-Jung; Fallon, Michael B

    2014-01-01

    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. PMID:24868321

  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. Current concepts and management approaches in nonalcoholic fatty liver disease.

    PubMed

    Attar, Bashar M; Van Thiel, David H

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction worldwide. NAFLD may progress to nonalcoholic steatohepatitis (NASH) and in turn cirrhosis. Importantly, hepatic cancer can occur in NASH in the absence of cirrhosis. The cardinal histologic feature of NAFLD is the presence of an excessive accumulation of triacylglycerols and diacylglycerols in hepatocytes. The presence of obesity and insulin resistance lead to an increased hepatic-free fatty acid (FFA) flux creating an environment appropriate for the development of NAFLD. The generation of toxic reactive oxygen species with the production of hepatic injury and inflammation as a consequence of FFA oxidation will ultimately lead to the initiation and progression of fibrosis. Lifestyle modifications specifically weight loss, physical exercise, and cognitive behavior therapy have been recommended as treatments for NASH. Dietary fructose is an independent risk factor for the development of NAFLD. Pioglitazone can be used to treat biopsy-proven NASH; however, its safety risks should be considered carefully. Greater consumption for coffee, independent of its caffeine component, has been associated with a significant reduced risk of advanced fibrosis in NASH. Additional data are needed before recommending bariatric surgery as an established option for the specific treatment of NASH. PMID:23576902

  12. Soft drinks consumption and nonalcoholic fatty liver disease

    PubMed Central

    Nseir, William; Nassar, Fares; Assy, Nimer

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a common clinical condition which is associated with metabolic syndrome in 70% of cases. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress combine to increase free fatty acid delivery to the liver, and increased hepatic triglyceride accumulation contributes to fatty liver. Regular soft drinks have high fructose corn syrup which contains basic sugar building blocks, fructose 55% and glucose 45%. Soft drinks are the leading source of added sugar worldwide, and have been linked to obesity, diabetes, and metabolic syndrome. The consumption of soft drinks can increase the prevalence of NAFLD independently of metabolic syndrome. During regular soft drinks consumption, fat accumulates in the liver by the primary effect of fructose which increases lipogenesis, and in the case of diet soft drinks, by the additional contribution of aspartame sweetener and caramel colorant which are rich in advanced glycation end products that potentially increase insulin resistance and inflammation. This review emphasizes some hard facts about soft drinks, reviews fructose metabolism, and explains how fructose contributes to the development of obesity, diabetes, metabolic syndrome, and NAFLD. PMID:20518077

  13. Vitamin E and Non-alcoholic Fatty Liver Disease

    PubMed Central

    Pacana, Tommy; Sanyal, Arun J.

    2016-01-01

    Purpose of review Oxidative stress plays a central role in the transition from simple steatosis to nonalcoholic steatohepatitis (NASH). An effective therapeutic strategy is to target reduction in oxidative stress in NASH patients. The aim of this review is to discuss the role of oxidative stress in NASH and biological activities of vitamin E and present available evidence on the therapeutic efficacy of vitamin E in NASH. Recent findings In Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, vitamin E therapy demonstrated a significant improvement in steatosis, inflammation, ballooning, and resolution of steatohepatitis in adult patients with aggressive NASH who do not have diabetes or cirrhosis. Although vitamin E showed a significant resolution of NASH in children, a sustained reduction of alanine aminotransferase was not attained in The Treatment of NAFLD in Children(TONIC) trial. Summary The prevalence of nonalcoholic fatty liver disease (NAFLD) is likely to increase over time due to the epidemics of obesity and diabetes. Presently, there is no definitive treatment for NAFLD. Based on available evidence, vitamin E (RRR-α-tocopherol) is only recommended in NASH adults without diabetes or cirrhosis and with aggressive histology. Validation is needed in children before its use can be recommended. Longer follow-up of randomized controlled trials are needed to assess long-term vitamin E safety. PMID:23075940

  14. Treatment of non-alcoholic fatty liver disease

    PubMed Central

    Tolman, Keith G; Dalpiaz, Anthony S

    2007-01-01

    Non-alcoholic fatty liver disease, defined as the presence of macrovascular steatosis in the presence of less than 20 gm of alcohol ingestion per day, is the most common liver disease in the USA. It is most commonly associated with insulin resistance/type 2 diabetes mellitus and obesity. It is manifested by steatosis, steatohepatitis, cirrhosis, and, rarely, hepatocellular carcinoma. Hepatic steatosis results from an imbalance between the uptake of fat and its oxidation and export. Insulin resistance, predisposing to lipolysis of peripheral fat with mobilization to and uptake of fatty acids by the liver, is the most consistent underlying pathogenic factor. It is not known why some patients progress to cirrhosis; however, the induction of CYP 2E1 with generation of reactive oxygen species appears to be important. Treatment is directed at weight loss plus pharmacologic therapy targeted toward insulin resistance or dyslipidemia. Bariatric surgery has proved effective. While no pharmacologic therapy has been approved, emerging data on thiazolidinediones have demonstrated improvement in both liver enzymes and histology. There are fewer, but promising data, with statins which have been shown to be hepatoprotective in other liver diseases. The initial enthusiasm for ursodeoxycholic acid has not been supported by histologic studies. PMID:18516264

  15. Advances in the treatment of nonalcoholic fatty liver disease

    PubMed Central

    Mehta, Sanjeev R.

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world, and its prevalence is predicted to rise in the future in parallel with rising levels of obesity and type 2 diabetes mellitus. It is commonly associated with insulin resistance. Many patients have coexisting obesity, hypertension, dyslipidaemia or hyperglycaemia, and are at increased risk of developing cardiovascular disease. Although patients with simple steatosis have a good prognosis, a significant percentage will develop nonalcoholic steatohepatitis which may progress to cirrhosis, end-stage liver failure and hepatocellular carcinoma. Despite promising results from several pilot studies and small to medium randomized controlled trials, there is currently no pharmacological agent that is licensed for the treatment of NAFLD. At present the mainstay of treatment for all patients is lifestyle modification using a combination of diet, exercise and behavioural therapy. With recent advances in the understanding of the pathogenesis of NAFLD, the goal of treatment has shifted from simply trying to clear fat from the liver and prevent progressive liver damage to addressing and treating the metabolic risk factors for the condition. To reduce liver-related and cardiovascular morbidity and mortality, all patients with NAFLD should be invited to enrol in adequately powered, randomized controlled studies testing novel therapies, many of which are targeted at reducing insulin resistance or preventing progressive liver disease. Coexisting obesity, hypertension, dyslipidaemia or hyperglycaemia should be treated aggressively. Orlistat, bariatric surgery, angiotensin receptor blockers, statins, fibrates, metformin and thiazolidinediones should all be considered, but treatments should be carefully tailored to meet the specific requirements of each patient. The efficacy and safety of any new treatment, as well as its cost-effectiveness, will need to be carefully evaluated

  16. Bile acid receptors and nonalcoholic fatty liver disease

    PubMed Central

    Yuan, Liyun; Bambha, Kiran

    2015-01-01

    With the high prevalence of obesity, diabetes, and other features of the metabolic syndrome in United States, nonalcoholic fatty liver disease (NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis (NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor (TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH. PMID:26668692

  17. 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

  18. Nutrition and Physical Activity in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Oliveira, Claudia P.; de Lima Sanches, Priscila; de Abreu-Silva, Erlon Oliveira; Marcadenti, Aline

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and it is associated with other medical conditions such as diabetes mellitus, metabolic syndrome, and obesity. The mechanisms of the underlying disease development and progression are not completely established and there is no consensus concerning the pharmacological treatment. In the gold standard treatment for NAFLD weight loss, dietary therapy, and physical activity are included. However, little scientific evidence is available on diet and/or physical activity and NAFLD specifically. Many dietary approaches such as Mediterranean and DASH diet are used for treatment of other cardiometabolic risk factors such as insulin resistance and type-2 diabetes mellitus (T2DM), but on the basis of its components their role in NAFLD has been discussed. In this review, the implications of current dietary and exercise approaches, including Brazilian and other guidelines, are discussed, with a focus on determining the optimal nonpharmacological treatment to prescribe for NAFLD. PMID:26770987

  19. Genetics of nonalcoholic Fatty liver disease: an overview.

    PubMed

    Puppala, Jharna; Siddapuram, Siva Prasad; Akka, Jyothy; Munshi, Anjana

    2013-01-20

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world today. Its incidence in adults and children is rising rapidly due to the ongoing epidemics of obesity and type 2 diabetes. Hence, it has become a global public health issue. Environmental factors have been found to play a major role in the etiology of NAFLD, especially for genetically susceptible populations. Among these, one of the most important factors is junk food, especially the typical "Western-style" diet rich in simple carbohydrates, saturated fat, and highly processed food materials. Genetic predisposition to NAFLD does occur; however, a precise definition of genetic factors responsible for NAFLD is still lacking. Specific variants of different genes have been shown to present a risk for NAFLD. Genetic studies might be helpful in the management of the disease by developing novel treatment strategies based on individual's genotype. PMID:23357341

  20. Nutrition and Physical Activity in Nonalcoholic Fatty Liver Disease.

    PubMed

    Oliveira, Claudia P; de Lima Sanches, Priscila; de Abreu-Silva, Erlon Oliveira; Marcadenti, Aline

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and it is associated with other medical conditions such as diabetes mellitus, metabolic syndrome, and obesity. The mechanisms of the underlying disease development and progression are not completely established and there is no consensus concerning the pharmacological treatment. In the gold standard treatment for NAFLD weight loss, dietary therapy, and physical activity are included. However, little scientific evidence is available on diet and/or physical activity and NAFLD specifically. Many dietary approaches such as Mediterranean and DASH diet are used for treatment of other cardiometabolic risk factors such as insulin resistance and type-2 diabetes mellitus (T2DM), but on the basis of its components their role in NAFLD has been discussed. In this review, the implications of current dietary and exercise approaches, including Brazilian and other guidelines, are discussed, with a focus on determining the optimal nonpharmacological treatment to prescribe for NAFLD. PMID:26770987

  1. 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

  2. Free Fatty Acids Differentially Downregulate Chemokines in Liver Sinusoidal Endothelial Cells: Insights into Non-Alcoholic Fatty Liver Disease

    PubMed Central

    McMahan, Rachel H.; Porsche, Cara E.; Edwards, Michael G.; Rosen, Hugo R.

    2016-01-01

    Non-alcoholic fatty liver disease is a prevalent problem throughout the western world. Liver sinusoidal endothelial cells (LSEC) have been shown to play important roles in liver injury and repair, but their role in the underlying pathogenetic mechanisms of non-alcoholic fatty liver disease remains undefined. Here, we evaluated the effects of steatosis on LSEC gene expression in a murine model of non-alcoholic fatty liver disease and an immortalized LSEC line. Using microarray we identified distinct gene expression profiles following exposure to free fatty acids. Gene pathway analysis showed a number of differentially expressed genes including those involved in lipid metabolism and signaling and inflammation. Interestingly, in contrast to hepatocytes, fatty acids led to decreased expression of pro-inflammatory chemokines including CCL2 (MCP-1), CXCL10 and CXCL16 in both primary and LSEC cell lines. Chemokine downregulation translated into a significant inhibition of monocyte migration and LSECs isolated from steatotic livers demonstrated a similar shift towards an anti-inflammatory phenotype. Overall, these pathways may represent a compensatory mechanism to reverse the liver damage associated with non-alcoholic fatty liver disease. PMID:27454769

  3. Dietary habits and behaviors associated with nonalcoholic fatty liver disease

    PubMed Central

    Yasutake, Kenichiro; Kohjima, Motoyuki; Kotoh, Kazuhiro; Nakashima, Manabu; Nakamuta, Makoto; Enjoji, Munechika

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of health problems in Western (industrialized) countries. Moreover, the incidence of infantile NAFLD is increasing, with some of these patients progressing to nonalcoholic steatohepatitis. These trends depend on dietary habits and life-style. In particular, overeating and its associated obesity affect the development of NAFLD. Nutritional problems in patients with NAFLD include excess intake of energy, carbohydrates, and lipids, and shortages of polyunsaturated fatty acids, vitamins, and minerals. Although nutritional therapeutic approaches are required for prophylaxis and treatment of NAFLD, continuous nutrition therapy is difficult for many patients because of their dietary habits and lifestyle, and because the motivation for treatment differs among patients. Thus, it is necessary to assess the nutritional background and to identify nutritional problems in each patient with NAFLD. When assessing dietary habits, it is important to individually evaluate those that are consumed excessively or insufficiently, as well as inappropriate eating behaviors. Successful nutrition therapy requires patient education, based on assessments of individual nutrients, and continuing the treatment. In this article, we update knowledge about NAFLD, review the important aspects of nutritional assessment targeting treatment success, and present some concrete nutritional care plans which can be applied generally. PMID:24587653

  4. 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

  5. Non-alcoholic fatty liver disease, diet and gut microbiota.

    PubMed

    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

  6. 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

  7. 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

  8. Pediatric nonalcoholic fatty liver disease: A clinical and laboratory challenge

    PubMed Central

    Pacifico, Lucia; Poggiogalle, Eleonora; Cantisani, Vito; Menichini, Guendalina; Ricci, Paolo; Ferraro, Flavia; Chiesa, Claudio

    2010-01-01

    The true prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is unknown. Challenges in determining the population prevalence of NAFLD include the type of test (and the reference intervals used to define normal and abnormal), the type of population (general population, hospital series), the demographic characteristics of the population sampled, and the nature of the study design. The natural history of pediatric NAFLD remains uncertain. The issue of when to perform a liver biopsy in children with suspected NAFLD remains controversial. Children with NAFLD but normal alanine aminotransferase are rarely investigated. However, evidence of alterations in glucose metabolism parameters should prompt a better understanding of the natural history of pediatric NAFLD not only in terms of the progression of liver disease but also regarding its potential relationship with other health outcomes such as type 2 diabetes mellitus and cardiovascular disease. This evidence could make liver biopsy mandatory in the majority of cases at risk of progressive and severe hepatic and extrahepatic disease. This conclusion, however, raises the question of the feasibility of liver biopsy assessment in an extremely large at risk population, and of the cost/effectiveness of this policy. There is a considerable, continuous interest in reliable, noninvasive alternatives that will allow the prognosis of pediatric NAFLD to be followed in large community or population-based studies. PMID:21161009

  9. 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

  10. Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

    PubMed Central

    Takahashi, Yoshihisa; Sugimoto, Keiichiro; Inui, Hiroshi; Fukusato, Toshio

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers (thiazolidinediones) and antioxidants (vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH. PMID:25852263

  11. Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in the United States and the Rest of the World.

    PubMed

    Sayiner, Mehmet; Koenig, Aaron; Henry, Linda; Younossi, Zobair M

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease with increasing prevalence, which can progress to cirrhosis and liver failure. Because of the obesity epidemic and increasing prevalence of metabolic syndrome, NAFLD and its progressive form, nonalcoholic steatohepatitis, are seen more commonly in different parts of the world. This article reviews the worldwide epidemiology of NAFLD and nonalcoholic steatohepatitis. The PubMed database was used to identify studies related to epidemiology of NAFLD in the adult population. It is estimated that the epidemic of obesity will continue to fuel the burden of NAFLD and its long-term complications. PMID:27063264

  12. Nonalcoholic fatty liver disease and aging: Epidemiology to management

    PubMed Central

    Bertolotti, Marco; Lonardo, Amedeo; Mussi, Chiara; Baldelli, Enrica; Pellegrini, Elisa; Ballestri, Stefano; Romagnoli, Dante; Loria, Paola

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is common in the elderly, in whom it carries a more substantial burden of hepatic (nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma) and extra-hepatic manifestations and complications (cardiovascular disease, extrahepatic neoplasms) than in younger age groups. Therefore, proper identification and management of this condition is a major task for clinical geriatricians and geriatric hepatologists. In this paper, the epidemiology and pathophysiology of this condition are reviewed, and a full discussion of the link between NAFLD and the aspects that are peculiar to elderly individuals is provided; these aspects include frailty, multimorbidity, polypharmacy and dementia. The proper treatment strategy will have to consider the peculiarities of geriatric patients, so a multidisciplinary approach is mandatory. Non-pharmacological treatment (diet and physical exercise) has to be tailored individually considering the physical limitations of most elderly people and the need for an adequate caloric supply. Similarly, the choice of drug treatment must carefully balance the benefits and risks in terms of adverse events and pharmacological interactions in the common context of both multiple health conditions and polypharmacy. In conclusion, further epidemiological and pathophysiological insight is warranted. More accurate understanding of the molecular mechanisms of geriatric NAFLD will help in identifying the most appropriate diagnostic and therapeutic approach for individual elderly patients. PMID:25339806

  13. Dietary Anthocyanins as Nutritional Therapy for Nonalcoholic Fatty Liver Disease

    PubMed Central

    Mazzocchi, Alessandra; Porrini, Marisa; Fargion, Silvia; Agostoni, Carlo

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD), defined by excessive lipid accumulation in the liver, is the hepatic manifestation of insulin resistance and the metabolic syndrome. Due to the epidemics of obesity, NAFLD is rapidly becoming the leading cause of altered liver enzymes in Western countries. NAFLD encompasses a wide spectrum of liver disease ranging from simple uncomplicated steatosis, to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Diet may affect the development of NAFLD either by increasing risk or by providing protective factors. Therefore, it is important to investigate the role of foods and/or food bioactives on the metabolic processes involved in steatohepatitis for preventive strategies. It has been reported that anthocyanins (ACNs) decrease hepatic lipid accumulation and may counteract oxidative stress and hepatic inflammation, but their impact on NAFLD has yet to be fully determined. ACNs are water-soluble bioactive compounds of the polyphenol class present in many vegetable products. Here, we summarize the evidence evaluating the mechanisms of action of ACNs on hepatic lipid metabolism in different experimental setting: in vitro, in vivo, and in human trials. Finally, a working model depicting the possible mechanisms underpinning the beneficial effects of ACNs in NAFLD is proposed, based on the available literature. PMID:24282628

  14. 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

  15. Nonalcoholic fatty liver disease and obstructive sleep apnea.

    PubMed

    Aron-Wisnewsky, Judith; Clement, Karine; Pépin, Jean-Louis

    2016-08-01

    Obstructive sleep apnea (OSA) and more importantly its hallmark, chronic intermittent hypoxia (CIH), are established factors in the pathogenesis and exacerbation of nonalcoholic fatty liver disease (NAFLD). This has been clearly demonstrated in rodent models exposed to intermittent hypoxia, and strong evidence now also exists in both paediatric and adult human populations. OSA and CIH induce insulin-resistance and dyslipidemia which are involved in NAFLD physiopathogenesis. CIH increases the expression of the hypoxia inducible transcription factor HIF1α and that of downstream genes involved in lipogenesis, thereby increasing β-oxidation and consequently exacerbating liver oxidative stress. OSA also disrupts the gut liver axis, increasing intestinal permeability and with a possible role of gut microbiota in the link between OSA and NAFLD. OSA patients should be screened for NAFLD and vice versa those with NAFLD for OSA. To date there is no evidence that treating OSA with continuous positive airway pressure (CPAP) will improve NAFLD but it might at least stabilize and slow its progression. Nevertheless, these multimorbid patients should be efficiently treated for all their metabolic co-morbidities and be encouraged to follow weight stabilization or weight loss programs and physical activity life style interventions. PMID:27324067

  16. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver.

    PubMed

    Aigner, Elmar; Weiss, Günter; Datz, Christian

    2015-02-27

    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. Hepatocarcinogenesis in non-alcoholic fatty liver disease in Japan.

    PubMed

    Tokushige, Katsutoshi; Hashimoto, Etsuko; Kodama, Kazuhiko

    2013-12-01

    In Japan, there has been a gradual increase in cases of non-viral chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), occurring with hepatocellular carcinoma (HCC). First, a national survey investigating the etiology of HCC in Japan was performed. Among HCCs based on non-viral disease, alcoholic liver disease with HCC accounted for 7.2% of all HCCs, followed by chronic liver disease of unknown etiology with HCC (5.1%) and NAFLD with HCC (2.0%). The clinical characteristics of these three HCC groups were clearly different. In our second analysis, the HCC development rates among liver cirrhosis with NAFLD, alcoholic cirrhosis, and cirrhosis with hepatitis C virus (HCV) were compared. HCC development rates were 11.3%/5 years in NAFLD cirrhosis, 30.5%/5 years in HCV cirrhosis, and 12.5%/5 years in alcoholic cirrhosis, suggesting that the hepatocarcinogenesis in NAFLD and alcoholic liver disease were similar but were lower than that in HCV. Using Cox hazards analysis, older age, higher serum γ-glutamyl transpeptidase level, and higher Child-Pugh score as risk factors of HCC were identified. Finally, clinical data of NAFLD-HCC with the data for HCC with HCV (HCV-HCC) were compared. The percentage of NAFLD-HCC patients with des-gamma-carboxy prothrombin-positive was higher than that with α-fetoprotein-positive. The 5-year survival and recurrence rates for NAFLD-HCC were almost similar to those for HCV-HCC. In Asian countries, the prevalence of NAFLD is increasing. Therefore, elucidating the pathogenesis and clinical features of HCC in patients with NAFLD is indeed an urgent problem. PMID:24251711

  18. 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

  19. 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

  20. Autophagy: a new target for nonalcoholic fatty liver disease therapy.

    PubMed

    Mao, Yuqing; Yu, Fujun; Wang, Jianbo; Guo, Chuanyong; Fan, Xiaoming

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) has gained importance in recent decades due to drastic changes in diet, especially in Western countries. NAFLD occurs as a spectrum from simple hepatic steatosis, steatohepatitis to cirrhosis, and even hepatocellular carcinoma. Although the molecular mechanisms underlying the development of NAFLD have been intensively investigated, many issues remain to be resolved. Autophagy is a cell survival mechanism for disposing of excess or defective organelles, and has become a hot spot for research. Recent studies have revealed that autophagy is linked to the development of NAFLD and regulation of autophagy has therapeutic potential. Autophagy reduces intracellular lipid droplets by enclosing them and fusing with lysosomes for degradation. Furthermore, autophagy is involved in attenuating inflammation and liver injury. However, autophagy is regarded as a double-edged sword, as it may also affect adipogenesis and adipocyte differentiation. Moreover, it is unclear as to whether autophagy protects the body from injury or causes diseases and even death, and the association between autophagy and NAFLD remains controversial. This review is intended to discuss, comment, and outline the progress made in this field and establish the possible molecular mechanism involved. PMID:27099536

  1. Function of Autophagy in Nonalcoholic Fatty Liver Disease.

    PubMed

    Czaja, Mark J

    2016-05-01

    Autophagy is a lysosomal degradative pathway that functions to promote cell survival by supplying energy in times of stress or by removing damaged organelles and proteins after injury. The involvement of autophagy in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) was first suggested by the finding that this pathway mediates the breakdown of intracellular lipids in hepatocytes and therefore may regulate the development of hepatic steatosis. Subsequent studies have demonstrated additional critical functions for autophagy in hepatocytes and other hepatic cell types such as macrophages and stellate cells that regulate insulin sensitivity, hepatocellular injury, innate immunity, fibrosis, and carcinogenesis. These findings suggest a number of possible mechanistic roles for autophagy in the development of NAFLD and progression to NASH and its complications. The functions of autophagy in the liver, together with findings of decreased hepatic autophagy in association with conditions that predispose to NAFLD such as obesity and aging, suggest that autophagy may be a novel therapeutic target in this disease. PMID:26725058

  2. Metabolic aspects of adult patients with nonalcoholic fatty liver disease.

    PubMed

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-08-21

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD. PMID:27610012

  3. Metabolic aspects of adult patients with nonalcoholic fatty liver disease

    PubMed Central

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD. PMID:27610012

  4. Cardiovascular Disease and Myocardial Abnormalities in Nonalcoholic Fatty Liver Disease.

    PubMed

    Mantovani, Alessandro; Ballestri, Stefano; Lonardo, Amedeo; Targher, Giovanni

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in many developed countries, affecting an estimated 30 % of the adult population. In this updated clinical review, we summarize the current knowledge regarding the strong association between NAFLD and the risk of coronary heart disease (CHD) and other functional, structural, and arrhythmic cardiac complications (e.g., left ventricular dysfunction, heart valve diseases and atrial fibrillation). We also briefly discuss the putative biological mechanisms linking NAFLD with these important extra-hepatic complications. To date, a large body of evidence has suggested that NAFLD is not simply a marker of CHD and other functional, structural, and arrhythmic cardiac complications, but also may play a part in the development and progression of these cardiac complications. The clinical implication of these findings is that patients with NAFLD may benefit from more intensive surveillance and early treatment interventions aimed at decreasing the risk of CHD and other cardiac and arrhythmic complications. PMID:26809873

  5. Autophagy: a new target for nonalcoholic fatty liver disease therapy

    PubMed Central

    Mao, Yuqing; Yu, Fujun; Wang, Jianbo; Guo, Chuanyong; Fan, Xiaoming

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) has gained importance in recent decades due to drastic changes in diet, especially in Western countries. NAFLD occurs as a spectrum from simple hepatic steatosis, steatohepatitis to cirrhosis, and even hepatocellular carcinoma. Although the molecular mechanisms underlying the development of NAFLD have been intensively investigated, many issues remain to be resolved. Autophagy is a cell survival mechanism for disposing of excess or defective organelles, and has become a hot spot for research. Recent studies have revealed that autophagy is linked to the development of NAFLD and regulation of autophagy has therapeutic potential. Autophagy reduces intracellular lipid droplets by enclosing them and fusing with lysosomes for degradation. Furthermore, autophagy is involved in attenuating inflammation and liver injury. However, autophagy is regarded as a double-edged sword, as it may also affect adipogenesis and adipocyte differentiation. Moreover, it is unclear as to whether autophagy protects the body from injury or causes diseases and even death, and the association between autophagy and NAFLD remains controversial. This review is intended to discuss, comment, and outline the progress made in this field and establish the possible molecular mechanism involved. PMID:27099536

  6. Chemoprevention of nonalcoholic fatty liver disease by dietary natural compounds.

    PubMed

    Pan, Min-Hsiung; Lai, Ching-Shu; Tsai, Mei-Ling; Ho, Chi-Tang

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver disease that is not from excess alcohol consumption, but is often associated with obesity, type 2 diabetes, and metabolic syndrome. NAFLD pathogenesis is complicated and involves oxidative stress, lipotoxicity, mitochondrial damage, insulin resistance, inflammation, and excessive dietary fat intake, which increase hepatic lipid influx and de novo lipogenesis and impair insulin signaling, thus promoting hepatic triglyceride accumulation and ultimately NAFLD. Overproduction of proinflammatory adipokines from adipose tissue also affects hepatic metabolic function. Current NAFLD therapies are limited; thus, much attention has been focused on identification of potential dietary substances from fruits, vegetables, and edible plants to provide a new strategy for NAFLD treatment. Dietary natural compounds, such as carotenoids, omega-3-PUFAs, flavonoids, isothiocyanates, terpenoids, curcumin, and resveratrol, act through a variety of mechanisms to prevent and improve NAFLD. Here, we summarize and briefly discuss the currently known targets and signaling pathways as well as the role of dietary natural compounds that interfere with NAFLD pathogenesis. PMID:24302567

  7. Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease.

    PubMed

    Haas, Joel T; Francque, Sven; Staels, Bart

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders characterized by abnormal hepatic fat accumulation, inflammation, and hepatocyte dysfunction. Importantly, it is also closely linked to obesity and the metabolic syndrome. NAFLD predisposes susceptible individuals to cirrhosis, hepatocellular carcinoma, and cardiovascular disease. Although the precise signals remain poorly understood, NAFLD pathogenesis likely involves actions of the different hepatic cell types and multiple extrahepatic signals. The complexity of this disease has been a major impediment to the development of appropriate metrics of its progression and effective therapies. Recent clinical data place increasing importance on identifying fibrosis, as it is a strong indicator of hepatic disease-related mortality. Preclinical modeling of the fibrotic process remains challenging, particularly in the contexts of obesity and the metabolic syndrome. Future studies are needed to define the molecular pathways determining the natural progression of NAFLD, including key determinants of fibrosis and disease-related outcomes. This review covers the evolving concepts of NAFLD from both human and animal studies. We discuss recent clinical and diagnostic methods assessing NAFLD diagnosis, progression, and outcomes; compare the features of genetic and dietary animal models of NAFLD; and highlight pharmacological approaches for disease treatment. PMID:26667070

  8. Sex Difference in the Association between Serum Homocysteine Level and Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Won, Bo-Youn; Lee, Soo-Hyun; Yun, Sung-Hwan; Kim, Moon-Jong; Park, Kye-Seon; Kim, Young-Sang; Haam, Ji-Hee; Kim, Hyung-Yuk; Kim, Hye-Jung; Park, Ki-Hyun

    2016-01-01

    Background The relationship between serum homocysteine levels and non-alcoholic fatty liver disease is poorly understood. This study aims to investigate the sex-specific relationship between serum homocysteine level and non-alcoholic fatty liver disease in the Korean population. Methods This cross-sectional study included 150 men and 132 women who participated in medical examination programs in Korea from January 2014 to December 2014. Patients were screened for fatty liver by abdominal ultrasound and patient blood samples were collected to measure homocysteine levels. Patients that consumed more than 20 grams of alcohol per day were excluded from this study. Results The homocysteine level (11.56 vs. 8.05 nmol/L) and the proportion of non-alcoholic fatty liver disease (60.7% vs. 19.7%) were significantly higher in men than in women. In men, elevated serum homocysteine levels were associated with a greater prevalence of non-alcoholic fatty liver disease (quartile 1, 43.6%; quartile 4, 80.6%; P=0.01); however, in females, there was no significant association between serum homocysteine levels and the prevalence of non-alcoholic fatty liver disease. In the logistic regression model adjusted for age and potential confounding parameters, the odds ratio for men was significantly higher in the uppermost quartile (model 3, quartile 4: odds ratio, 6.78; 95% confidential interval, 1.67 to 27.56); however, serum homocysteine levels in women were not associated with non-alcoholic fatty liver disease in the crude model or in models adjusted for confounders. Conclusion Serum homocysteine levels were associated with the prevalence of non-alcoholic fatty liver disease in men. PMID:27468343

  9. Systematic review of genetic association studies involving histologically confirmed non-alcoholic fatty liver disease

    PubMed Central

    Wood, Kayleigh L; Miller, Michael H; Dillon, John F

    2015-01-01

    Non-alcoholic fatty liver disease has an increasing prevalence in Western countries, affecting up to 20% of the population. Objective The aim of this project was to systematically review and summarise the genetic association studies that investigate possible genetic influences that confer susceptibility to non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Design The MEDLINE and SCOPUS databases were searched to identify candidate gene studies on histologically diagnosed non-alcoholic fatty liver disease. Results A total of 85 articles have been summarised and categorised on the basis of the general pathway each candidate gene is involved in, including lipid metabolism, lipoprotein processing, cholesterol synthesis, glucose homoeostasis, inflammatory response, protection against oxidative stress and whole body metabolism. Conclusions The main findings demonstrate a small but consistent association of PNPLA3 with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Genetic association studies have investigated general disease susceptibility, histological characteristics, severity and progression. However, further study is required to better elucidate the genetic factors influencing fatty liver disease. PMID:26462272

  10. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

    PubMed Central

    Jiang, Changtao; Xie, Cen; Li, Fei; Zhang, Limin; Nichols, Robert G.; Krausz, Kristopher W.; Cai, Jingwei; Qi, Yunpeng; Fang, Zhong-Ze; Takahashi, Shogo; Tanaka, Naoki; Desai, Dhimant; Amin, Shantu G.; Albert, Istvan; Patterson, Andrew D.; Gonzalez, Frank J.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet–induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota–associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment. PMID:25500885

  11. Long-term fatty liver-induced insulin resistance in orotic acid-induced nonalcoholic fatty liver rats.

    PubMed

    Han, Xiuqing; Liu, Chunhua; Xue, Yong; Wang, Jingfeng; Xue, Changhu; Yanagita, Teruyoshi; Gao, Xiang; Wang, Yuming

    2016-04-01

    We investigated whether fatty liver preceded insulin resistance or vice versa using a long-term orotic acid (OA)-induced nonalcoholic fatty liver disease (NAFLD) model without the confounding effects of obesity and hyperlipidemia and explored the role of the liver in insulin resistance. Male Wistar rats were fed with or without OA supplementation for 30, 60, and 90 days. The NAFLD group showed increased liver lipid at 30, 60, and 90 days; glucose intolerance was noted at 60 and 90 days. Furthermore, partial liver proteins and gene expressions related to upstream signaling of insulin were decreased. However, the liver glycogen content was elevated, and gluconeogenesis genes expressions were obviously decreased at 90 days. The occurrence of fatty liver preceded insulin resistance in OA-induced NAFLD without the interference of obesity and hyperlipidemia, and hepatic insulin resistance may not play a conclusive role in insulin resistance in this model. PMID:26775542

  12. Comparative efficacy of interventions on nonalcoholic fatty liver disease (NAFLD)

    PubMed Central

    Sawangjit, Ratree; Chongmelaxme, Bunchai; Phisalprapa, Pochamana; Saokaew, Surasak; Thakkinstian, Ammarin; Kowdley, Kris V.; Chaiyakunapruk, Nathorn

    2016-01-01

    Abstract Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) has significantly increased over the last decades. Despite existence of several interventions, there remains unclear which interventions work the best. Methods: A systematic review and network meta-analysis of randomized trials comparing efficacy of all treatment options in NAFLD were performed to determine comparative efficacy and safety of interventions in the management of NAFLD. Several electronic databases were searched up to Nov 15, 2015. Outcomes include liver histological outcomes (i.e., fibrosis), all-cause mortality, cirrhosis, and safety. A network meta-analysis was applied to estimate pooled risk ratios (RR). Quality of evidence was assessed using GRADE criteria. Results: A total of 44 studies (n = 3802) were eligible. When compared with placebo, obeticholic acid (OCA) was the only intervention that significantly improved fibrosis with RR (95% CI) of 1.91 (1.15, 3.16), while pentoxyfylline (PTX) demonstrated improved fibrosis without statistical significance with RR (95% CI) of 2.27 (0.81, 6.36). Only thiazolidinedione (TZD) and vitamin E use resulted in significant increase in resolution of NASH, while OCA, TZD, and vitamin E significantly improved other outcomes including NAS, steatosis, ballooning, and inflammation outcomes. Quality of evidence varied from very low (i.e., metformin, PTX on mean change of ballooning grade) to high (OCA, TZD, vitamin E on improving histological outcomes). Limitations of this study were lack of relevant long-term outcomes (e.g., cirrhosis, death, safety), possible small study effect, and few head-to-head studies. Conclusions: Our study suggests potential efficacy of OCA, TZD, and vitamin E in improving histologic endpoints in NAFLD. These findings are however based on a small number of studies. Additional studies are awaited to strengthen this network meta-analysis. PMID:27512874

  13. Diet, weight loss, and liver health in nonalcoholic fatty liver disease: Pathophysiology, evidence, and practice.

    PubMed

    Marchesini, Giulio; Petta, Salvatore; Dalle Grave, Riccardo

    2016-06-01

    Fatty liver accumulation results from an imbalance between lipid deposition and removal, driven by the hepatic synthesis of triglycerides and de novo lipogenesis. The habitual diet plays a relevant role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), and both risky (e.g., fructose) and protective foods (Mediterranean diet) have been described, but the contribution of excess calories remains pivotal. Accordingly, weight loss is the most effective way to promote liver fat removal. Several controlled studies have confirmed that an intense approach to lifestyle changes, carried on along the lines of cognitive-behavior treatment, is able to attain the desired 7%-10% weight loss, associated with reduced liver fat, nonalcoholic steatohepatitis (NASH) remission, and also reduction of fibrosis. Even larger effects are reported after bariatric surgery-induced weight loss in NAFLD, where 80% of subjects achieve NASH resolution at 1-year follow-up. These results provide solid data to evaluate the safety and effectiveness of the pharmacological treatment of NASH. The battle against metabolic diseases, largely fueled by increased liver fat, needs a comprehensive approach to be successful in an obesiogenic environment. In this review, we will discuss the role of hepatic lipid metabolism, genetic background, diet, and physical activity on fatty liver. They are the basis for a lifestyle approach to NAFLD treatment. (Hepatology 2016;63:2032-2043). PMID:26663351

  14. Noninvasive diagnosis of nonalcoholic fatty liver disease: Are we there yet?

    PubMed

    Alkhouri, Naim; Feldstein, Ariel E

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) has rapidly become the most common form of chronic liver disease in the United States affecting approximately 80-100 million Americans. NAFLD includes a spectrum of diseases ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to fibrosis and eventually cirrhosis. Patients with NASH and significant fibrosis on liver biopsy have an increased risk for liver-related morbidity and mortality compared to those with NAFL. Due to the high prevalence of NAFLD and its progressive nature, there has been an urgent need to develop reliable noninvasive tests that can accurately predict the presence of advanced disease without the need for liver biopsy. These tests can be divided into those that predict the presence of NASH and those that predict the presence of fibrosis. In this review, we provide a concise overview of different noninvasive methods for staging the severity of NAFLD. PMID:26972222

  15. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  16. Medical nutrition therapy in non-alcoholic fatty liver disease – a review of literature

    PubMed Central

    Rusu, E; Enache, G; Jinga, M; Dragut, R; Nan, R; Popescu, H; Parpala, C; Homentcovschi, C; Nitescu, M; Stoian, M; Costache, A; Posea, M; Rusu, F; Jinga, V; Mischianu, D; Radulian, G

    2015-01-01

    Background and aim: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, with a prevalence of 20%-40% in Western populations. The purpose of this article is to review data related to lifestyle changes in patients with NAFLD. Method: We searched a public domain database (PubMed) with the following categories: disease (NAFLD, fatty liver, and non-alcoholic steatohepatitis [NASH]) and intervention (lifestyle intervention, diet, nutrition) with each possible combination through 25 September 2014, for relevant articles. Review of articles was restricted to those published in English. We selected the studies involving adult patients only. Conclusion: There is no consensus as to what diet or lifestyle approach is the best for NAFLD patients. However, patients with NAFLD may benefit from a moderate- to low-carbohydrate (40%–45% of total calories) diet, coupled with increased dietary MUFA and n-3 PUFAs, reduced SFAs. More CRT are needed to clarify the specific effects of different diets and dietary components on the health of NAFLD patients. Abbreviations: NAFL = Non-alcoholic fatty liver, NAFLD = non-alcoholic fatty liver disease, NASH = non-alcoholic steatohepatitis, HCC = hepatocarcinoma, BEE = basal energy expenditure, CRT = A small clinical randomized trial showed that short-term carbohydrate restriction is more efficacious in reducing intrahepatic triglyceride, IHT = intrahepatic triglyceride, VLCD = Very low calorie diets, AST = aspartate aminotransferases, SFAs = saturated fatty acids. PMID:26351523

  17. [Role of the endocrine system in the pathogenesis of non-alcoholic fatty liver disease].

    PubMed

    Hagymási, Krisztina; Reismann, Péter; Rácz, Károly; Tulassay, Zsolt

    2009-11-29

    The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future. PMID:19923096

  18. Resveratrol inhibits nonalcoholic fatty liver disease in rats

    PubMed Central

    Bujanda, Luis; Hijona, Elizabeth; Larzabal, Mikel; Beraza, Marta; Aldazabal, Pablo; García-Urkia, Nerea; Sarasqueta, Cristina; Cosme, Angel; Irastorza, Belen; González, Alberto; Arenas, Juan I

    2008-01-01

    Background The prevalence of nonalcoholic fatty liver disease (NAFLD) is high. NAFLD is linked to obesity, diabetes mellitus, and hypertriglyceridemia. Approximately 20% of patients with NAFLD will eventually develop cirrhosis. Our purpose was to investigate whether resveratrol decreased hepatic steatosis in an animal model of steatosis, and whether this therapeutic approach resulted in a decrease in tumor necrosis factor α (TNF-α) production, lipid peroxidation and oxidative stress. Methods Male Wistar CRL: Wi (Han) (225 g) rats were randomized into three groups. A control group (n = 12) was given free access to regular dry rat chow for 4 weeks. The steatosis (n = 12) and resveratrol (n = 12) groups were given free access to feed (a high carbohydrate-fat free modified diet) and water 4 days per week, and fasted for the remaining 3 days for 4 weeks. Rats in the resveratrol group were given resveratrol 10 mg daily by the oral route. All rats were killed at 4 weeks and assessed for fatty infiltration and bacterial translocation. Levels of TNF-α in serum, hepatic malondialdehyde (MDA), oxidative stress (superoxide dismutase, glutathione peroxidase, catalase and nitric oxide synthase) and biochemical parameters were measured. Results Fat deposition was decreased in the resveratrol group as compared to the steatosis group (Grade 1 vs Grade 3, P < 0.05). TNF-α and MDA levels were significantly increased in the steatosis group (TNF-α; 33.4 ± 5.2 vs 26.24 ± 3.47 pg/ml and MDA; 9.08 ± 0.8 vs 3.17 ± 1.45 μM respectively, P < 0.05). This was accompanied by increased superoxide dismutase, glutathione peroxidase and catalase and decreased nitric oxide synthase in the liver of resveratrol group significantly (P < 0.05 vs steatosis group). Bacterial translocation was not found in any of the groups. Glucose levels were decreased in the group of rats given resveratrol (P < 0.05). Conclusion Resveratrol decreased NAFLD severity in rats. This effect was mediated, at least

  19. The Correlation Between Serum Adipokines and Liver Cell Damage in Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Jamali, Raika; Hatami, Neda; Kosari, Farid

    2016-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic hepatitis, which can lead to cirrhosis and hepatocellular carcinoma. Objectives The aim of the study was to evaluate the correlation between serum adipocytokines and the histologic findings of the liver in patients with non-alcoholic fatty liver disease (NAFLD). Patients and Methods This case-control study was performed on those with persistent elevated liver enzymes and with evidence of fatty liver in ultrasonography. After exclusion of patients with other etiologies causing abnormal liver function tests, the resulting patients underwent liver biopsies. NAFLD was diagnosed based on liver histology according to the Brunt scoring system. Results Waist circumferences and levels of blood glucose (after fasting), insulin, triglycerides, alanine aminotransferases (ALT), and aspartate aminotransferases (AST) were higher in patients with NAFLD than in those in the control group. ALT, AST, and gamma glutamine transferase (GGT) levels were lower in patients with liver steatosis of a grade of less than 33% than those with higher degrees of steatosis. Serum low-density lipoprotein (LDL), cholesterol, and hepcidin levels were significantly higher in those with lobular inflammation of grade 0 - 1 than in those with inflammation of grade 2 - 3 (Brunt score). Meanwhile, AST was significantly lower in those with lobular inflammation of grade 1 than in those with grade 2-3. Hepcidin and resistin levels were significantly higher in patients with moderate to severe fibrosis than in those with mild fibrosis. Conclusions It seems that surrogate liver function tests and adipocytokine levels were correlated with the histologic findings of the liver. PMID:27313636

  20. Non-alcoholic fatty liver disease and diabetes.

    PubMed

    Hazlehurst, Jonathan M; Woods, Conor; Marjot, Thomas; Cobbold, Jeremy F; Tomlinson, Jeremy W

    2016-08-01

    Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) are common conditions that regularly co-exist and can act synergistically to drive adverse outcomes. The presence of both NAFLD and T2DM increases the likelihood of the development of complications of diabetes (including both macro- and micro- vascular complications) as well as augmenting the risk of more severe NAFLD, including cirrhosis, hepatocellular carcinoma and death. The mainstay of NAFLD management is currently to reduce modifiable metabolic risk. Achieving good glycaemic control and optimising weight loss are pivotal to restricting disease progression. Once cirrhosis has developed, it is necessary to screen for complications and minimise the risk of hepatic decompensation. Therapeutic disease modifying options for patients with NAFLD are currently limited. When diabetes and NAFLD co-exist, there are published data that can help inform the clinician as to the most appropriate oral hypoglycaemic agent or injectable therapy that may improve NAFLD, however most of these data are drawn from observations in retrospective series and there is a paucity of well-designed randomised double blind placebo controlled studies with gold-standard end-points. Furthermore, given the heterogeneity of inclusion criteria and primary outcomes, as well as duration of follow-up, it is difficult to draw robust conclusions that are applicable across the entire spectrum of NAFLD and diabetes. In this review, we have summarised and critically evaluated the available data, with the aim of helping to inform the reader as to the most pertinent issues when managing patients with co-existent NAFLD and T2DM. PMID:26856933

  1. Association between Puberty and Features of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Suzuki, Ayako; Abdelmalek, Manal F.; Schwimmer, Jeffrey B.; Lavine, Joel E.; Scheimann, Ann; Unalp-Arida, Aynur; Yates, Katherine; Sanyal, Arun; Guy, Cynthia D; Diehl, Anna Mae

    2012-01-01

    Background & Aims Physiologic changes that occur during puberty may affect pathologic features of nonalcoholic fatty liver disease (NAFLD). We investigated associations between pubertal development and clinical and histopathologic features of NAFLD. Methods We studied 186 children (age<18 years, 143 boys) with biopsy-proven NAFLD. The population was divided into 3 groups, based on Tanner stage (pre-puberty, puberty, and post-puberty). Clinical characteristics and histologic features were compared among groups. Multivariable regression models were used to adjust for potential confounders. Results After adjusting for other factors, hyperuricemia and low levels of high-density lipoprotein cholesterol were more prevalent among children who entered puberty with lower levels of quantitative insulin-sensitivity check index (P<.05). The degree of steatosis, numbers of Mallory-Denk bodies, and diagnostic categories of NAFLD differed among groups (P<.05). There were potential sex differences in associations between stages of puberty and lobular inflammation, hepatocyte ballooning, and borderline steatohepatitis of zone 3; these were therefore not included in multivariable analyses of the overall population. Following adjustment for different sets of confounders, patients at or beyond puberty were less likely to have high-grade steatosis, severe portal inflammation, borderline steatohepatitis (zone 1), or a high stage of fibrosis than patients who had not entered puberty (P<.05). On the contrary, the prevalence of Mallory-Denk body was greater among post-puberty subjects (P=.06). Conclusion Steatosis, portal inflammation, and fibrosis are less severe during or after puberty than before puberty among subjects with NAFLD. Post-pubescent individuals have a lower prevalence of borderline steatohepatitis of zone 1 but are more likely to have Mallory-Denk bodies. These findings indicate that puberty affects the pathologic features of NAFLD. PMID:22343513

  2. FGF21 ameliorates nonalcoholic fatty liver disease by inducing autophagy.

    PubMed

    Zhu, Shenglong; Wu, Yunzhou; Ye, Xianlong; Ma, Lei; Qi, Jianying; Yu, Dan; Wei, Yuquan; Lin, Guangxiao; Ren, Guiping; Li, Deshan

    2016-09-01

    The aim of this study is to evaluate the role of fibroblast growth factor 21 (FGF21) in nonalcoholic fatty liver disease (NAFLD) and seek to determine if its therapeutic effect is through induction of autophagy. In this research, Monosodium L-glutamate (MSG)-induced obese mice or normal lean mice were treated with vehicle, Fenofibrate, and recombinant murine FGF21, respectively. After 5 weeks of treatment, metabolic parameters including body weight, blood glucose and lipid levels, hepatic and fat gene expression levels were monitored and analyzed. Also, fat-loaded HepG2 cells were treated with vehicle or recombinant murine FGF21. The expression levels of proteins associated with autophagy were detected by western blot, real-time PCR, and transmission electron microscopy (TEM). Autophagic flux was monitored by laser confocal microscopy and western blot. Results showed that FGF21 significantly reduced body weight (P < 0.01) and serum triglyceride, improved insulin sensitivity, and reversed hepatic steatosis in the MSG model mice. In addition, FGF21 significantly increased the expression of several proteins related to autophagy both in MSG mice and fat-loaded HepG2 cells, such as microtubule associated protein 1 light chain 3, Bcl-2-interacting myosin-like coiled-coil protein-1 (Beclin-1), and autophagy-related gene 5. Furthermore, the evidence of TEM revealed an increased number of autophagosomes and lysosomes in the model cells treated with FGF21. In vitro experimental results also showed that FGF21 remarkably increased autophagic flux. Taken together, FGF21 corrects multiple metabolic parameters on NAFLD in vitro and in vivo by inducing autophagy. PMID:27435856

  3. Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Pirola, Carlos J.; Scian, Romina; Gianotti, Tomas Fernández; Dopazo, Hernán; Rohr, Cristian; Martino, Julio San; Castaño, Gustavo O.; Sookoian, Silvia

    2015-01-01

    Abstract The 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification whose role in the pathogenesis of metabolic-related complex diseases remains unexplored; 5-hmC appears to be prevalent in the mitochondrial genome. The Ten-Eleven-Translocation (TET) family of proteins is responsible for catalyzing the conversion of 5-methylcytosine to 5-hmC. We hypothesized that epigenetic editing by 5-hmC might be a novel mechanism through which nonalcoholic fatty liver disease (NAFLD)-associated molecular traits could be explained. Hence, we performed an observational study to explore global levels of 5-hmC in fresh liver samples of patients with NAFLD and controls (n = 90) using an enzyme-linked-immunosorbent serologic assay and immunohistochemistry. We also screened for genetic variation in TET 1–3 loci by next generation sequencing to explore its contribution to the disease biology. The study was conducted in 2 stages (discovery and replication) and included 476 participants. We observed that the amount of 5-hmC in the liver of both NAFLD patients and controls was relatively low (up to 0.1%); a significant association was found with liver mitochondrial DNA copy number (R = 0.50, P = 0.000382) and PPARGC1A-mRNA levels (R = −0.57, P = 0.04). We did not observe any significant difference in the 5-hmC nuclear immunostaining score between NAFLD patients and controls; nevertheless, we found that patients with NAFLD (0.4 ± 0.5) had significantly lower nonnuclear-5-hmC staining compared with controls (1.8 ± 0.8), means ± standard deviation, P = 0.028. The missense p.Ile1123Met variant (TET1-rs3998860) was significantly associated with serum levels of caspase-generated CK-18 fragment-cell death biomarker in the discovery and replication stage, and the disease severity (odds ratio: 1.47, 95% confidence interval: 1.10–1.97; P = 0.005). The p.Ile1762Val substitution (TET2-rs2454206) was associated with liver PPARGC1A-methylation and

  4. The Effects of Metabolic Surgery on Fatty Liver Disease and Nonalcoholic Steatohepatitis.

    PubMed

    Clanton, Jesse; Subichin, Michael

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is an under-recognized but increasingly important manifestation of the metabolic syndrome. Bariatric surgery, both through direct weight loss and more indirect effects on insulin resistance and improvements in inflammatory proteins, can have a profound effect on NAFLD, resulting in improvement or resolution of even high-grade liver disease. PMID:27473796

  5. The Risk of Abdominal Obesity according to the Degree of Non-Alcoholic Fatty Liver Disease in Korean Men

    PubMed Central

    2016-01-01

    Although non-alcoholic fatty liver disease has been reported as a cardiometabolic risk factor, the effect of non-alcoholic fatty liver is yet to be clarified on abdominal obesity. Therefore, this study was conducted to investigate the longitudinal relationship of non-alcoholic fatty liver on the development of abdominal obesity. The study participants were composed of 11,212 Korean men without abdominal obesity. They were followed up from 2005 to 2010 to be monitored for the development of abdominal obesity according to their degree of non-alcoholic fatty liver disease (normal, mild, and moderate to severe). Cox-proportional hazard model was used to calculate the hazard ratios for abdominal obesity according to the degree of non-alcoholic fatty liver disease. While the average incidence was 15.5%, the incidence of abdominal obesity increased according to the degree of non-alcoholic fatty liver (normal: 11.6%, mild: 25.2%, moderate to severe: 41.0%, P < 0.001). Multivariable-adjusted hazard ratios for abdominal obesity independently increased proportionally to the degree of NAFLD (mild [1.07; 0.94-1.23], moderate to severe [1.58; 1.11-2.26], P for trend < 0.001). The risk of abdominal obesity increased proportionally to the degree of non-alcoholic fatty liver disease. This finding guarantees further studies to reveal the incidental relationship of abdominal obesity with non-alcoholic fatty liver disease. PMID:26955242

  6. Murine Models of Nonalcoholic Fatty Liver Disease and Steatohepatitis

    PubMed Central

    Ninomiya, Masashi; Kondo, Yasuteru; Shimosegawa, Tooru

    2013-01-01

    In 1980, Ludwig et al. first reported patients of steatohepatitis who lacked a history of excessive alcohol consumption but showed liver histology resembling alcoholic hepatitis and progression to cirrhosis of the liver accompanied by inflammation and fibrosis. The development of nonalcoholic steatohepatitis (NASH) is associated with obesity, diabetes mellitus, insulin resistance, and hyperlipidemia. However, the pathogenesis of NASH remains incomplete. A “multiple-hit” hypothesis for the pathogenesis of NASH based on an animal model has been proposed and remains a foundation for research in this field. We review the important dietary and genetic animal models and discuss the pathogenesis of NASH. PMID:27335818

  7. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease

    PubMed Central

    Donnelly, Kerry L.; Smith, Coleman I.; Schwarzenberg, Sarah J.; Jessurun, Jose; Boldt, Mark D.; Parks, Elizabeth J.

    2005-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage. The goal of the present study was to directly quantify the biological sources of hepatic and plasma lipoprotein TAG in NAFLD. Patients (5 male and 4 female; 44 ± 10 years of age) scheduled for a medically indicated liver biopsy were infused with and orally fed stable isotopes for 4 days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipoprotein TAG. Hepatic and lipoprotein TAG fatty acids were analyzed by gas chromatography/mass spectrometry. NAFLD patients were obese, with fasting hypertriglyceridemia and hyperinsulinemia. Of the TAG accounted for in liver, 59.0% ± 9.9% of TAG arose from NEFAs; 26.1% ± 6.7%, from DNL; and 14.9% ± 7.0%, from the diet. The pattern of labeling in VLDL was similar to that in liver, and throughout the 4 days of labeling, the liver demonstrated reciprocal use of adipose and dietary fatty acids. DNL was elevated in the fasting state and demonstrated no diurnal variation. These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD. PMID:15864352

  8. Portal Chronic Inflammation in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Brunt, Elizabeth M.; Kleiner, David E.; Wilson, Laura A.; Unalp, Aynur; Behling, Cynthia E.; Lavine, Joel E.; Neuschwander-Tetri, Brent A.

    2009-01-01

    Untreated adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in the portal-based pediatric pattern of NAFLD, portal CI may be a predominant component. This study was undertaken to correlate clinical features with portal CI in the subjects enrolled in the NASH CRN. Methods Histology from central grading and clinical parameters temporally related to the biopsy were evaluated from 728 adults and 205 children. Results Sixty percent of adult biopsies had mild, 23% had more than mild, and 16% had no portal CI. In children, 76% had mild, 14% were more than mild, and 10% had no portal CI. In neither group were autoantibodies, elevated ALT, or generic use of “any” medications associated with the presence or degree of portal CI. Clinical features associated with “more than mild” in adults were older age (51 y v 44 y) (p<0.0001), female gender (p=0.001), higher BMI (p<0.0001), elevated insulin levels (median 20 v 14uU/ml) (p=0.001), higher HOMA-IR (median 5 v 3) (p<0.0001), and medications used for NAFLD (p=0.0004), diabetes (p<0.0001), and hypertension (p<0.0001). The same comparisons for “more than mild” v “none” in the pediatric biopsies showed only an association with younger age (12 y v 14 y) (p=0.01), but there was a trend favoring boys. There was no association with BMI, insulin or HOMA-IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with a definite steatohepatitis diagnosis (p<0.0001 for both). Features in the adult biopsies associated with “more than mild” were steatosis amount (p=0.01and location (p<0.0001), presence of ballooning (p<0.0001), and advanced fibrosis (p<0.0001). In the pediatric biopsies, “more than mild” compared with “none” was associated with steatosis location (p=0.0008), and fibrosis score (p<0.0001), specifically, the pediatric (zone 1 accentuation) pattern (p<0.001) and portal

  9. 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

  10. 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

  11. Metabolic syndrome and non-alcoholic fatty liver disease in liver surgery: The new scourges?

    PubMed Central

    Cauchy, François; Fuks, David; Zarzavadjian Le Bian, Alban; Belghiti, Jacques; Costi, Renato

    2014-01-01

    The aim of this topic highlight is to review relevant evidence regarding the influence of the metabolic syndrome (MS) and its associated liver manifestation, non-alcoholic fatty liver disease (NAFLD), on the development of liver cancer as well as their impact on the results of major liver surgery. MS and NAFLD, whose incidences are significantly increasing in Western countries, are leading to a changing profile of the patients undergoing liver surgery. A MEDLINE search was performed for relevant articles using the key words “metabolic syndrome”, “liver resection”, “liver transplantation”, “non alcoholic fatty liver disease”, “non-alcoholic steatohepatitis” and “liver cancer”. On one hand, the MS favors the development of primary liver malignancies (hepatocellular carcinoma and cholangiocarcinoma) either through NAFLD liver parenchymal alterations (steatosis, steatohepatitis, fibrosis) or in the absence of significant underlying liver parenchyma changes. Also, the existence of NAFLD may have a specific impact on colorectal liver metastases recurrence. On the other hand, the postoperative period following partial liver resection and liver transplantation is at increased risk of both postoperative complications and mortality. These deleterious effects seem to be related to the existence of liver specific complications but also higher cardio-vascular sensitivity in a setting of MS/NAFLD. Finally, the long-term prognosis after curative surgery joins that of patients operated on with other types of underlying liver diseases. An increased rate of patients with MS/NAFLD referred to hepatobiliary units has to be expected. The higher operative risk observed in this subset of patients will require specific improvements in their perioperative management. PMID:24868324

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

    PubMed Central

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

    2016-01-01

    AIM: To assess significance of serum adipokines to determine the histological severity of non-alcoholic fatty liver disease. METHODS: 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. RESULTS: 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

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

    PubMed Central

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

    2016-01-01

    AIM: To determine the discriminatory performance of fatty liver index (FLI) for non-alcoholic fatty liver disease (NAFLD). METHODS: 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. RESULTS: 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). CONCLUSION: Although FLI had acceptable discriminatory power in the diagnosis of NAFLD, WC was a simpler and more accessible index with a similar performance. PMID:26973398

  14. Discrimination of Nonalcoholic Steatohepatitis Using Transient Elastography in Patients with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Kim, Seung Up; Jang, Jae Young; Park, Hana; Kim, Ja Kyung; Lee, Chun Kyon; Chon, Young Eun; Han, Kwang-Hyub

    2016-01-01

    Background/aims The accuracy of noninvasive markers to discriminate nonalcoholic steatohepatitis (NASH) is unsatisfactory. We investigated whether transient elastography (TE) could discriminate patients with NASH from those with nonalcoholic fatty liver disease (NAFLD). Methods The patients suspected of NAFLD who underwent liver biopsy and concomitant TE were recruited from five tertiary centers between November 2011 and December 2013. Results The study population (n = 183) exhibited a mean age of 40.6 years and male predominance (n = 111, 60.7%). Of the study participants, 89 (48.6%) had non-NASH and 94 (51.4%) had NASH. The controlled attenuation parameter (CAP) and liver stiffness (LS) were significantly correlated with the degrees of steatosis (r = 0.656, P<0.001) and fibrosis (r = 0.714, P<0.001), respectively. The optimal cut-off values for steatosis were 247 dB/m for S1, 280 dB/m for S2, and 300 dB/m for S3. Based on the independent predictors derived from multivariate analysis [P = 0.044, odds ratio (OR) 4.133, 95% confidence interval (CI) 1.037–16.470 for CAP>250 dB/m; P = 0.013, OR 3.399, 95% CI 1.295–8.291 for LS>7.0 kPa; and P<0.001, OR 7.557, 95% CI 2.997–19.059 for Alanine aminotransferase>60 IU/L], we developed a novel CLA model for discriminating patients with NASH. The CLA model showed good discriminatory capability, with an area under the receiver operating characteristic curve (AUROC) of 0.812 (95% CI 0.724–0.880). To assess discriminatory power, the AUROCs, as determined by the bootstrap method, remained largely unchanged between iterations, with an average value of 0.833 (95% CI 0.740–0.893). Conclusion This novel TE-based CLA model showed acceptable accuracy in discriminating NASH from simple steatosis. However, further studies are required for external validation. PMID:27284700

  15. Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis.

    PubMed

    Ni, Yinhua; Zhuge, Fen; Nagashimada, Mayumi; Ota, Tsuguhito

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is considered a hepatic manifestation of metabolic syndrome; however, mechanisms underlying the onset and progression of NAFLD are still unclear. Resident and recruited macrophages are key players in the homeostatic function of the liver and in the progression of NAFLD to NASH. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of macrophages. New NAFLD therapies will likely involve modification of macrophage polarization by restraining M1 activation or driving M2 activation. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this review, we summarize the molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. From our review, we propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis. PMID:27347998

  16. Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis

    PubMed Central

    Ni, Yinhua; Zhuge, Fen; Nagashimada, Mayumi; Ota, Tsuguhito

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is considered a hepatic manifestation of metabolic syndrome; however, mechanisms underlying the onset and progression of NAFLD are still unclear. Resident and recruited macrophages are key players in the homeostatic function of the liver and in the progression of NAFLD to NASH. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of macrophages. New NAFLD therapies will likely involve modification of macrophage polarization by restraining M1 activation or driving M2 activation. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this review, we summarize the molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. From our review, we propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis. PMID:27347998

  17. Risk for nonalcoholic fatty liver disease in Hispanic Youth with BMI > or = 95th percentile

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To characterize children at risk for nonalcoholic fatty liver disease (NAFLD) and to explore possible mechanisms underlying the development of NAFLD in Hispanic youth with a body mass index > or =95th percentile. Hispanic nonoverweight (n = 475) and overweight (n = 517) children, ages 4 to 19 y, wer...

  18. Coffee consumption and nonalcoholic fatty liver onset: a prospective study in the general population.

    PubMed

    Zelber-Sagi, Shira; Salomone, Federico; Webb, Muriel; Lotan, Roni; Yeshua, Hanny; Halpern, Zamir; Santo, Erwin; Oren, Ran; Shibolet, Oren

    2015-03-01

    Retrospective studies suggest that coffee consumption may exert beneficial effects in patients with nonalcoholic fatty liver; however, prospective data supporting a protective role on liver steatosis development are lacking. In this study, we aimed to evaluate the association between coffee consumption and fatty liver onset in the general population. The analysis was performed both in a cross-sectional cohort (n = 347) and, prospectively, in a subcohort of patients without fatty liver at baseline and followed-up for 7 years (n = 147). Fatty liver was diagnosed with abdominal ultrasound and liver steatosis was quantified noninvasively by hepatorenal index (HRI) and SteatoTest, whereas FibroTest was used to assess fibrosis degree. A structured questionnaire on coffee consumption was administrated during a face-to-face interview. Neither the incidence nor the prevalence of fatty liver according to ultrasonography, SteatoTest, and the HRI was associated with coffee consumption. In the cross-sectional study, high coffee consumption was associated with a lower proportion of clinically significant fibrosis ≥ F2 (8.8% vs 16.3%; P = 0.038); consistently, in multivariate logistic regression analysis, high coffee consumption was associated with lower odds for significant fibrosis (odds ratio = 0.49, 95% confidence interval, 0.25-0.97; P = 0.041) and was the strongest predictor for significant fibrosis. No association was demonstrated between coffee consumption and the new onset of nonalcoholic fatty liver, but coffee intake may exert beneficial effects on fibrosis progression. PMID:25468486

  19. 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

  20. Nonalcoholic Fatty Liver Disease: Key Considerations Before and After Liver Transplantation.

    PubMed

    Patel, Yuval A; Berg, Carl L; Moylan, Cynthia A

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver disease in developed countries and is on trajectory to become the leading indication for liver transplantation in the USA and much of the world. Patients with NAFLD cirrhosis awaiting liver transplant face unique challenges and increased risk for waiting list stagnation and dropout due to burdensome comorbidities including obesity, diabetes, cardiovascular disease, and kidney disease. Thus far, patients transplanted for NAFLD cirrhosis have excellent mid- and long-term patient and graft survival, but concerns regarding short-term morbidity and mortality continue to exist. Post-liver transplantation, NAFLD occurs as both a recurrent and de novo manifestation, each with unique outcomes. NAFLD in the donor population is of concern given the growing demand for liver transplantation and mounting pressure to expand the donor pool. This review addresses key issues surrounding NAFLD as an indication for transplantation, including its increasing prevalence, unique patient demographics, outcomes related to liver transplantation, development of post-liver transplantation NAFLD, and NAFLD in the liver donor population. It also highlights exciting areas where further research is needed, such as the role of bariatric surgery and preconditioning of marginal donor grafts. PMID:26815171

  1. Is there any progress in the treatment of non-alcoholic fatty liver disease?

    PubMed Central

    Tsochatzis, Emmanuel A; Papatheodoridis, George V

    2011-01-01

    Despite the fact that non-alcoholic fatty liver disease (NAFLD) and its severe clinical form, non-alcoholic steatohepatitis, are becoming increasingly prevalent in the industrialised countries, there are no licensed pharmacological treatments for them. Weight loss and life modifications, antioxidant therapies and insulin-sensitising agents are the current treatment strategies and have all been tested with inconclusive results. Low sample numbers, inadequate treatment duration and invalid surrogate markers for treatment response might all account for these results. As NAFLD is a systemic rather than a liver disease, future trials should address the patient as a whole and also address cardiovascular risk factors. PMID:21577310

  2. 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

  3. Investigating Nonalcoholic Fatty Liver Disease in a Liver-on-a-Chip Microfluidic Device

    PubMed Central

    Simonelli, Maria Chiara; Giannitelli, Sara Maria; Businaro, Luca; Trombetta, Marcella; Rainer, Alberto

    2016-01-01

    Background and Aim Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease worldwide, ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to cirrhosis, eventually leading to hepatocellular carcinoma (HCC). HCC ranks as the third highest cause of cancer-related death globally, requiring an early diagnosis of NAFLD as a potential risk factor. However, the molecular mechanisms underlying NAFLD are still under investigation. So far, many in vitro studies on NAFLD have been hampered by the limitations of 2D culture systems, in which cells rapidly lose tissue-specific functions. The present liver-on-a-chip approach aims at filling the gap between conventional in vitro models, often scarcely predictive of in vivo conditions, and animal models, potentially biased by their xenogeneic nature. Methods HepG2 cells were cultured into a microfluidically perfused device under free fatty acid (FFA) supplementation, namely palmitic and oleic acid, for 24h and 48h. The device mimicked the endothelial-parenchymal interface of a liver sinusoid, allowing the diffusion of nutrients and removal of waste products similar to the hepatic microvasculature. Assessment of intracellular lipid accumulation, cell viability/cytotoxicity and oxidative stress due to the FFA overload, was performed by high-content analysis methodologies using fluorescence-based functional probes. Results The chip enables gradual and lower intracellular lipid accumulation, higher hepatic cell viability and minimal oxidative stress in microfluidic dynamic vs. 2D static cultures, thus mimicking the chronic condition of steatosis observed in vivo more closely. Conclusions Overall, the liver-on-a-chip system provides a suitable culture microenvironment, representing a more reliable model compared to 2D cultures for investigating NAFLD pathogenesis. Hence, our system is amongst the first in vitro models of human NAFLD developed within a microfluidic device in a sinusoid

  4. Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease.

    PubMed

    Anstee, Quentin M; Seth, Devanshi; Day, Christopher P

    2016-06-01

    Genome-wide association studies and candidate gene studies have informed our understanding of factors contributing to the well-recognized interindividual variation in the progression and outcomes of alcoholic liver disease and nonalcoholic fatty liver disease. We discuss the mounting evidence for shared modifiers and common pathophysiological processes that contribute to development of both diseases. We discuss the functions of proteins encoded by risk variants of genes including patatin-like phospholipase domain-containing 3 and transmembrane 6 superfamily member 2, as well as epigenetic factors that contribute to the pathogenesis of alcoholic liver disease and nonalcoholic fatty liver disease. We also discuss important areas of future genetic research and their potential to affect clinical management of patients. PMID:26873399

  5. Atherogenic dyslipidemia and cardiovascular risk in children with nonalcoholic fatty liver disease

    PubMed Central

    Alkhouri, Naim; Carter-Kent, Christine; Elias, Michael; Feldstein, Ariel E

    2011-01-01

    Nonalcoholic fatty liver disease is now regarded as the most common form of chronic liver disease in adults and children. The close association between nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome has been extensively described. Moreover, a growing body of evidence suggest that NAFLD by itself confers a substantial cardiovascular risk independent of the other components of the metabolic syndrome. Given the significant potential for morbidity and mortality in these patients, and the large proportion of both pediatric and adult population affected, it is important that we clearly define the overall risk, identify early predictors for cardiovascular disease progression, and establish management strategies. In this article, we will focus on current data linking NAFLD and the severity of liver damage present in children with cardiovascular risk. PMID:22162978

  6. 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. PMID:27179602

  7. Liver Toxicity of Anabolic Androgenic Steroid Use in an Adolescent with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Awai, Hannah I; Yu, Elizabeth L; Ellis, Linda S; Schwimmer, Jeffrey B

    2013-01-01

    The prevalence of obesity and related morbidities such as nonalcoholic fatty liver disease (NAFLD) is high among adolescents. Current treatment recommendations for NAFLD focus on lifestyle optimization via nutrition and exercise. After encouraging exercise, many adolescents choose to participate in organized sports, which may lead to use of illicit substances such as anabolic androgenic steroids (AAS) to boost athletic performance. Approximately 3,000,000 individuals use non-therapeutic AAS at supra-physiologic doses in the United States.1 In 2012, 5.9% of adolescent boys reported steroid use in the previous year.2 We anticipate adolescents with pre-existing liver disease are at increased risk for AAS induced hepatotoxicity. We present such a case with IRB approval and written individual patient consent. PMID:23568051

  8. 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

  9. Metabolomic analysis of human cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis diseases.

    PubMed

    Safaei, Akram; Arefi Oskouie, Afsaneh; Mohebbi, Seyed Reza; Rezaei-Tavirani, Mostafa; Mahboubi, Mohammad; Peyvandi, Maryam; Okhovatian, Farshad; Zamanian-Azodi, Mona

    2016-01-01

    Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies. PMID:27458508

  10. Metabolomic analysis of human cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis diseases

    PubMed Central

    Safaei, Akram; Arefi Oskouie, Afsaneh; Mohebbi, Seyed Reza; Rezaei-Tavirani, Mostafa; Mahboubi, Mohammad; Peyvandi, Maryam; Okhovatian, Farshad; Zamanian-Azodi, Mona

    2016-01-01

    Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies. PMID:27458508

  11. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease.

    PubMed

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

    2015-09-01

    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

  12. 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

  13. Nonalcoholic fatty liver disease and hepatic cirrhosis: Comparison with viral hepatitis-associated steatosis.

    PubMed

    Haga, Yuki; Kanda, Tatsuo; Sasaki, Reina; Nakamura, Masato; Nakamoto, Shingo; Yokosuka, Osamu

    2015-12-14

    Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus (HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity, type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review, the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed. PMID:26675364

  14. Nonalcoholic fatty liver disease and hepatic cirrhosis: Comparison with viral hepatitis-associated steatosis

    PubMed Central

    Haga, Yuki; Kanda, Tatsuo; Sasaki, Reina; Nakamura, Masato; Nakamoto, Shingo; Yokosuka, Osamu

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus (HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity, type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review, the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed. PMID:26675364

  15. Treatment of Nonalcoholic Fatty Liver Disease: The Role of Medical, Surgical, and Endoscopic Weight Loss

    PubMed Central

    Popov, Violeta B.; Lim, Joseph K.

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents a rapidly growing cause of chronic liver disease in the United States and is associated with significant morbidity and mortality, including progression to liver cirrhosis and hepatocellular carcinoma. NAFLD comprises a spectrum of liver conditions, ranging from simple steatosis to steatosis with inflammation (steatohepatitis) and progressive fibrosis. Weight loss represents a first line therapeutic modality for the management of NAFLD. Herein, we review the evidence base for medical, surgical, and endoscopic approaches to weight loss and their potential impact on the natural history of NAFLD. PMID:26623270

  16. Use of liver breath tests to assess severity of nonalcoholic fatty liver disease.

    PubMed

    Furnari, Manuele; Savarino, Vincenzo; Giannini, Edoardo G

    2014-01-01

    As the prevalence of obesity and insulin-resistance continues to increase in the general population, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions, thus becoming one of the leading causes of chronic liver disease worldwide. It may present as simple steatosis (NAFL) or steatohepatitis (NASH), which in turn may develop fibrosis and ultimately cirrhosis. Conventional biochemical liver test and radiological investigations are not able to provide reliable information on liver functional reserve, and liver biopsy remains the gold standard to stage NAFLD, differentiate simple steatosis from NASH, and grade fibrosis. However, liver biopsy has some limitations, and is not preferred by patients due to its invasiveness. Thus, non-invasive assessment of disease stage by using liver breath tests - which are based on hepatic clearance of non-radioactive stable (13)C-labelled drugs - may be of interest to stage disease and assess patients prognosis due to good accuracy and repeatability. These substrates are orally administered and are cleaved by enzymes specifically located in the liver thus reflecting either the microsomal, cytosolic, or mitochondrial functions. (13)C-Breath Tests have been initially oriented to differentiate broad categories of patients and more recently to refine stage differentiation in patients with early stages of liver disease. In NAFLD patients, (13)C-BTs were able to distinguish simple steatosis from NASH and had good correlation with both histological fibrosis stage and biochemical markers of fibrogenesis. Although promising results have been achieved in this field, their use in clinical practice is still restricted to a specialized niche. However, concordant data from literature conferred to (13)C-Breath Tests a potential role in providing punctual and longitudinal evaluation of patients, identifying those patients where liver biopsy may selectively be performed to stage disease, monitoring and predicting therapeutic

  17. Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis

    PubMed Central

    Dongiovanni, Paola; Romeo, Stefano; Valenti, Luca

    2015-01-01

    Liver fat accumulation generally related to systemic insulin resistance characterizes nonalcoholic fatty liver disease (NAFLD), which in the presence of nonalcoholic steatohepatitis (NASH) can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease in Western countries. Epidemiological, familial, and twin studies provide evidence for a strong genetic component of NAFLD susceptibility. Recently, genome-wide association studies led to the identification of the major inherited determinants of hepatic fat accumulation: patatin-like phospholipase domain-containing 3 (PNPLA3) I148M gene and transmembrane 6 superfamily member 2 (TM6SF2) E167K gene variants, involved in lipid droplets remodelling and very low-density lipoproteins secretion, are the major determinants of interindividual differences in liver steatosis, and susceptibility to progressive NASH. In this review, we aimed to provide an overview of recent insights into the genetics of hepatic fat accumulation and steatohepatitis. PMID:26273621

  18. Macrophage Activation in Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) Correlates with Hepatic Progenitor Cell Response via Wnt3a Pathway

    PubMed Central

    Renzi, Anastasia; De Stefanis, Cristiano; Stronati, Laura; Franchitto, Antonio; Alisi, Anna; Onori, Paolo; De Vito, Rita; Alpini, Gianfranco; Gaudio, Eugenio

    2016-01-01

    Non-alcoholic fatty liver disease is one of the most important causes of liver-related morbidity in children. In non-alcoholic fatty liver disease, the activation of liver resident macrophage pool is a central event in the progression of liver injury. The aims of the present study were to evaluate the polarization of liver macrophages and the possible role of Wnt3a production by macrophages in hepatic progenitor cell response in the progression of pediatric non-alcoholic fatty liver disease. 32 children with biopsy-proven non-alcoholic fatty liver disease were included. 20 out of 32 patients were treated with docosahexaenoic acid for 18 months and biopsies at the baseline and after 18 months were included. Hepatic progenitor cell activation, macrophage subsets and Wnt/β-catenin pathway were evaluated by immunohistochemistry and immunofluorescence. Our results indicated that in pediatric non-alcoholic fatty liver disease, pro-inflammatory macrophages were the predominant subset. Macrophage polarization was correlated with Non-alcoholic fatty liver disease Activity Score, ductular reaction, and portal fibrosis; docosahexaenoic acid treatment determined a macrophage polarization towards an anti-inflammatory phenotype in correlation with the reduction of serum inflammatory cytokines, with increased macrophage apoptosis, and with the up-regulation of macrophage Wnt3a expression; macrophage Wnt3a expression was correlated with β-catenin phosphorylation in hepatic progenitor cells and signs of commitment towards hepatocyte fate. In conclusion, macrophage polarization seems to have a key role in the progression of pediatric non-alcoholic fatty liver disease; the modulation of macrophage polarization could drive hepatic progenitor cell response by Wnt3a production. PMID:27310371

  19. Nutrition: a promising route for prevention and management of obesity-related nonalcoholic fatty liver disease.

    PubMed

    Tarantino, Giovanni

    2014-11-01

    When dealing with the treatment of obesity-linked illnesses - in particular nonalcoholic fatty liver disease - beyond diet, various nutritional ingredients are reported to be useful as silymarin, spirulina, choline, folic acid, methionine and vitamin E, all of them showing promising but not definite results. An emerging field of study is represented by prebiotics/probiotics and restoration of normal gut flora, which could play a fundamental role diet and various its components. It is noteworthy to point out that both improving or reducing the severity of nonalcoholic fatty liver disease bear a positive consequence on evolution of atherosclerosis and its cardiovascular-associated disease, such as coronary artery disease, even though the involved immunologic mechanisms are gaining greater credit in the most recent literature, without excluding the role of nutrition in modulating the acquired immunity in this condition. PMID:25460293

  20. Genetic factors associated with the presence and progression of nonalcoholic fatty liver disease: a narrative review.

    PubMed

    Hernaez, Ruben

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Whereas insulin resistance and obesity are considered major risk factors for the development and progression of NAFLD, the genetic underpinnings are unclear. Before 2008, candidate gene studies based on prior knowledge of pathophysiology of fatty liver yielded conflicting results. In 2008, Romeo et al. published the first genome wide association study and reported the strongest genetic signal for the presence of fatty liver (PNPLA3, patatin-like phospholipase domain containing 3; rs738409). Since then, two additional genome wide scans were published and identified 9 additional genetic variants. Whereas these results shed light into the understanding of the genetics of NAFLD, most of associations have not been replicated in independent samples and, therefore, remain undetermined the significance of these findings. This review aims to summarize the understanding of genetic epidemiology of NAFLD and highlights the gaps in knowledge. PMID:22093607

  1. Gut Microbiota and Clinical Disease: Obesity and Nonalcoholic Fatty Liver Disease

    PubMed Central

    Seo, Ji Hyun; Youn, Hee-Shang

    2013-01-01

    The prevalence of obesity is increasing worldwide. Obesity can cause hyperlipidemia, hypertension, cardiovascular diseases, metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Many environmental or genetic factors have been suggested to contribute to the development of obesity, but there is no satisfactory explanation for its increased prevalence. This review discusses the latest updates on the role of the gut microbiota in obesity and NAFLD. PMID:24010102

  2. Non-alcoholic fatty liver disease (NAFLD): a tale of fat and sugar?

    PubMed

    Longato, Lisa

    2013-01-01

    The global diffusion of the so-called Western diet, which is enriched in fat and carbohydrates, such as fructose, has been proposed to be an underlying cause of the increased prevalence of metabolic conditions, including non-alcoholic fatty liver disease (NAFLD). This Smart Card summarizes the main metabolic and hepatic histological features of rodent models fed with diets combining high fat and fructose. PMID:23866299

  3. Association of homocysteine level with biopsy-proven non-alcoholic fatty liver disease: a meta-analysis

    PubMed Central

    Dai, Yining; Zhu, Jinzhou; Meng, Di; Yu, Chaohui; Li, Youming

    2016-01-01

    Previous studies have reported inconsistent findings regarding the association between plasmatic higher of homocysteine level and non-alcoholic fatty liver disease. We aimed to investigate this association by conducting a meta-analysis. Literature was searched on PubMed from inception to January 2015. Eight studies evaluating plasma level of homocysteine in biopsy-proven non-alcoholic fatty liver disease subjects compared to healthy controls were included. Compared with the controls, non-alcoholic fatty liver disease patients witnessed a higher level of homocysteine [standard mean difference (SMD): 0.66 µmol/L, 95% CI: 0.41, 0.92 µmol/L], and were associated with a significant increased risk for hyperhomocysteinemia [odds ratio (OR) 5.09, 95% CI: 1.69, 15.32]. In addition, patients with non-alcoholic fatty liver presented 0.45 µmol/L higher levels of homocysteine compared to healthy controls (95% CI: 0.09, 0.82 µmol/L), whereas non-alcoholic steatohepatitis patients had 1.02 µmol/L higher levels of homocysteine (95% CI: 0.28, 1.76 µmol/L). There was neither difference of folate level nor vitamin B12 level between non-alcoholic fatty liver disease subjects and healthy controls. This study revealed that non-alcoholic fatty liver disease patients presented an increased serum concentration of homocysteine, and were associated with an increased risk of hyperhomocysteinemia. Further studies are needed to demonstrate a causal role of hyperhomocysteinemia in non-alcoholic fatty liver disease. PMID:26798201

  4. Simple Resistance Exercise helps Patients with Non-alcoholic Fatty Liver Disease.

    PubMed

    Takahashi, A; Abe, K; Usami, K; Imaizumi, H; Hayashi, M; Okai, K; Kanno, Y; Tanji, N; Watanabe, H; Ohira, H

    2015-10-01

    To date, only limited evidence has supported the notion that resistance exercise positively impacts non-alcoholic fatty liver disease. We evaluated the effects of resistance exercise on the metabolic parameters of non-alcoholic fatty liver disease (NAFLD) in 53 patients who were assigned to either a group that performed push-ups and squats 3 times weekly for 12 weeks (exercise group; n=31) or a group that did not (control; n=22). Patients in the control group proceeded with regular physical activities under a restricted diet throughout the study. The effects of the exercise were compared between the 2 groups after 12 weeks. Fat-free mass and muscle mass significantly increased, whereas hepatic steatosis grade, mean insulin and ferritin levels, and the homeostasis model assessment-estimated insulin resistance index were significantly decreased in the exercise group. Compliance with the resistance exercise program did not significantly correlate with patient background characteristics such as age, sex, BMI and metabolic complications. These findings show that resistance exercise comprising squats and push-ups helps to improve the characteristics of metabolic syndrome in patients with non-alcoholic fatty liver disease. PMID:26090879

  5. Increased accumulation of 4-hydroxynonenal adducts in female GSTA4/PPAR alpha double knockout mice enhance steatosis and inflammation in a model of pediatric nonalcoholic fatty liver disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hepatocellular injury resulting from increased lipid peroxidation products and oxidative stress is considered a potential mechanism driving the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitsis (NASH). To test the significance of lipid peroxidation and protein...

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

    SciTech Connect

    Prasad, Vikram; Chirra, Shivani; Kohli, Rohit; Shull, Gary E.

    2014-07-25

    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 liver 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.

  7. Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis

    PubMed Central

    Polimeni, Licia; Del Ben, Maria; Baratta, Francesco; Perri, Ludovica; Albanese, Fabiana; Pastori, Daniele; Violi, Francesco; Angelico, Francesco

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and more severe liver complications such as cirrhosis, hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidaemia, and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and, to a lesser extent, to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus, oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed, with conflicting results. In particular, vitamin E supplementation has been suggested for the treatment of non-diabetic, non-cirrhotic adults with active NASH, although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol, silybin, L-carnitine and pentoxiphylline. No trial so far, has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New, large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed. PMID:26052378

  8. Obesity and non-alcoholic fatty liver disease: Disparate associations among Asian populations

    PubMed Central

    Wong, Robert J; Ahmed, Aijaz

    2014-01-01

    Obesity is a global epidemic contributing to an increasing prevalence of obesity-related systemic disorders, including nonalcoholic fatty liver disease. The rising prevalence of nonalcoholic steatohepatitis (NASH) will in the near future lead to end-stage liver disease in a large cohort of patients with NASH-related cirrhosis and NASH is predicted to be a leading indication for liver transplantation in the coming decade. However, the prevalence of obesity and the progression of hepatic histological damage associated with NASH exhibit significant ethnic disparities. Despite a significantly lower body mass index and lower rates of obesity compared to other ethnic groups, Asians continue to demonstrate a significant prevalence of hypertension, diabetes, metabolic syndrome and NASH. Ethnic disparities in central adiposity and visceral fat distribution have been hypothesized to contribute to these ethnic disparities. The current review focuses on the epidemiology of obesity and NASH among Asian populations. PMID:24868320

  9. Republished: Non-alcoholic fatty liver disease: a practical approach to treatment

    PubMed Central

    Dyson, J K; Anstee, Q M; McPherson, S

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population in many developed countries. Between 10% and 30% of patients with NAFLD have non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis. There are metabolic risk factors common to both NAFLD and cardiovascular disease, so patients with NASH have an increased risk of liver-related and cardiovascular death. Management of patients with NAFLD depends largely on the stage of disease, emphasising the importance of careful risk stratification. There are four main areas to focus on when thinking about management strategies in NAFLD: lifestyle modification, targeting the components of the metabolic syndrome, liver-directed pharmacotherapy for high risk patients and managing the complications of cirrhosis. PMID:25655252

  10. Non-alcoholic fatty liver disease: a practical approach to treatment

    PubMed Central

    Dyson, J K; Anstee, Q M; McPherson, S

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population in many developed countries. Between 10% and 30% of patients with NAFLD have non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis. There are metabolic risk factors common to both NAFLD and cardiovascular disease, so patients with NASH have an increased risk of liver-related and cardiovascular death. Management of patients with NAFLD depends largely on the stage of disease, emphasising the importance of careful risk stratification. There are four main areas to focus on when thinking about management strategies in NAFLD: lifestyle modification, targeting the components of the metabolic syndrome, liver-directed pharmacotherapy for high risk patients and managing the complications of cirrhosis. PMID:25285192

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

    SciTech Connect

    Lin, Connie; Rountree, Carl B.; Methratta, Sosamma; LaRusso, Salvatore; Kunselman, Allen R.; Spanier, Adam J.

    2014-07-15

    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 the 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.

  12. Contribution of Alcoholic and Nonalcoholic Fatty Liver Disease to the Burden of Liver-Related Morbidity and Mortality.

    PubMed

    Younossi, Zobair; Henry, Linda

    2016-06-01

    Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. NAFLD is associated with obesity and metabolic syndrome whereas ALD is associated with excessive alcohol consumption. Both diseases can progress to cirrhosis, hepatocellular carcinoma, and liver-related death. A higher proportion of patients with NAFLD die from cardiovascular disorders than patients with ALD, whereas a higher proportion of patients with ALD die from liver disease. NAFLD and ALD each are associated with significant morbidity, impairment to health-related quality of life, and economic costs to society. PMID:26980624

  13. 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. PMID:26961580

  14. Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease.

    PubMed

    Machado, M V; Michelotti, G A; Jewell, M L; Pereira, T A; Xie, G; Premont, R T; Diehl, A M

    2016-01-01

    Obesity and its resulting metabolic disturbances are major health threats. In response to energy surplus, overtaxed adipocytes release fatty acids and pro-inflammatory factors into the circulation, promoting organ fat accumulation (including nonalcoholic fatty liver disease), insulin resistance and the metabolic syndrome. Recently, caspase-2 was linked to lipoapoptosis, so we hypothesized that caspase-2 might be a critical determinant of metabolic syndrome pathogenesis. Caspase-2-deficient and wild-type mice were fed a Western diet (high-fat diet, enriched with saturated fatty acids and 0.2% cholesterol, supplemented with fructose and glucose in the drinking water) for 16 weeks. Metabolic and hepatic outcomes were evaluated. In vitro studies assessed the role of caspase-2 in adipose tissue proliferative properties and susceptibility for lipoapoptosis. Caspase-2-deficient mice fed a Western diet were protected from abdominal fat deposition, diabetes mellitus, dyslipidemia and hepatic steatosis. Adipose tissue in caspase-2-deficient mice was more proliferative, upregulated mitochondrial uncoupling proteins consistent with browning, and was resistant to cell hypertrophy and cell death. The liver was protected from steatohepatitis through a decrease in circulating fatty acids and more efficient hepatic fat metabolism, and from fibrosis as a consequence of reduced fibrogenic stimuli from fewer lipotoxic hepatocytes. Caspase-2 deficiency protected mice from diet-induced obesity, metabolic syndrome and nonalcoholic fatty liver disease. Further studies are necessary to assess caspase-2 as a therapeutic target for those conditions. PMID:26890135

  15. Omega-3 fatty acids for the treatment of non-alcoholic fatty liver disease

    PubMed Central

    Di Minno, Matteo Nicola Dario; Russolillo, Anna; Lupoli, Roberta; Ambrosino, Pasquale; Di Minno, Alessandro; Tarantino, Giovanni

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) has been recognized as a major health burden. It is the most important cause of chronic liver disease and a major independent cardiovascular risk factor. Lacking a definite treatment for NAFLD, a specific diet and an increase in physical activity represent the most commonly used therapeutic approaches. In this review, major literature data about the use of omega-3 polyunsaturated fatty acids (n-3 PUFAs) as a potential treatment of NAFLD have been described. n-3 PUFAs, besides having a beneficial impact on most of the cardio-metabolic risk factors (hypertension, hyperlipidemia, endothelial dysfunction and atherosclerosis) by regulating gene transcription factors [i.e., peroxisome proliferator-activated receptor (PPAR) α, PPARγ, sterol regulatory element-binding protein-1, carbohydrate responsive element-binding protein], impacts both lipid metabolism and on insulin sensitivity. In addition to an enhancement of hepatic beta oxidation and a decrease of the endogenous lipid production, n-3 PUFAs are able to determine a significant reduction of the expression of pro-inflammatory molecules (tumor necrosis factor-α and interleukin-6) and of oxygen reactive species. Further strengthening the results of the in vitro studies, both animal models and human intervention trials, showed a beneficial effect of n-3 PUFAs on the severity of NAFLD as expressed by laboratory parameters and imaging measurements. Despite available results provided encouraging data about the efficacy of n-3 PUFAs as a treatment of NAFLD in humans, well-designed randomized controlled trials of adequate size and duration, with histological endpoints, are needed to assess the long-term safety and efficacy of PUFA, as well as other therapies, for the treatment of NAFLD and non-alcoholic steatohepatitis patients. It is worthwhile to consider that n-3 PUFAs cannot be synthesized by the human body and must be derived from exogenous sources (fish oil, flaxseeds, olive

  16. Role of Docosahexaenoic Acid Treatment in Improving Liver Histology in Pediatric Nonalcoholic Fatty Liver Disease

    PubMed Central

    Alisi, Anna; De Vito, Rita; Franchitto, Antonio; Alpini, Gianfranco; Onori, Paolo; Gaudio, Eugenio

    2014-01-01

    Introduction 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. Patients and Methods 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. Results 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. Conclusions 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. PMID

  17. Impact of physical activity on nonalcoholic steatohepatitis in people with nonalcoholic simple fatty liver: A prospective cohort study.

    PubMed

    Tsunoda, Kenji; Kai, Yuko; Kitano, Naruki; Uchida, Ken; Kuchiki, Tsutomu; Nagamatsu, Toshiya

    2016-07-01

    Preventing nonalcoholic simple fatty liver (NASFL) from progressing to nonalcoholic steatohepatitis (NASH) is a key to avoiding cirrhosis. Physical activity (PA) may help manage fatty liver; however, there is a lack of prospective studies showing an association between PA and NASH. Our current prospective study investigated whether PA prevents NASFL from progressing to NASH. Study data were obtained from the health check-up program of Meiji Yasuda Shinjuku Medical Center in Tokyo, Japan. From a baseline survey between 2005 and 2007, 1149 people with NASFL met eligibility criteria including low alcohol consumption. We followed participants until 2014 assessing liver status via ultrasound and liver enzyme levels, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). We classified participants with fatty liver and higher levels of either ALT or AST as having NASH. Through a self-reported questionnaire, we classified PA into three intensities: moderate low-intensity PA (MLPA, 3-5 METs), moderate high-intensity PA (MHPA, 5-7 METs), and vigorous-intensity PA (VPA, ≥7 METs). During a mean follow-up of 4.2years (4804person-years), 318 of the 1149 participants (27.7%) progressed from NASFL to NASH. A multivariate-adjusted Cox model showed a significant preventive effect of VPA on progression to NASH (HR=0.55, 95% CI=0.32-0.94) and no significant associations between MLPA (HR=1.01, 95% CI=0.79-1.30) or MHPA (HR=0.97, 95% CI=0.66-1.42) and progression to NASH. Only VPA prevented NASFL from progressing to NASH; MLPA and MHPA had no preventive effect on NASH. Higher intensity PA may be needed to manage NASH. PMID:27143495

  18. Naturally Occurring Stilbenoid TSG Reverses Non-Alcoholic Fatty Liver Diseases via Gut-Liver Axis.

    PubMed

    Lin, Pei; Lu, Jianmei; Wang, Yanfang; Gu, Wen; Yu, Jie; Zhao, Ronghua

    2015-01-01

    The gut-liver axis is largely involved in the development of non-alcoholic fatty liver disease (NAFLD). We investigated whether 2, 3, 5, 4'-tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) could reverse NAFLD induced by a high-fat diet (HFD) and whether it did so via the gut-liver axis. Results showed that TSG could reduce the accumulation of FFA and it did so by reducing the expression of L-FABP and FATP4. TSG regulated gut microbiota balanced and increased the protein expression of ZO-1 and occludin, which could improve the function of the intestinal mucosal barrier and reduce serum LPS content by about 25%. TSG reduced TL4 levels by 56% and NF-κB expression by 23% relative to the NAFLD model group. This suggests that prevention of NAFLD by TSG in HFD-fed rats is mediated by modulation of the gut microbiota and TLR4/NF-κB pathway, which may alleviate chronic low-grade inflammation by reducing the exogenous antigen load on the host. PMID:26474417

  19. Naturally Occurring Stilbenoid TSG Reverses Non-Alcoholic Fatty Liver Diseases via Gut-Liver Axis

    PubMed Central

    Lin, Pei; Lu, Jianmei; Wang, Yanfang; Gu, Wen; Yu, Jie; Zhao, Ronghua

    2015-01-01

    The gut-liver axis is largely involved in the development of non-alcoholic fatty liver disease (NAFLD). We investigated whether 2, 3, 5, 4′-tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) could reverse NAFLD induced by a high-fat diet (HFD) and whether it did so via the gut-liver axis. Results showed that TSG could reduce the accumulation of FFA and it did so by reducing the expression of L-FABP and FATP4. TSG regulated gut microbiota balanced and increased the protein expression of ZO-1 and occludin, which could improve the function of the intestinal mucosal barrier and reduce serum LPS content by about 25%. TSG reduced TL4 levels by 56% and NF-κB expression by 23% relative to the NAFLD model group. This suggests that prevention of NAFLD by TSG in HFD-fed rats is mediated by modulation of the gut microbiota and TLR4/NF-κB pathway, which may alleviate chronic low-grade inflammation by reducing the exogenous antigen load on the host. PMID:26474417

  20. Non-Alcoholic Fatty Liver Disease in Children: Focus on Nutritional Interventions

    PubMed Central

    Yang, Min; Gong, Sitang; Ye, Shui Qing; Lyman, Beth; Geng, Lanlan; Chen, Peiyu; Li, Ding-You

    2014-01-01

    With increasing prevalence of childhood obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of NAFLD. Recently, there has been a growing body of evidence to implicate altered gut microbiota in the development of NAFLD through the gut-liver axis. The first line of prevention and treatment of NAFLD in children should be intensive lifestyle interventions such as changes in diet and physical activity. Recent advances have been focused on limitation of dietary fructose and supplementation of antioxidants, omega-3 fatty acids, and prebiotics/probiotics. Convincing evidences from both animal models and human studies have shown that reduction of dietary fructose and supplement of vitamin E, omega-3 fatty acids, and prebiotics/probiotics improve NAFLD. PMID:25353664

  1. Non-alcoholic fatty liver disease in children: focus on nutritional interventions.

    PubMed

    Yang, Min; Gong, Sitang; Ye, Shui Qing; Lyman, Beth; Geng, Lanlan; Chen, Peiyu; Li, Ding-You

    2014-11-01

    With increasing prevalence of childhood obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of NAFLD. Recently, there has been a growing body of evidence to implicate altered gut microbiota in the development of NAFLD through the gut-liver axis. The first line of prevention and treatment of NAFLD in children should be intensive lifestyle interventions such as changes in diet and physical activity. Recent advances have been focused on limitation of dietary fructose and supplementation of antioxidants, omega-3 fatty acids, and prebiotics/probiotics. Convincing evidences from both animal models and human studies have shown that reduction of dietary fructose and supplement of vitamin E, omega-3 fatty acids, and prebiotics/probiotics improve NAFLD. PMID:25353664

  2. Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management.

    PubMed

    Ravi Kanth, Vishnubhotla Venkata; Sasikala, Mitnala; Sharma, Mithun; Rao, Padaki Nagaraja; Reddy, Duvvuru Nageshwar

    2016-07-18

    Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day (diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease (NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individual's genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD. PMID:27458502

  3. Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management

    PubMed Central

    Ravi Kanth, Vishnubhotla Venkata; Sasikala, Mitnala; Sharma, Mithun; Rao, Padaki Nagaraja; Reddy, Duvvuru Nageshwar

    2016-01-01

    Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day (diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease (NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individual’s genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD. PMID:27458502

  4. The Progression and Natural History of Pediatric Nonalcoholic Fatty Liver Disease.

    PubMed

    Goyal, Nidhi P; Schwimmer, Jeffrey B

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States. Childhood NAFLD is associated with hepatic and nonhepatic morbidity and mortality. Nonhepatic associations include cardiovascular, metabolic, pulmonary, and psychological disorders. Cardiovascular conditions observed in childhood include left ventricular dysfunction. Furthermore, childhood obesity is associated with greater odds of having hepatocellular carcinoma as an adult. Evidence suggests that NAFLD may begin in utero in children of diabetic mothers. Thus rigorous efforts for structured diagnosis and follow-up are a priority to better develop the understanding of outcomes in pediatric NAFLD. PMID:27063272

  5. Effect of Weight Loss, Diet, Exercise, and Bariatric Surgery on Nonalcoholic Fatty Liver Disease.

    PubMed

    Hannah, William N; Harrison, Stephen A

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD is the most common liver disease in developed countries. Weight reduction of 3% to 5% is associated with improved steatosis; reductions of 5% to 7% are necessary for decreased inflammation; with 7% to 10%, individuals may experience NAFLD/NASH remission and regression of fibrosis. No specific dietary intervention has proven beneficial beyond calorie restriction. Physical activity without weight loss seems to decrease hepatic steatosis. Bariatric surgery is associated with decreased cardiovascular risk and improved overall mortality in addition to reduction in hepatic steatosis, inflammation, and fibrosis. PMID:27063273

  6. 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

  7. SIRT3 as a Regulator of Non-alcoholic Fatty Liver Disease.

    PubMed

    Cho, Eun-Hee

    2014-09-01

    Non-alcoholic fatty liver disease (NAFLD) is a hepatic presentation of obesity and metabolic syndrome. NAFLD includes a large spectrum of hepatic pathologies that range from simple steatosis and non-alcoholic steatohepatitis (NASH), to liver cirrhosis without an all-encompassing approved therapeutic strategy. Mitochondrial dysfunction is a key component of many metabolic diseases, such as obesity, type 2 diabetes, cancer, NAFLD, and aging. Sirtuin 3 (SIRT3) is a NAD(+)-dependent deacetylase that regulates many of the mitochondrial proteins that are involved with metabolic homeostasis, oxidative stress, and cell survival. This review discusses the association between mitochondrial dysfunction and insulin resistance and later explore the possibility that SIRT3 plays a protective role against NAFLD by improving mitochondrial dysfunction. PMID:26064858

  8. 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

  9. 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

    2015-10-01

    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

  10. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease.

    PubMed

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

    2014-12-01

    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

  11. 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

  12. Gut microbiota and non-alcoholic fatty liver disease: new insights.

    PubMed

    Aron-Wisnewsky, J; Gaborit, B; Dutour, A; Clement, K

    2013-04-01

    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. A 'two-hit' mechanism has been proposed; however, the complete physiopathogenesis remains incompletely understood. 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. PMID:23452163

  13. SIRT3 as a Regulator of Non-alcoholic Fatty Liver Disease

    PubMed Central

    Cho, Eun-Hee

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a hepatic presentation of obesity and metabolic syndrome. NAFLD includes a large spectrum of hepatic pathologies that range from simple steatosis and non-alcoholic steatohepatitis (NASH), to liver cirrhosis without an all-encompassing approved therapeutic strategy. Mitochondrial dysfunction is a key component of many metabolic diseases, such as obesity, type 2 diabetes, cancer, NAFLD, and aging. Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase that regulates many of the mitochondrial proteins that are involved with metabolic homeostasis, oxidative stress, and cell survival. This review discusses the association between mitochondrial dysfunction and insulin resistance and later explore the possibility that SIRT3 plays a protective role against NAFLD by improving mitochondrial dysfunction. PMID:26064858

  14. [Genomic, proteomic and metabolomic predictors of nonalcoholic fatty liver disease development in obese patients. Part I].

    PubMed

    Chernyak, O O; Sentsova, T B; Vorozhko, I V; Tutelyan, V A; Gapparova, K M; Isakov, V A

    2015-01-01

    The prevention, diagnosis and treatment of diseases associated to obesity require a qualitative increase of efficiency. There are still disputable questions about diagnostic significance of some molecules, including genomic, proteomic and metabolomic biomarkers. We observed 72 obese patients (20 men and 52 women, mean age--41.3 +/- 2.5) and performed ultrasound elastography and ultrasound of liver. We have identified two groups of patients: Group 1 consisted of 50 obese patients without complications (BMI 43.2 +/- 0.6), group 2 consisted of 22 patients with obesity complicated with nonalcoholic fatty liver disease (BMI 45.8 +/- 2.3). Determination of the adipokines (adiponectin, ghrelin, resistin, visfatin, and apelin), cytokine (interleukin--6, TNFalpha) oxidized lipoproteins (oxLDL), adhesion molecule sICAM (soluble intercellular cell adhesion molecule), fatty acid transporter L-FABP in serum was performed by ELISA. The study of the lipid metabolism involved determination of the concentration of total cholesterols, triglycerides, low and high density lipoproteins (LDL and HDL) by turbidimetry and spectrophotometry by analyzer. In addition, we conducted analysis of polymorphic alleles epsilon2, epsilon3, episolon4 of ApoE gene using polymerase chain reaction. Our data indicate that reducing the concentration of adiponectin (0.46-1.71 mcg/ml), increasing the level of glucose (5.57-6.25 mmol/l), triglycerides (2.06-3.94 mmol/l), TNFalpha (5.07-16.68 pg/ml) and L-FABP (11.62-23.76 pg/ml) are predictors of nonalcoholic fatty liver disease in obese patients, and the presence of genotype epsilon3/epsilon4 of ApoE gene is a poor prognostic marker of severity of nonalcoholic fatty liver disease. PMID:26852528

  15. Knowing What’s Out There: Awareness of Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Ghevariya, Vishal; Sandar, Nan; Patel, Kishor; Ghevariya, Nehal; Shah, Ruchit; Aron, Joshua; Anand, Sury

    2014-01-01

    Background: Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder, which poses a significant health burden in the western countries. As the epidemic of obesity slides health downward, the incidence of NAFLD is evidently increasing. Aim: We aimed to ascertain the awareness of NAFLD and its risk factors in the general population, which may be helpful in designing educational tools to promote prevention, early detection, and treatment of this disorder. Methods: A survey of 5000 non-institutionalized residents of Brooklyn, NY, USA was conducted. Sixteen items were included in the survey questionnaire including awareness of fatty liver, predisposing factors of NAFLD, awareness of cirrhosis, and conditions that advance to cirrhosis. The questionnaire also addressed awareness of prevention, diagnostic methods and treatment of NAFLD, and education of physicians to their patients about NAFLD. Results: Overwhelming majority of the subjects was not aware of NAFLD and stated that their physicians did not have a discussion about NAFLD. Conclusion: Non-alcoholic fatty liver disease is a preventable liver disorder with limited treatment options. Thorough counseling by primary care physicians can be of paramount importance in preventive strategy for NAFLD. We should target our teenage population in an era of obesity epidemics of all times. PMID:25798442

  16. 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

  17. 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

  18. Interobserver Agreement on Pathologic Features of Liver Biopsy Tissue in Patients with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Jung, Eun Sun; Lee, Kyoungbun; Yu, Eunsil; Kang, Yun Kyung; Cho, Mee-Yon; Kim, Joon Mee; Moon, Woo Sung; Jeong, Jin Sook; Park, Cheol Keun; Park, Jae-Bok; Kang, Dae Young; Sohn, Jin Hee; Jin, So-Young

    2016-01-01

    Background: The histomorphologic criteria for the pathological features of liver tissue from patients with non-alcoholic fatty liver disease (NAFLD) remain subjective, causing confusion among pathologists and clinicians. In this report, we studied interobserver agreement of NAFLD pathologic features and analyzed causes of disagreement. Methods: Thirty-one cases of clinicopathologically diagnosed NAFLD from 10 hospitals were selected. One hematoxylin and eosin and one Masson’s trichrome-stained virtual slide from each case were blindly reviewed with regard to 12 histological parameters by 13 pathologists in a gastrointestinal study group of the Korean Society of Pathologists. After the first review, we analyzed the causes of disagreement and defined detailed morphological criteria. The glass slides from each case were reviewed a second time after a consensus meeting. The degree of interobserver agreement was determined by multi-rater kappa statistics. Results: Kappa values of the first review ranged from 0.0091–0.7618. Acidophilic bodies (k = 0.7618) and portal inflammation (k = 0.5914) showed high levels of agreement, whereas microgranuloma (k = 0.0984) and microvesicular fatty change (k = 0.0091) showed low levels of agreement. After the second review, the kappa values of the four major pathological features increased from 0.3830 to 0.5638 for steatosis grade, from 0.1398 to 0.2815 for lobular inflammation, from 0.1923 to 0.3362 for ballooning degeneration, and from 0.3303 to 0.4664 for fibrosis. Conclusions: More detailed histomorphological criteria must be defined for correct diagnosis and high interobserver agreement of NAFLD. PMID:27086596

  19. Pediatric non-alcoholic fatty liver disease: New insights and future directions

    PubMed Central

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

    2014-01-01

    One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease (NAFLD), which is the most common form of liver disease in children. NAFLD is defined by hepatic fat infiltration > 5% hepatocytes, as assessed by liver biopsy, in the absence of excessive alcohol intake, viral, autoimmune and drug-induced liver disease. It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis, which, in turn, can evolve into cirrhosis and end stage liver disease. Obesity and insulin resistance are the main risk factors for pediatric NAFLD. In fact, NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome, prediabetes and type 2 diabetes mellitus (T2D). In particular, it has been clearly shown in obese youth that the prevalence of metabolic syndrome, pre-diabetes and type 2 diabetes increases with NAFLD severity progression. Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition. Recently, a non-synonymous SNP (rs738409), characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene (PNPLA3), has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children. Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein. The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes, is aimed at acting upon specific targets involved in the pathogenesis. There are some therapeutic approaches that are being studied in children. This article reviews the current knowledge regarding

  20. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis[S

    PubMed Central

    Feldstein, Ariel E.; Lopez, Rocio; Tamimi, Tarek Abu-Rajab; Yerian, Lisa; Chung, Yoon-Mi; Berk, Michael; Zhang, Renliang; McIntyre, Thomas M.; Hazen, Stanley L.

    2010-01-01

    Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). However, the pathways that contribute to oxidative damage in vivo are poorly understood. Our aims were to define the circulating profile of lipid oxidation products in NAFLD patients, the source of these products, and assess whether their circulating levels reflect histological changes in the liver. The levels of multiple structurally specific oxidized fatty acids, including individual hydroxy-eicosatetraenoic acids (HETE), hydroxy-octadecadenoic acids (HODE), and oxo-octadecadenoic acids (oxoODE), were measured by mass spectrometry in plasma at time of liver biopsy in an initial cohort of 73 and a validation cohort of 49 consecutive patients. Of the markers monitored, 9- and 13-HODEs and 9- and 13-oxoODEs, products of free radical-mediated oxidation of linoleic acid (LA), were significantly elevated in patients with nonalcoholic steatohepatitis (NASH), compared with patients with steatosis. A strong correlation was revealed between these oxidation products and liver histopathology (inflammation, fibrosis, and steatosis). Further analyses of HODEs showed equivalent R and S chiral distribution. A risk score for NASH (oxNASH) was developed in the initial clinical cohort and shown to have high diagnostic accuracy for NASH versus steatosis in the independent validation cohort. Subjects with elevated oxNASH levels (top tertile) were 9.7-fold (P < 0.0001) more likely to have NASH than those with low levels (bottom tertile). Collectively, these findings support a key role for free radical-mediated linoleic acid oxidation in human NASH and define a risk score, oxNASH, for noninvasive detection of the presence of NASH. PMID:20631297

  1. Oxysterols induce mitochondrial impairment and hepatocellular toxicity in non-alcoholic fatty liver disease.

    PubMed

    Bellanti, Francesco; Mitarotonda, Domenica; Tamborra, Rosanna; Blonda, Maria; Iannelli, Giuseppina; Petrella, Antonio; Sanginario, Vittorio; Iuliano, Luigi; Vendemiale, Gianluigi; Serviddio, Gaetano

    2014-10-01

    Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic disorder affecting up to 25% of the general population. Several intracellular events leading to NAFLD and progression to non-alcoholic steatohepatitis (NASH) have been identified, including lipid accumulation, mitochondrial dysfunction and oxidative stress. Emerging evidence links both hepatic free fatty acids (FFAs) and cholesterol (FC) accumulation in NAFLD development; in particular oxysterols, the oxidative products of cholesterol, may contribute to liver injury. We performed a targeted lipidomic analysis of oxysterols in the liver of male Wistar rats fed a high-fat (HF), high-cholesterol (HC) or high-fat/high-cholesterol (HF/HC) diet. Both HF and HC diets caused liver steatosis, but the HF/HC diet resulted in steatohepatitis with associated mitochondrial dysfunction. Above all, the oxysterol cholestane-3beta,5alpha,6beta-triol (triol) was particularly increased in the liver of rats fed diets rich in cholesterol. To verify the molecular mechanism involved in mitochondrial dysfunction and hepatocellular toxicity, Huh7 and primary rat hepatocytes were exposed to palmitic acid (PA) and/or oleic acid (OA), with or without triol. This compound induced apoptosis in cells co-exposed to both PA and OA, and this was associated with impaired mitochondrial respiration as well as down-regulation of PGC1-alpha, mTFA and NRF1.In conclusion, our data show that hepatic free fatty acid or oxysterols accumulation per se induce low hepatocellular toxicity. On the contrary, hepatic accumulation of both fatty acids and toxic oxysterols such as triol are determinant in the impairment of mitochondrial function and biogenesis, contributing to liver pathology in NAFLD. PMID:26461297

  2. Micro RNAs in the development of non-alcoholic fatty liver disease

    PubMed Central

    Gerhard, Glenn S; DiStefano, Johanna K

    2015-01-01

    Nonalcoholic fatty liver disease or nonalcoholic fatty liver disease (NAFLD) refers to a group of disorders that arise from the accrual of fat in hepatocytes. Although various factors have been associated with the development of NAFLD, including genetic predisposition and environmental exposures, little is known about the underlying pathogenesis of the disease. Research efforts are ongoing to identify biological targets and signaling pathways that mediate NAFLD. Emerging evidence has implicated a role for micro RNAs (miRNAs), short single-stranded molecules that regulate gene expression either transcriptionally, through targeting of promoter regions, or post-transcriptionally, by blocking translation or promoting cleavage of specific target mRNAs. Several miRNAs have been associated with NAFLD, although our understanding of the biology underlying their role is still emerging. The goal of this review is to present an overview of the current state of knowledge of miRNAs involved in the development of NAFLD across a range of in vitro and in vivo models, including miRNAs that contribute to pathological mechanisms related to fatty liver in humans. Much less is known about the specific targets of miRNAs in cells, nor the molecular mechanisms involved in the development and progression NAFLD and related outcomes. More recently, the identification and validation of miRNA signatures in serum may facilitate the development of improved methods for diagnosis and clinical monitoring of disease progression. PMID:25729477

  3. Incretin based therapies: A novel treatment approach for non-alcoholic fatty liver disease

    PubMed Central

    Blaslov, Kristina; Bulum, Tomislav; Zibar, Karin; Duvnjak, Lea

    2014-01-01

    Non-alcoholic fatty liver disease is considered a hepatic manifestation of metabolic syndrome (MS). The current treatment of non-alcoholic fatty liver disease (NAFLD) principally includes amelioration of MS components by lifestyle modifications but the lack of success in their implementation and sustainment arises the need for effective pharmacological agent in fatty liver treatment. Incretins are gut derived hormones secreted into the circulation in response to nutrient ingestion that enhances glucose-stimulated insulin secretion. Glucagon-like peptide-1 (GLP-1) is the most important incretin. Its receptor agonist and inhibitors of dipeptidyl peptidase-4 (DPP-4) are used in treatment of type 2 diabetes mellitus. DPP-4 serum activity and hepatic expression are shown to be elevated in several hepatic diseases. There are several experimental and clinical trials exploring the efficacy of incretin based therapies in NAFLD treatment. They suggest that GLP-1 analogues might have beneficial effect on hepatic steatosis acting as insulin sensitizers and directly by stimulating GLP-1 receptors expressed on hepatocytes. The use of DPP-4 inhibitors also results in hepatic fat reduction but the mechanism of action remains unclear. There is growing evidence that incretin based therapies have beneficial effects on hepatocytes, however further study analysis are needed to assess the long term effect of incretin based therapies on NAFLD. PMID:24966606

  4. Experimental models of non-alcoholic fatty liver disease in rats

    PubMed Central

    Kucera, Otto; Cervinkova, Zuzana

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and it persists at a high prevalence. NAFLD is characterised by the accumulation of triglycerides in the liver and includes a spectrum of histopathological findings, ranging from simple fatty liver through non-alcoholic steatohepatitis (NASH) to fibrosis and ultimately cirrhosis, which may progress to hepatocellular carcinoma. The pathogenesis of NAFLD is closely related to the metabolic syndrome and insulin resistance. Understanding the pathophysiology and treatment of NAFLD in humans has currently been limited by the lack of satisfactory animal models. The ideal animal model for NAFLD should reflect all aspects of the intricate etiopathogenesis of human NAFLD and the typical histological findings of its different stages. Within the past several years, great emphasis has been placed on the development of an appropriate model for human NASH. This paper reviews the widely used experimental models of NAFLD in rats. We discuss nutritional, genetic and combined models of NAFLD and their pros and cons. The choice of a suitable animal model for this disease while respecting its limitations may help to improve the understanding of its complex pathogenesis and to discover appropriate therapeutic strategies. Considering the legislative, ethical, economical and health factors of NAFLD, animal models are essential tools for the research of this disease. PMID:25024595

  5. Non-alcoholic fatty liver disease in HIV infection associated with altered hepatic fatty acid composition.

    PubMed

    Arendt, Bianca M; Mohammed, Saira S; Ma, David W L; Aghdassi, Elaheh; Salit, Irving E; Wong, David K H; Guindi, Maha; Sherman, Morris; Heathcote, E Jenny; Allard, Johane P

    2011-03-01

    Hepatic fatty acid (FA) composition, especially a reduction in n-3 polyunsaturated FA (PUFA) may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which is common in HIV-infection.. In a cross-sectional study we compared hepatic FA composition between 20 HIV-infected men with NAFLD (HIV/NAFLD), 21 HIV-negative men with NAFLD (NAFLD), and 7 healthy controls. Within HIV/NAFLD we compared simple steatosis (HIV/SS) to steatohepatitis (HIV/NASH). FA composition in liver and erythrocytes, oxidative stress, diet, and exercise were assessed. Major findings (P<0.05) were: 1) higher hepatic n-6/n-3 ratio in HIV/NAFLD [median (range)] [8.08 (1.08-21.52)] compared to controls [5.83 (3.58-6.93)] and NAFLD [5.97 (1.46-10.40)], with higher n-6 PUFA in HIV/NAFLD compared to NAFLD; 2) lower n-3 PUFA in erythrocytes (mol%), a marker for dietary intake, in HIV/NAFLD [5.26 (1.04-11.75)] compared to controls [8.92 (4.79-12.67)]; 3) the ratios of long-chain PUFA products to essential FA precursors of the n-6 and n-3 series were lower in HIV/NAFLD and NAFLD compared to controls. In contrast, the ratio of oleic/stearic acid was higher in HIV/NAFLD compared to the other groups. These ratios are indirect markers of enzymatic FA desaturation and elongation. Hepatic PUFA, especially biologically active long-chain PUFA, were also lower in HIV/NASH compared to HIV/SS. Oxidative stress was not different among the groups. We conclude that HIV/NAFLD is associated with altered hepatic FA composition. Changes may be due to impaired FA metabolism or suboptimal n-3 PUFA intake. The potential role of n-3 PUFA (e.g. fish oil) to treat or prevent HIV/NAFLD warrants further investigation. PMID:21434863

  6. Noninvasive Assessment of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Buzzetti, Elena; Lombardi, Rosa; De Luca, Laura; Tsochatzis, Emmanuel A.

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is prevalent in 20–25% of the general population and is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. Histologically, NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. As NASH develops in only 10–15% of patients with NAFLD, it is not practical to biopsy all patients who present with NAFLD. Noninvasive fibrosis tests have been extensively developed recently and offer alternatives for staging fibrosis. Despite their increasing use, such tests cannot adequately differentiate simple steatosis from NASH. At present, such tests can be used as first line tests to rule out patients without advanced fibrosis and thus prevent unnecessary secondary care referrals in a significant number of patients. In this review we present the evidence for the use of noninvasive fibrosis tests in patients with NAFLD. PMID:26064107

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

    PubMed

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

    2015-12-01

    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 was 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

  8. Gut Microbiota and Nonalcoholic Fatty Liver Disease: Insights on Mechanism and Application of Metabolomics

    PubMed Central

    He, Xuyun; Ji, Guang; Jia, Wei; Li, Houkai

    2016-01-01

    Gut microbiota are intricately involved in the development of obesity-related metabolic diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, and insulin resistance. In the current review, we discuss the role of gut microbiota in the development of NAFLD by focusing on the mechanisms of gut microbiota-mediated host energy metabolism, insulin resistance, regulation of bile acids and choline metabolism, as well as gut microbiota-targeted therapy. We also discuss the application of a metabolomic approach to characterize gut microbial metabotypes in NAFLD. PMID:26999104

  9. Influence of gut bacteria on development and progression of non-alcoholic fatty liver disease

    PubMed Central

    Abdul-Hai, Ali; Abdallah, Ali; Malnick, Stephen DH

    2015-01-01

    The intestine of the human contains a dynamic population of microbes that have a symbiotic relationship with the host. In addition, there is an effect of the intestinal microbiota on metabolism and digestion. Non-alcoholic fatty liver disease (NAFLD) is a common cause worldwide of hepatic pathology and is thought to be the hepatic manifestation of the metabolic syndrome. In this review we examine the effect of the human microbiome on the components and pathogenesis of the metabolic syndrome. We are now on the threshold of therapeutic interventions on the human microbiome in order to effect human disease including NAFLD. PMID:26140087

  10. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?

    PubMed

    Bhatia, Lokpal S; Curzen, Nicholas P; Calder, Philip C; Byrne, Christopher D

    2012-05-01

    Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population worldwide and may confer increased cardiometabolic risk with consequent adverse cardiovascular outcomes independent of traditional cardiovascular risk factors and the metabolic syndrome. It is characterized almost universally by insulin resistance and is strongly associated with type 2 diabetes and obesity. Non-alcoholic fatty liver disease is a marker of pathological ectopic fat accumulation combined with a low-grade chronic inflammatory state. This results in several deleterious pathophysiological processes including abnormal glucose, fatty acid and lipoprotein metabolism, increased oxidative stress, deranged adipokine profile, hypercoaguability, endothelial dysfunction, and accelerated progression of atherosclerosis. This ultimately leads to a dysfunctional cardiometabolic phenotype with cardiovascular mortality representing the main mode of premature death in NAFLD. This review is aimed at introducing NAFLD to the clinical cardiologist by discussing in-depth the evidence to date linking NAFLD with cardiovascular disease, reviewing the likely mechanisms underlying this association, as well as summarizing from a cardiologist's perspective, current and potential future treatment options for this increasingly prevalent disease. PMID:22408036

  11. Ameliorative potential of Tamarindus indica on high fat diet induced nonalcoholic fatty liver disease in rats.

    PubMed

    Sasidharan, Suja Rani; Joseph, Joshua Allan; Anandakumar, Senthilkumar; Venkatesan, Vijayabalaji; Madhavan, Chandrasekharan Nair Ariyattu; Agarwal, Amit

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD), the prevalence of which is rising globally with current upsurge in obesity, is one of the most frequent causes of chronic liver diseases. The present study evaluated the ameliorative effect of extract of Tamarindus indica seed coat (ETS) on high fat diet (HFD) induced NAFLD, after daily administration at 45, 90, and 180 mg/kg body weight dose levels for a period of 6 weeks, in albino Wistar rats. Treatment with ETS at all tested dose levels significantly attenuated the pathological alterations associated with HFD induced NAFLD viz. hepatomegaly, elevated hepatic lipid and lipid peroxides, serum alanine aminotransferase, and free fatty acid levels as well as micro-/macrohepatic steatosis. Moreover, extract treatment markedly reduced body weight and adiposity along with an improvement in insulin resistance index. The study findings, therefore suggested the therapeutic potential of ETS against NAFLD, acting in part through antiobesity, insulin sensitizing, and antioxidant mechanisms. PMID:24688399

  12. [Non-alcoholic fatty liver disease in obese children and adolescents].

    PubMed

    Denzer, C

    2013-04-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and adolescents in industrialized countries. Recent studies have demonstrated a prevalence rate of NAFLD in overweight and obese children and adolescents in Germany of up to 30%. The spectrum of NAFLD ranges from pure fatty infiltration (simple steatosis) to inflammation (steatohepatitis, synonymous NASH) to fibrosis and cirrhosis. Age, gender, ethnicity, insulin resistance, and sex steroids are implicated in the pathogenesis of NAFLD in childhood and adolescence. Moreover, NAFLD in the pediatric age group is associated with marked cardiovascular comorbidities. This review focuses on current data regarding epidemiology, pathophysiology, comorbidities, and treatment of NAFLD in children and adolescents. PMID:23529597

  13. Ameliorative Potential of Tamarindus indica on High Fat Diet Induced Nonalcoholic Fatty Liver Disease in Rats

    PubMed Central

    Sasidharan, Suja Rani; Anandakumar, Senthilkumar; Venkatesan, Vijayabalaji; Ariyattu Madhavan, Chandrasekharan Nair; Agarwal, Amit

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD), the prevalence of which is rising globally with current upsurge in obesity, is one of the most frequent causes of chronic liver diseases. The present study evaluated the ameliorative effect of extract of Tamarindus indica seed coat (ETS) on high fat diet (HFD) induced NAFLD, after daily administration at 45, 90, and 180 mg/kg body weight dose levels for a period of 6 weeks, in albino Wistar rats. Treatment with ETS at all tested dose levels significantly attenuated the pathological alterations associated with HFD induced NAFLD viz. hepatomegaly, elevated hepatic lipid and lipid peroxides, serum alanine aminotransferase, and free fatty acid levels as well as micro-/macrohepatic steatosis. Moreover, extract treatment markedly reduced body weight and adiposity along with an improvement in insulin resistance index. The study findings, therefore suggested the therapeutic potential of ETS against NAFLD, acting in part through antiobesity, insulin sensitizing, and antioxidant mechanisms. PMID:24688399

  14. Relevant Aspects of Nutritional and Dietary Interventions in Non-Alcoholic Fatty Liver Disease.

    PubMed

    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

  15. Genetically modified mouse models for the study of nonalcoholic fatty liver disease

    PubMed Central

    Nagarajan, Perumal; Mahesh Kumar, M Jerald; Venkatesan, Ramasamy; Majundar, Subeer S; Juyal, Ramesh C

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and type 2 diabetes. NAFLD represents a large spectrum of diseases ranging from (1) fatty liver (hepatic steatosis); (2) steatosis with inflammation and necrosis; to (3) cirrhosis. The animal models to study NAFLD/nonalcoholic steatohepatitis (NASH) are extremely useful, as there are still many events to be elucidated in the pathology of NASH. The study of the established animal models has provided many clues in the pathogenesis of steatosis and steatohepatitis, but these remain incompletely understood. The different mouse models can be classified in two large groups. The first one includes genetically modified (transgenic or knockout) mice that spontaneously develop liver disease, and the second one includes mice that acquire the disease after dietary or pharmacological manipulation. Although the molecular mechanism leading to the development of hepatic steatosis in the pathogenesis of NAFLD is complex, genetically modified animal models may be a key for the treatment of NAFLD. Ideal animal models for NASH should closely resemble the pathological characteristics observed in humans. To date, no single animal model has encompassed the full spectrum of human disease progression, but they can imitate particular characteristics of human disease. Therefore, it is important that the researchers choose the appropriate animal model. This review discusses various genetically modified animal models developed and used in research on NAFLD. PMID:22468076

  16. 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

  17. Non-invasive methods for the diagnosis of nonalcoholic fatty liver disease

    PubMed Central

    Papagianni, Marianthi; Sofogianni, Areti; Tziomalos, Konstantinos

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and includes simple steatosis and nonalcoholic steatohepatitis (NASH). Since NASH progresses to cirrhosis more frequently and increases liver-related and cardiovascular disease risk substantially more than simple steatosis, there is a great need to differentiate the two entities. Liver biopsy is the gold standard for the diagnosis of NAFLD but its disadvantages, including the risk of complications and sampling bias, stress the need for developing alternative diagnostic methods. Accordingly, several non-invasive markers have been evaluated for the diagnosis of simple steatosis and NASH, including both serological indices and imaging methods. The present review summarizes the current knowledge on the role of these markers in the diagnosis of NAFLD. Current data suggest that ultrasound and the fibrosis-4 score are probably the most appealing methods for detecting steatosis and for distinguishing NASH from simple steatosis, respectively, because of their low cost and relatively high accuracy. However, currently available methods, both serologic and imaging, cannot obviate the need for liver biopsy for diagnosing NASH due to their substantial false positive and false negative rates. Therefore, the current role of these methods is probably limited in patients who are unwilling or have contraindications for undergoing biopsy. PMID:25866601

  18. Hedgehog Pathway Activation Parallels Histologic Severity of Injury and Fibrosis in Human Nonalcoholic Fatty Liver Disease

    PubMed Central

    Guy, Cynthia D.; Suzuki, Ayako; Zdanowicz, Marzena; Abdelmalek, Manal F.; Burchette, James; Unalp, Aynur; Diehl, Anna Mae

    2012-01-01

    The Hedgehog (Hh) signaling pathway mediates several processes that are deregulated in patients with the metabolic syndrome (e.g., fat mass regulation, vascular/endothelial remodeling, liver injury and repair, and carcinogenesis). The severity of nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome generally correlate. Therefore, we hypothesized that the level of Hh pathway activation would increase in parallel with the severity of liver damage in NAFLD. To assess potential correlations between known histologic and clinical predictors of advanced liver disease and Hh pathway activation, immunohistochemistry was performed on liver biopsies from a large well-characterized cohort of NAFLD patients (n=90) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Database 1 study. Increased Hh activity (evidenced by accumulation of Hh-ligand producing cells and Hh-responsive target cells) strongly correlated with portal inflammation, ballooning, and fibrosis stage (each p<0.0001), supporting a relationship between Hh pathway activation and liver damage. Pathway activity also correlated significantly with markers of liver repair, including numbers of hepatic progenitors and myofibroblastic cells (both p<0.03). In addition, various clinical parameters that have been linked to histologically-advanced NAFLD, including increased patient age (p<0.005), BMI (p<0.002), waist circumference (p<0.0007), homeostatic model assessment of insulin resistance (HOMA-IR) (p<0.0001) and hypertension (p<0.02), correlated with hepatic Hh activity. Conclusion: In NAFLD patients, the level of hepatic Hh pathway activity is highly correlated with the severity of liver damage and with metabolic syndrome parameters that are known to be predictive of advanced liver disease. Hence, deregulation of the Hh signaling network may contribute to the pathogenesis and sequelae of liver damage that develops with the metabolic syndrome. PMID:22213086

  19. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    SciTech Connect

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  20. Surgical treatment of nonalcoholic fatty liver disease in severely obese patients

    PubMed Central

    Vander Naalt, Steven J; Gurria, Juan P; Holterman, AiXuan L

    2014-01-01

    Obesity is a multi-organ system disease with underlying metabolic abnormalities and chronic systemic inflammation. Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of obesity metabolic dysfunction and its associated cardiovascular- and liver-related morbidities and mortality. Our current understanding of NAFLD pathogenesis, disease characteristics, the role of insulin resistance, chronic inflammation, gut–liver and gut–brain crosstalk and the effectiveness of pharmacotherapy is still evolving. Bariatric surgery significantly improves metabolic and NAFLD histology in severely obese patients, although its positive effects on fibrosis are not universal. Bariatric surgery benefits NAFLD through its metabolic effect on insulin resistance, inflammation, and insulinotropic and anorexinogenic gastrointestinal hormones. Further studies are needed to understand the natural course of NAFLD in severely obese patients and the role of weight loss surgery as a primary treatment for NAFLD. PMID:25378958

  1. Non-alcoholic fatty liver disease and risk of cardiovascular disease.

    PubMed

    Lonardo, Amedeo; Sookoian, Silvia; Pirola, Carlos J; Targher, Giovanni

    2016-08-01

    Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liver-related mortality and morbidity. During the past decade, it has also become increasingly evident that NAFLD is a multisystem disease that affects many extra-hepatic organ systems, including the heart and the vascular system. In this updated clinical review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong association of NAFLD with cardiovascular diseases (CVDs) and other functional and structural myocardial abnormalities. We also discuss some recently published data that correlate NAFLD due to specific genetic polymorphisms with the risk of CVDs. Finally, we briefly examine the assessment tools for estimating the global CVD risk in patients with NAFLD as well as the conventional and the more innovative pharmacological approaches for the treatment of CVD risk in this group of patients. PMID:26477269

  2. Non-Alcoholic Fatty Liver Disease and Extra-Hepatic Cancers.

    PubMed

    Sanna, Claudia; Rosso, Chiara; Marietti, Milena; Bugianesi, Elisabetta

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease but the second cause of death among NAFLD patients are attributed to malignancies at both gastrointestinal (liver, colon, esophagus, stomach, and pancreas) and extra-intestinal sites (kidney in men, and breast in women). Obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers. NAFLD has an intertwined relationship with metabolic syndrome and significantly contributes to the risk of hepatocellular carcinoma (HCC), but recent evidence have fuelled concerns that NAFLD may be a new, and added, risk factor for extra-hepatic cancers, particularly in the gastrointestinal tract. In this review we critically appraise key studies on NAFLD-associated extra-hepatic cancers and speculate on how NAFLD may influence carcinogenesis at these sites. PMID:27187365

  3. Non-Alcoholic Fatty Liver Disease and Extra-Hepatic Cancers

    PubMed Central

    Sanna, Claudia; Rosso, Chiara; Marietti, Milena; Bugianesi, Elisabetta

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease but the second cause of death among NAFLD patients are attributed to malignancies at both gastrointestinal (liver, colon, esophagus, stomach, and pancreas) and extra-intestinal sites (kidney in men, and breast in women). Obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers. NAFLD has an intertwined relationship with metabolic syndrome and significantly contributes to the risk of hepatocellular carcinoma (HCC), but recent evidence have fuelled concerns that NAFLD may be a new, and added, risk factor for extra-hepatic cancers, particularly in the gastrointestinal tract. In this review we critically appraise key studies on NAFLD-associated extra-hepatic cancers and speculate on how NAFLD may influence carcinogenesis at these sites. PMID:27187365

  4. Role of Gut Barrier Function in the Pathogenesis of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Dai, Xin; Wang, Bangmao

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease, and its incidence is increasing year by year. Many efforts have been made to investigate the pathogenesis of this disease. Since 1998 when Marshall proposed the conception of “gut-liver axis,” more and more researchers have paid close attention to the role of gut barrier function in the pathogenesis of NAFLD. The four aspects of gut barrier function, including physical, chemical, biological, and immunological barriers, are interrelated closely and related to NAFLD. In this paper, we present a summary of research findings on the relationship between gut barrier dysfunction and the development of NAFLD, aiming at illustrating the role of gut barrier function in the pathogenesis of this disease. PMID:25945084

  5. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease.

    PubMed

    Lake, April D; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D; Lu, Zhenqiang; Lehman-McKeeman, Lois D; Cherrington, Nathan J

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the 'classical' (neutral) and 'alternative' (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. PMID:23391614

  6. Phosphatase and tensin homolog is a differential diagnostic marker between nonalcoholic and alcoholic fatty liver disease

    PubMed Central

    Sanchez-Pareja, Andrea; Clément, Sophie; Peyrou, Marion; Spahr, Laurent; Negro, Francesco; Rubbia-Brandt, Laura; Foti, Michelangelo

    2016-01-01

    AIM: To investigate the protein expression of phosphatase and tensin homolog (PTEN) in human liver biopsies of patients with alcoholic and non-alcoholic liver disease. METHODS: PTEN protein expression was assessed by immunohistochemistry in formalin-fixed, paraffin-embedded liver sections of patients with non-alcoholic fatty liver disease (NAFLD) (n = 44) or alcoholic liver disease (ALD) (n = 25). Liver resections obtained from 3 healthy subjects candidate for partial liver donation served as controls. Histological evaluations were performed by two experienced pathologists, and diagnoses established based on international criteria. The intensity of the PTEN staining in nuclei was compared between steatotic and non-steatotic areas of each liver fragment analyzed. For each liver specimen, the antibody-stained sections were examined and scored blindly by three independent observers, who were unaware of the patients’ clinical history. RESULTS: In healthy individuals, PTEN immunostaining was intense in both the cytoplasm and nuclei of all hepatocytes. However, PTEN was strongly downregulated in both the nucleus and the cytoplasm of hepatocytes from steatotic areas in patients with NAFLD, independently of the disease stage. In contrast, no changes in PTEN protein expression were observed in patients with ALD, regardless of the presence of steatosis or the stage of the disease. The degree of PTEN downregulation in hepatocytes of patients with NAFLD correlated with the percentage of steatosis (r = 0.3061, P = 0.0459) and the BMI (r = 0.4268, P = 0.0043). Hovewer, in patients with ALD, PTEN expression was not correlated with the percentage of steatosis with or without obesity as a confounding factor (P = 0.5574). Finally, PTEN expression level in steatotic areas of ALD patients was significantly different from that seen in steatotic areas of NAFLD patients (P < 0.0001). CONCLUSION: PTEN protein expression is downregulated early in NAFLD, but not in ALD. PTEN

  7. The effect of a silybin-vitamin e-phospholipid complex on nonalcoholic fatty liver disease: a pilot study.

    PubMed

    Loguercio, Carmela; Federico, Alessandro; Trappoliere, Marco; Tuccillo, Concetta; de Sio, Ilario; Di Leva, Agnese; Niosi, Marco; D'Auria, Mauro Valeriano; Capasso, Rita; Del Vecchio Blanco, Camillo

    2007-09-01

    Oxidative stress leads to chronic liver damage. Silybin has been conjugated with vitamin E and phospholipids to improve its antioxidant activity. Eighty-five patients were divided into 2 groups: those affected by nonalcoholic fatty liver disease (group A) and those with HCV-related chronic hepatitis associated with nonalcoholic fatty liver disease (group B), nonresponders to treatment. The treatment consisted of silybin/vitamin E/phospholipids. After treatment, group A showed a significant reduction in ultrasonographic scores for liver steatosis. Liver enzyme levels, hyperinsulinemia, and indexes of liver fibrosis showed an improvement in treated individuals. A significant correlation among indexes of fibrosis, body mass index, insulinemia, plasma levels of transforming growth factor-beta, tumor necrosis factor-alpha, degree of steatosis, and gamma-glutamyl transpeptidase was observed. Our data suggest that silybin conjugated with vitamin E and phospholipids could be used as a complementary approach to the treatment of patients with chronic liver damage. PMID:17410454

  8. 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. PMID:25933096

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

    PubMed Central

    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. PMID:25933096

  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. Epidemiology and natural history of non-alcoholic fatty liver disease.

    PubMed

    Fazel, Yousef; Koenig, Aaron B; Sayiner, Mehmet; Goodman, Zachary D; Younossi, Zobair M

    2016-08-01

    Non-alcoholic steatohepatitis (NASH) is part of the spectrum of non-alcoholic fatty liver disease (NAFLD) that leads to progressive liver disease and presents a growing challenge to public health. Because of the increased prevalence of metabolic syndrome and obesity, NAFLD and NASH have expanded to a substantial extent. In NASH patients, advanced fibrosis is the major predictor of morbidity and liver-related mortality, and an accurate diagnosis of NASH is mandatory. Although there is currently no validated test of serum biomarkers available to diagnose NASH, and histologic evaluation with a liver biopsy remains the gold standard, screening for fibrosis is recommended in patients with suspicion of NASH. Clinical prediction models and serum biomarkers for advanced fibrosis have relatively good negative predictive value and can be useful for screening. Also, transient elastography is increasingly available to estimate fibrosis in NASH. Therefore, due to the lack of a reliable and accepted non-invasive diagnostic modality, screening for NASH in the general population is not currently recommended. Better understanding of the natural history of NASH is needed to evaluate the utility and cost-effectiveness of screening. PMID:26997539

  12. Recent advances in dietary supplementation, in treating non-alcoholic fatty liver disease

    PubMed Central

    Eslamparast, Tannaz; Eghtesad, Sareh; Poustchi, Hossein; Hekmatdoost, Azita

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is currently known as the most common liver problem, characterized by excessive lipid accumulation in hepatocytes, which may progress to other liver diseases such as nonalcoholic steatohepatitis, hepatic tissue fibrosis, liver cirrhosis, and failure or hepatocellular carcinoma. Since NAFLD is positively associated with the development of obesity, insulin resistance, and ultimately type 2 diabetes mellitus, it is often regarded as the hepatic manifestation of the metabolic syndrome. No pharmacologic treatment has yet been proven for this disease. For most patients with presumed or confirmed NAFLD, the only proven strategy is to offer lifestyle advice that can lead to sustained weight loss. Since insulin resistance, oxidative stress, inflammation, and necro-apoptosis are involved in NAFLD pathogenesis, it seems that every potential therapeutic agent should target one or some of these pathologic events. There are many well known anti-oxidants, anti-inflammatory, and insulin sensitizer dietary supplements which have shown beneficial effects on NAFLD improvement in animal and human studies. The purpose of this review is to explore the existing evidences on dietary supplements considered to have hepatoprotective properties, and to present some proposed mechanisms by which they may protect against NAFLD. PMID:25729475

  13. Nonalcoholic fatty liver disease: An overview of current insights in pathogenesis, diagnosis and treatment

    PubMed Central

    Schreuder, Tim CMA; Verwer, Bart J; van Nieuwkerk, Carin MJ; Mulder, Chris JJ

    2008-01-01

    Estimates of people suffering from overweight (one billion) and obesity (300 million) are increasing. The accumulation of triglycerides in the liver, in the absence of excess alcohol intake, has been described in the early sixties. It was not until 1980, however, that Ludwig et al named this condition nonalcoholic steatohepatitis (NASH). Subsequently, nonalcoholic fatty liver disease (NAFLD) has been used as a general name for conditions ranging from simple steatosis through steatohepatitis to end-stage liver disease (cirrhosis). Many studies have demonstrated the significant correlation with obesity and insulin resistance. Other studies have revealed a significant correlation between hepatic steatosis, cardiovascular disease and increased intima-media thickness. WHO estimated that at least two million patients will develop cirrhosis due to hepatic steatosis in the years to come. Longitudinal cohort studies have demonstrated that those patients with cirrhosis have a similar risk to develop hepatocellular carcinoma as those with other causes of cirrhosis. Taken all together, NAFLD has become the third most important indication for liver transplantation. Therefore, training programmes in internal medicine, gastroenterology and hepatology should stress the importance of diagnosing this entity and treat properly those at risk for developing complications of portal hypertension and concomittant cardiovascular disease. This review will focus on the clinical characteristics, pathophysiology, imaging techniques and the readily available therapeutic options. PMID:18442193

  14. Epidemiology and Natural History of Non-alcoholic Fatty Liver Disease

    PubMed Central

    Mishra, Alita; Younossi, Zobair M

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease burden across the world. By definition, although the histopathologic features of NAFLD are identical to that of alcoholic liver disease, its diagnosis requires absence of significant alcohol use and absence of other causes of chronic liver disease. We now know that NAFLD is not simply a disease of the Western world. It is manifested across the world, in varying rates, across gender, across varying ethnicities, and in its association with other host factors. In this review article, the definition of NAFLD, its spectrum, ranging from mild steatosis to hepatocellular injury and inflammation defined as non-alcoholic steatohepatitis (NASH) is discussed. Mild steatosis is generally a stable disease whereas NASH can be progressive. Based on current published literature, current incidence and prevalence of NAFLD and NASH are discussed. It is also accepted that these processes will continue to increase in prevalence with the rise of obesity, type II diabetes, and associated metabolic syndrome. Some of the risk factors have been well-established and are discussed. In addition, this review also presents emerging associations with other risk factors for NAFLD. Natural history of NAFLD is variable depending upon the histologic subtypes and other underlying comorbidities and is discussed in this review as well. PMID:25755422

  15. Hepatoprotective Effect of Herb Formula KIOM2012H against Nonalcoholic Fatty Liver Disease

    PubMed Central

    Park, Hwayong; Hwang, Youn-Hwan; Kim, Dong-Gun; Jeon, Jongwook; Ma, Jin Yeul

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a hepatic ailment with a rapidly increasing incidence due to dietary hypernutrition and subsequent obesity. Fatty liver disease can lead to steatohepatitis, fibrosis, cirrhosis, and even cancer, which is associated with various complications. Discovering effective natural materials and herbs can provide alternative and complementary medical treatments to current chemical pharmaceuticals. To develop an effective natural agent for NAFLD, we formulated a combination of four herb mixtures (KIOM2012H) and observed lipid-lowering efficacy. The inhibitory effects of KIOM2012H on free fatty acid-induced lipid accumulation, triglyceride contents, and gene expressions were analyzed in HepG2 cells. Using high fat diet-fed mice, body weight changes, gross liver appearances, hepatic triglyceride contents, and gene expressions were evaluated. KIOM2012H dose-dependently inhibited lipid accumulation and gene expressions involved in lipogenesis and related regulators. Experimental animals also showed a decrease in body weight changes and lipid-associated physiological parameters. This study shows that KIOM2012H has an alleviating effect on fatty acid and lipid accumulation, and therefore can be applied for development of new therapeutic pharmaceuticals for treatment of NAFLD using natural products and herbs. PMID:25849950

  16. Hepatoprotective effect of herb formula KIOM2012H against nonalcoholic fatty liver disease.

    PubMed

    Park, Hwayong; Hwang, Youn-Hwan; Kim, Dong-Gun; Jeon, Jongwook; Ma, Jin Yeul

    2015-04-01

    Nonalcoholic fatty liver disease (NAFLD) is a hepatic ailment with a rapidly increasing incidence due to dietary hypernutrition and subsequent obesity. Fatty liver disease can lead to steatohepatitis, fibrosis, cirrhosis, and even cancer, which is associated with various complications. Discovering effective natural materials and herbs can provide alternative and complementary medical treatments to current chemical pharmaceuticals. To develop an effective natural agent for NAFLD, we formulated a combination of four herb mixtures (KIOM2012H) and observed lipid-lowering efficacy. The inhibitory effects of KIOM2012H on free fatty acid-induced lipid accumulation, triglyceride contents, and gene expressions were analyzed in HepG2 cells. Using high fat diet-fed mice, body weight changes, gross liver appearances, hepatic triglyceride contents, and gene expressions were evaluated. KIOM2012H dose-dependently inhibited lipid accumulation and gene expressions involved in lipogenesis and related regulators. Experimental animals also showed a decrease in body weight changes and lipid-associated physiological parameters. This study shows that KIOM2012H has an alleviating effect on fatty acid and lipid accumulation, and therefore can be applied for development of new therapeutic pharmaceuticals for treatment of NAFLD using natural products and herbs. PMID:25849950

  17. 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

    2016-01-01

    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

  18. 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

  19. Prediction of Nonalcoholic Fatty Liver Disease Via a Novel Panel of Serum Adipokines.

    PubMed

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

    2016-02-01

    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 sensitivity and specificity of 90

  20. 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

  1. The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Almeda-Valdes, Paloma; Aguilar Olivos, Nancy E.; Barranco-Fragoso, Beatriz; Uribe, Misael; Méndez-Sánchez, Nahum

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs) in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance. PMID:26339640

  2. Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease

    PubMed Central

    Gentile, Christopher L.; Nivala, Angela M.; Gonzales, Jon C.; Pfaffenbach, Kyle T.; Wang, Dong; Wei, Yuren; Jiang, Hua; Orlicky, David J.; Petersen, Dennis R.; Maclean, Kenneth N.

    2011-01-01

    The incidence of obesity is now at epidemic proportions and has resulted in the emergence of nonalcoholic fatty liver disease (NAFLD) as a common metabolic disorder that can lead to liver injury and cirrhosis. Excess sucrose and long-chain saturated fatty acids in the diet may play a role in the development and progression of NAFLD. One factor linking sucrose and saturated fatty acids to liver damage is dysfunction of the endoplasmic reticulum (ER). Although there is currently no proven, effective therapy for NAFLD, the amino sulfonic acid taurine is protective against various metabolic disturbances, including alcohol-induced liver damage. The present study was undertaken to evaluate the therapeutic potential of taurine to serve as a preventative treatment for diet-induced NAFLD. We report that taurine significantly mitigated palmitate-mediated caspase-3 activity, cell death, ER stress, and oxidative stress in H4IIE liver cells and primary hepatocytes. In rats fed a high-sucrose diet, dietary taurine supplementation significantly reduced hepatic lipid accumulation, liver injury, inflammation, plasma triglycerides, and insulin levels. The high-sucrose diet resulted in an induction of multiple components of the unfolded protein response in the liver consistent with ER stress, which was ameliorated by taurine supplementation. Treatment of mice with the ER stress-inducing agent tunicamycin resulted in liver injury, unfolded protein response induction, and hepatic lipid accumulation that was significantly ameliorated by dietary supplementation with taurine. Our results indicate that dietary supplementation with taurine offers significant potential as a preventative treatment for NAFLD. PMID:21957160

  3. An Animal Model for the Juvenile Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

    PubMed Central

    Marin, Veronica; Rosso, Natalia; Dal Ben, Matteo; Raseni, Alan; Boschelle, Manuela; Degrassi, Cristina; Nemeckova, Ivana; Nachtigal, Petr; Avellini, Claudio; Tiribelli, Claudio; Gazzin, Silvia

    2016-01-01

    Non Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) are the hepatic manifestations of the metabolic syndrome; worrisome is the booming increase in pediatric age. To recreate the full spectrum of juvenile liver pathology and investigate the gender impact, male and female C57Bl/6 mice were fed with high fat diet plus fructose in the drinking water (HFHC) immediately after weaning (equal to 3-years old human), and disease progression followed for 16 weeks, until adults (equal to 30-years old human). 100% of subjects of both genders on HFHC diet developed steatosis in 4weeks, and some degree of fibrosis in 8weeks, with the 86% of males and 15% of females presenting a stage 2 fibrosis at 16weeks. Despite a similar final liver damage both groups, a sex difference in the pathology progression was observed. Alterations in glucose homeostasis, dyslipidemia, hepatomegaly and obese phenotype were evident from the very beginning in males with an increased hepatic inflammatory activity. Conversely, such alterations were present in females only at the end of the HFHC diet (with the exception of insulin resistance and the hepatic inflammatory state). Interestingly, only females showed an altered hepatic redox state. This juvenile model appears a good platform to unravel the underlying gender dependent mechanisms in the progression from NAFLD to NASH, and to characterize novel therapeutic approaches. PMID:27391242

  4. Bile Acids and Dysbiosis in Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Bandsma, Robert; Comelli, Elena M.; Arendt, Bianca M.; Zhang, Ling; Fung, Scott; Fischer, Sandra E.; McGilvray, Ian G.; Allard, Johane P.

    2016-01-01

    Background & Aims Non-alcoholic fatty liver disease (NAFLD) is characterized by dysbiosis. The bidirectional effects between intestinal microbiota (IM) and bile acids (BA) suggest that dysbiosis may be accompanied by an altered bile acid (BA) homeostasis, which in turn can contribute to the metabolic dysregulation seen in NAFLD. This study sought to examine BA homeostasis in patients with NAFLD and to relate that with IM data. Methods This was a prospective, cross-sectional study of adults with biopsy-confirmed NAFLD (non-alcoholic fatty liver: NAFL or non-alcoholic steatohepatitis: NASH) and healthy controls (HC). Clinical and laboratory data, stool samples and 7-day food records were collected. Fecal BA profiles, serum markers of BA synthesis 7-alpha-hydroxy-4-cholesten-3-one (C4) and intestinal BA signalling, as well as IM composition were assessed. Results 53 subjects were included: 25 HC, 12 NAFL and 16 NASH. Levels of total fecal BA, cholic acid (CA), chenodeoxycholic acid (CDCA) and BA synthesis were higher in patients with NASH compared to HC (p<0.05 for all comparisons). The primary to secondary BA ratio was higher in NASH compared to HC (p = 0.004), but ratio of conjugated to unconjugated BAs was not different between the groups. Bacteroidetes and Clostridium leptum counts were decreased in in a subset of 16 patients with NASH compared to 25 HC, after adjusting for body mass index and weight-adjusted calorie intake (p = 0.028 and p = 0.030, respectively). C. leptum was positively correlated with fecal unconjugated lithocholic acid (LCA) (r = 0.526, p = 0.003) and inversely with unconjugated CA (r = -0.669, p<0.0001) and unconjugated CDCA (r = - 0.630, p<0.0001). FGF19 levels were not different between the groups (p = 0.114). Conclusions In adults with NAFLD, dysbiosis is associated with altered BA homeostasis, which renders them at increased risk of hepatic injury. PMID:27203081

  5. Role of diet and nutritional management in non-alcoholic fatty liver disease.

    PubMed

    Fan, Jian-Gao; Cao, Hai-Xia

    2013-12-01

    Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis, which causes an increased risk of cirrhosis, type 2 diabetes, and cardiovascular complications. With the worldwide growing incidence of obesity, sedentary lifestyle, and unhealthy dietary pattern, NAFLD has currently been recognized as a major health burden. Dietary patterns and nutrients are the important contributors to the development, progression, and treatment of NAFLD and associated metabolic comorbidities. Generally, hypercaloric diet, especially rich in trans/saturated fat and cholesterol, and fructose-sweetened beverages seem to increase visceral adiposity and stimulate hepatic lipid accumulation and progression into non-alcoholic steatohepatitis, whereas reducing caloric intake, increasing soy protein and whey consumption, and supplement of monounsaturated fatty acids, omega-3 fatty acids, and probiotics have preventive and therapeutic effects. In addition, choline, fiber, coffee, green tea, and light alcohol drinking might be protective factors for NAFLD. Based on available data, at least 3-5% of weight loss, achieved by hypocaloric diet alone or in conjunction with exercise and behavioral modification, generally reduces hepatic steatosis, and up to 10% weight loss may be needed to improve hepatic necroinflammation. A sustained adherence to diet rather than the actual diet type is a major predictor of successful weight loss. Moreover, a healthy diet has benefits beyond weight reduction on NAFLD patients whether obese or of normal weight. Therefore, nutrition serves as a major route of prevention and treatment of NAFLD, and patients with NAFLD should have an individualized diet recommendation. PMID:24251710

  6. Exercise and diet in the management of nonalcoholic fatty liver disease.

    PubMed

    Mahady, Suzanne E; George, Jacob

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition worldwide, and is projected to become the leading cause for liver transplantation in the United States as early as 2020. The mainstay of treatment remains lifestyle modification with diet and exercise recommendations, as although some pharmacological treatments such as glitazones and Vitamin E have shown benefit, there are concerns regarding long term safety. The evidence base for dietary interventions in NAFLD such as the Mediterranean diet, omega-3 polyunsaturated fatty acids and coffee is mainly derived from observational data with questionable validity. Where trials exist, they have shown benefit for surrogate outcomes such as hepatic steatosis and insulin resistance, but no trials have been conducted with salient clinical outcomes such as reduction in progression to chronic liver disease. Benefit in surrogate outcomes has also been seen for aerobic, anaerobic and combined modality exercise but it remains unclear if one type is superior. Furthermore, a reduction in sedentary time appears equally important. To provide a sound evidence base for lifestyle recommendations to people with NAFLD, longer duration trials of standardized dietary or exercise interventions, and testing various doses, types and with liver related outcomes, are essential. PMID:26805014

  7. Understanding nutritional interventions and physical exercise in non-alcoholic fatty liver disease.

    PubMed

    Ordonez, R; Carbajo-Pescador, S; Mauriz, J L; Gonzalez-Gallego, J

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in adults and its prevalence is rising around the world. This pathology is characterized by accumulation of liver fat, which exceeds 5% of liver weight in absence of alcohol consumption, viral infection or other hepatic etiology. Since NAFLD has been associated with obesity, insulin resistance, diabetes or alteration of lipid profiles, it is considered as the liver manifestation of metabolic syndrome. Pathogenic mechanisms of NAFLD have not been clearly elucidated, but different events such as lipid accumulation, insulin resistance, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction and inflammation are involved. Modifications in lifestyle constitute the first line for the management of NAFLD. Nutritional interventions include low fat and carbohydrate diet with higher polyunsaturated fatty acids ingestion. Moreover, supplementation with antioxidant and cytoprotective agents could be useful to decrease oxidative stress, inflammation and fibrosis. Physical activity enables to reduce the expression of lipogenic genes, fat accumulation, or insulin resistance and improves cardiorespiratory fitness. Benefits have been found following both aerobic exercise and resistance training, and remain even after exercise cessation. However, more studies are required to analyze the molecular and cellular mechanisms involved in nutritional and physical intervention, and to define the volume of activity required and its association with weight loss. In this paper, we offer an updated overview of the mechanisms implicated in the progression of NAFLD, and analyze the beneficial effects of nutritional interventions and physical exercise in the prevention and treatment of this condition. PMID:25601465

  8. Nonalcoholic fatty liver disease and vascular disease: State-of-the-art

    PubMed Central

    Fargion, Silvia; Porzio, Marianna; Fracanzani, Anna Ludovica

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD), the most common of chronic liver disease in Western Country, is closely related to insulin resistance and oxidative stress and includes a wide spectrum of liver diseases ranging from steatosis alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome with which shares several characteristics, however recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of metabolic syndrome. Accumulating evidence suggests that the clinical burden of NAFLD is not restricted to liver-related morbidity and mortality, with the majority of deaths in NAFLD patients related to cardiovascular disease and cancer and not to the progression of liver disease. Retrospective and prospective studies provide evidence of a strong association between NAFLD and subclinical manifestation of atherosclerosis (increased intima-media thickness, endothelial dysfunction, arterial stiffness, impaired left ventricular function and coronary calcification). A general agreement emerging from these studies indicates that patients with NASH are at higher risk of cardiovascular diseases than those with simple steatosis, emphasizing the role of chronic inflammation in the pathogenesis of atherosclerosis of these patients. It is very likely that the different mechanisms involved in the pathogenesis of atherosclerosis in patients with NAFLD have a different relevance in the patients according to individual genetic background. In conclusion, in the presence of NAFLD patients should undergo a complete cardiovascular evaluation to prevent future atherosclerotic complications. Specific life-style modification and aggressive pharmaceutical modification will not only reduce the progression of liver disease, but also reduce morbidity for cardiovascular

  9. Epigenetic Mechanisms Underlying the Link between Non-Alcoholic Fatty Liver Diseases and Nutrition

    PubMed Central

    Lee, Joo Ho; Friso, Simonetta; Choi, Sang-Woon

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is defined as a pathologic accumulation of fat in the form of triglycerides (TG) in the liver (steatosis) that is not caused by alcohol. A subgroup of NAFLD patients shows liver cell injury and inflammation coupled with the excessive fat accumulation (steatohepatitis), which is referred to as non-alcoholic steatohepatitis (NASH). Patients with NASH may develop cirrhosis and hepatocellular carcinoma (HCC). NAFLD shares the key features of metabolic syndrome including obesity, hyperlipidemia, hypertension, and insulin resistance. The pathogenesis of NAFLD is multi-factorial, however the oxidative stress seems to plays a major role in the development and progression of the disease. The emerging field of epigenetics provides a new perspective on the pathogenesis of NAFLD. Epigenetics is an inheritable but reversible phenomenon that affects gene expression without altering the DNA sequence and refers to DNA methylation, histone modifications and microRNAs. Epigenetic manipulation through metabolic pathways such as one-carbon metabolism has been proposed as a promising approach to retard the progression of NAFLD. Investigating the epigenetic modifiers in NAFLD may also lead to the development of preventive or therapeutic strategies for NASH-associated complications. PMID:25195642

  10. Epigenetic mechanisms in non-alcoholic fatty liver disease: An emerging field.

    PubMed

    Gallego-Durán, Rocío; Romero-Gómez, Manuel

    2015-10-28

    Non-alcoholic fatty liver disease (NAFLD) is an emerging health concern in both developed and non-developed world, encompassing from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and liver cancer. Incidence and prevalence of this disease are increasing due to the socioeconomic transition and change to harmful diet. Currently, gold standard method in NAFLD diagnosis is liver biopsy, despite complications and lack of accuracy due to sampling error. Further, pathogenesis of NAFLD is not fully understood, but is well-known that obesity, diabetes and metabolic derangements played a major role in disease development and progression. Besides, gut microbioma and host genetic and epigenetic background could explain considerable interindividual variability. Knowledge that epigenetics, heritable events not caused by changes in DNA sequence, contribute to development of diseases has been a revolution in the last few years. Recently, evidences are accumulating revealing the important role of epigenetics in NAFLD pathogenesis and in NASH genesis. Histone modifications, changes in DNA methylation and aberrant profiles or microRNAs could boost development of NAFLD and transition into clinical relevant status. PNPLA3 genotype GG has been associated with a more progressive disease and epigenetics could modulate this effect. The impact of epigenetic on NAFLD progression could deserve further applications on therapeutic targets together with future non-invasive methods useful for the diagnosis and staging of NAFLD. PMID:26523202

  11. Epigenetic mechanisms in non-alcoholic fatty liver disease: An emerging field

    PubMed Central

    Gallego-Durán, Rocío; Romero-Gómez, Manuel

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an emerging health concern in both developed and non-developed world, encompassing from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and liver cancer. Incidence and prevalence of this disease are increasing due to the socioeconomic transition and change to harmful diet. Currently, gold standard method in NAFLD diagnosis is liver biopsy, despite complications and lack of accuracy due to sampling error. Further, pathogenesis of NAFLD is not fully understood, but is well-known that obesity, diabetes and metabolic derangements played a major role in disease development and progression. Besides, gut microbioma and host genetic and epigenetic background could explain considerable interindividual variability. Knowledge that epigenetics, heritable events not caused by changes in DNA sequence, contribute to development of diseases has been a revolution in the last few years. Recently, evidences are accumulating revealing the important role of epigenetics in NAFLD pathogenesis and in NASH genesis. Histone modifications, changes in DNA methylation and aberrant profiles or microRNAs could boost development of NAFLD and transition into clinical relevant status. PNPLA3 genotype GG has been associated with a more progressive disease and epigenetics could modulate this effect. The impact of epigenetic on NAFLD progression could deserve further applications on therapeutic targets together with future non-invasive methods useful for the diagnosis and staging of NAFLD. PMID:26523202

  12. Mitochondrial Molecular Pathophysiology of Nonalcoholic Fatty Liver Disease: A Proteomics Approach

    PubMed Central

    Nuño-Lámbarri, Natalia; Barbero-Becerra, Varenka J.; Uribe, Misael; Chávez-Tapia, Norberto C.

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that can progress to nonalcoholic steatohepatitis, cirrhosis and cancer. It is considered an emerging health problem due to malnourishment or a high-fat diet (HFD) intake, which is observed worldwide. It is well known that the hepatocytes’ apoptosis phenomenon is one of the most important features of NAFLD. Thus, this review focuses on revealing, through a proteomics approach, the complex network of protein interactions that promote fibrosis, liver cell stress, and apoptosis. According to different types of in vitro and murine models, it has been found that oxidative/nitrative protein stress leads to mitochondrial dysfunction, which plays a major role in stimulating NAFLD damage. Human studies have revealed the importance of novel biomarkers, such as retinol-binding protein 4, lumican, transgelin 2 and hemoglobin, which have a significant role in the disease. The post-genome era has brought proteomics technology, which allows the determination of molecular pathogenesis in NAFLD. This has led to the search for biomarkers which improve early diagnosis and optimal treatment and which may effectively prevent fatal consequences such as cirrhosis or cancer. PMID:26999105

  13. Review of nonalcoholic fatty liver disease in women with polycystic ovary syndrome

    PubMed Central

    Kelley, Carly E; Brown, Ann J; Diehl, Anna Mae; Setji, Tracy L

    2014-01-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. Women with PCOS frequently have metabolic complications including insulin resistance (IR), early diabetes, hypertension and dyslipidemia. Recent studies have demonstrated an association between PCOS and another metabolic complication: nonalcoholic fatty liver disease (NAFLD). NAFLD occurs as a result of abnormal lipid handling by the liver, which sensitizes the liver to injury and inflammation. It can progress to nonalcoholic steatohepatitis (NASH), which is characterized by hepatocyte injury and apoptosis. With time and further inflammation, NASH can progress to cirrhosis. Thus, given the young age at which NAFLD may occur in PCOS, these women may be at significant risk for progressive hepatic injury over the course of their lives. Many potential links between PCOS and NAFLD have been proposed, most notably IR and hyperandrogenemia. Further studies are needed to clarify the association between PCOS and NAFLD. In the interim, clinicians should be aware of this connection and consider screening for NAFLD in PCOS patients who have other metabolic risk factors. The optimal method of screening is unknown. However, measuring alanine aminotransferase and/or obtaining ultrasound on high-risk patients can be considered. First line treatment consists of lifestyle interventions and weight loss, with possible pharmacologic interventions in some cases. PMID:25339805

  14. An Accessible and Pragmatic Experimental Model of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Emamat, Hadi; Noori, Maryam; Foroughi, Forough; Rismanchi, Marjan; Eini–Zinab, Hassan; Hekmatdoost, Azita

    2016-01-01

    BACKGROUND There is no convenient cheap pragmatic experimental model for Nonalcoholic Fatty Liver Disease (NAFLD)/Nonalcoholic Steatohepatitis (NASH). Objective: Our objective was to create a pragmatic model of NAFLD/NASH. METHODS Sprague-Dawley rats were fed a high-fat, high sugar homemade diet ad libitum for seven weeks. The high-fat, high sugar diet included 59% of energy derived from fat, 30% from carbohydrates, and 11% from protein. Serum levels of fasting glucose, triglyceride, cholesterol, liver enzymes, insulin, and hepatic tumor necrosis factor-alpha (TNF-α) gene expression were determined. Hepatic histology was examined by H&E stain. RESULTS Rats fed the high-fat, high sugar diet developed hepatic steatosis, and a moderate inflammation, which was associated with increased serum levels of liver enzymes, glucose, insulin, triglyceride, cholesterol, and hepatic TNF-α gene expression. CONCLUSION This rat model resembles the key features of human NAFLD/NASH and provides a simple pragmatic experimental model for elucidating the disease prevention and treatment. PMID:27252817

  15. Non-alcoholic fatty liver disease: What has changed in the treatment since the beginning?

    PubMed Central

    Baran, Bülent; Akyüz, Filiz

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an umbrella term to describe the entire spectrum of this common liver disease. In patients with NAFLD, especially those with non-alcoholic steatohepatitis (NASH), most often have one or more components of the metabolic syndrome, but this is not universal. Although most patients with NAFLD share many clinical features, only a subset of patients develops significant liver inflammation and progressive fibrosis. On the other hand, not all patients with NASH exhibit insulin resistance. NASH can be seen in patients who are lean and have no identifiable risk factors. Many clinical studies have tried numerous drugs and alternative medicine, however, investigators have failed to identify a safe and effective therapy for patients with NASH. As summarized, the heterogeneity of pathogenic pathways in individual patients with NASH may warrant the development of an individualized treatment according to the underlying pathogenic pathway. The differentiation of pathogenetic targets may require the development of diagnostic and prognostic biomarkers, and the identification of genetic susceptibilities. At present, evidence-based medicine provides only a few options including life-style modifications targeting weight loss, pioglitazone and vitamin E in non-diabetic patients with biopsy-proven NASH. PMID:25339808

  16. Non-alcoholic fatty liver disease and diabetes: From physiopathological interplay to diagnosis and treatment

    PubMed Central

    Leite, Nathalie C; Villela-Nogueira, Cristiane A; Cardoso, Claudia R L; Salles, Gil F

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with diabetes mellitus and increasing evidence suggests that patients with type 2 diabetes are at a particularly high risk for developing the progressive forms of NAFLD, non-alcoholic steatohepatitis and associated advanced liver fibrosis. Moreover, diabetes is an independent risk factor for NAFLD progression, and for hepatocellular carcinoma development and liver-related mortality in prospective studies. Notwithstanding, patients with NAFLD have an elevated prevalence of prediabetes. Recent studies have shown that NAFLD presence predicts the development of type 2 diabetes. Diabetes and NAFLD have mutual pathogenetic mechanisms and it is possible that genetic and environmental factors interact with metabolic derangements to accelerate NAFLD progression in diabetic patients. The diagnosis of the more advanced stages of NAFLD in diabetic patients shares the same challenges as in non-diabetic patients and it includes imaging and serological methods, although histopathological evaluation is still considered the gold standard diagnostic method. An effective established treatment is not yet available for patients with steatohepatitis and fibrosis and randomized clinical trials including only diabetic patients are lacking. We sought to outline the published data including epidemiology, pathogenesis, diagnosis and treatment of NAFLD in diabetic patients, in order to better understand the interplay between these two prevalent diseases and identify the gaps that still need to be fulfilled in the management of NAFLD in patients with diabetes mellitus. PMID:25024596

  17. Nonalcoholic fatty liver disease: an emerging threat to obese and diabetic individuals

    PubMed Central

    Masuoka, Howard C; Chalasani, Naga

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world and its incidence is increasing rapidly. NAFLD is a spectrum ranging from simple steatosis, which is relatively benign hepatically, to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis. Obesity, insulin resistance, type 2 diabetes mellitus, and dyslipidemia are the most important risk factors for NAFLD. Due to heavy enrichment with metabolic risk factors, individuals with NAFLD are at significantly higher risk for cardiovascular disease. Individuals with NAFLD have higher incidence of type 2 diabetes. The diagnosis of NAFLD requires imaging evidence of hepatic steatosis in the absence of competing etiologies including significant alcohol consumption. Liver biopsy remains the gold standard for diagnosing NASH and for determining prognosis. Weight loss remains a cornerstone of treatment. Weight loss of ∼5% is believed to improve steatosis, whereas ∼10% weight loss is necessary to improve steatohepatitis. A number of pharmacologic therapies have been investigated to treat NASH, and agents such as vitamin E and thiazolidinediones have shown promise in select patient subgroups. PMID:23363012

  18. Mitochondrial Molecular Pathophysiology of Nonalcoholic Fatty Liver Disease: A Proteomics Approach.

    PubMed

    Nuño-Lámbarri, Natalia; Barbero-Becerra, Varenka J; Uribe, Misael; Chávez-Tapia, Norberto C

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that can progress to nonalcoholic steatohepatitis, cirrhosis and cancer. It is considered an emerging health problem due to malnourishment or a high-fat diet (HFD) intake, which is observed worldwide. It is well known that the hepatocytes' apoptosis phenomenon is one of the most important features of NAFLD. Thus, this review focuses on revealing, through a proteomics approach, the complex network of protein interactions that promote fibrosis, liver cell stress, and apoptosis. According to different types of in vitro and murine models, it has been found that oxidative/nitrative protein stress leads to mitochondrial dysfunction, which plays a major role in stimulating NAFLD damage. Human studies have revealed the importance of novel biomarkers, such as retinol-binding protein 4, lumican, transgelin 2 and hemoglobin, which have a significant role in the disease. The post-genome era has brought proteomics technology, which allows the determination of molecular pathogenesis in NAFLD. This has led to the search for biomarkers which improve early diagnosis and optimal treatment and which may effectively prevent fatal consequences such as cirrhosis or cancer. PMID:26999105

  19. Association between sonographic diagnosis of fatty liver with histopathologic abnormalities and liver biopsy findings in middle age patient with non-alcoholic fatty liver disease

    PubMed Central

    Kalantari, Hamid; Moradi, Farhad; Hassanzade, Akbar

    2016-01-01

    Background: Liver biopsy is required to diagnose non-alcoholic steatohepatitis in patients with suspected non-alcoholic fatty liver disease (NAFLD). This study aimed to examine the relationship between sonographic diagnosis of fatty liver with histopathologic abnormalities and liver biopsy findings in patient with NAFLD. Materials and Methods: In this cross-sectional study, a total of 180 patients, with an age range of 18-60 year old, with NAFLD based on ultrasonograghic findings were evaluated. Age, sex, body mass index, diabetes mellitus, hypertension, family history of liver disease and laboratory parameters recorded for all patients. Hence, grade of steatosis and stage of fibrosis were evaluated by liver biopsy. Results: A total of 220 patients were enrolled. Liver biopsy was performed in 180 patients. Mean age was 43 ± 10.6 years old and 66% were male. Ultrasonograghic findings showed mild, moderate and severe NAFLD was define in 100 (55.5%), 72 (40%) and 8 (4.5%) of patients, respectively. Liver biopsies showed that steatosis scores of <5%, 5-33% and 33-66% was define in 56 (31%), 116 (64%) and 9 (5%) of patients, respectively. Furthermore, fibrosis was defined as follow; none 92 (51%), mild 68 (38%), moderate 11 (6%), bridging 5 (3%) and cirrhosis 3 (2%) patients. There was no statistically significant relationship between ultrasonograghic findings and steatosis scores (P = 0.44), but statistically significant relationship was found between ultrasonograghic findings and fibrosis stage (P = 0.017). Conclusion: Findings revealed that, in patients with NAFLD, ultrasonographic finding were not in associate to steatosis, but were in relation with fibrosis stage. PMID:27563632

  20. Dietary supplements and pediatric non-alcoholic fatty liver disease: Present and the future

    PubMed Central

    Rahimlou, Mehran; Ahmadnia, Hoda; Hekmatdoost, Azita

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. High prevalence of pediatric obesity and sedentary lifestyle has augmented the incidence of NAFLD in children. Obesity is associated with an increased risk of NAFLD through various mechanisms such as intensification of insulin resistance and increased levels of inflammatory markers. There is no approved medical intervention for treatment of pediatric NAFLD; the only proven strategy in management of pediatric NAFLD is lifestyle modification. Recently, the effects of nutritional supplements have been examined in the management of pediatric NAFLD. The purpose of this review is to summarize the studies evaluating the effects of nutritional supplements on pediatric NAFLD and explain the future direction in this field. PMID:26557952

  1. Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia

    PubMed Central

    Lee, Soo Min; Nguyen, Dara; Anand, Marie; Kant, Ritu; Köhncke, Clemens; Lisewski, Ulrike; Roepke, Torsten K.; Hu, Zhaoyang; Abbott, Geoffrey W.

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide, with genetic, epigenetic, and environmental components. Here, we describe the first example of NAFLD caused by genetic disruption of a mammalian potassium channel subunit. Mice with germline deletion of the KCNE2 potassium channel β subunit exhibited NAFLD as early as postnatal day 7. Using mouse genetics, histology, liver damage assays and transcriptomics we discovered that iron deficiency arising from KCNE2-dependent achlorhydria is a major factor in early-onset NAFLD in Kcne2─/─ mice, while two other KCNE2-dependent defects did not initiate NAFLD. The findings uncover a novel genetic basis for NAFLD and an unexpected potential factor in human KCNE2-associated cardiovascular pathologies, including atherosclerosis. PMID:26984260

  2. Alimentary regimen in non-alcoholic fatty liver disease: Mediterranean diet

    PubMed Central

    Abenavoli, Ludovico; Milic, Natasa; Peta, Valentina; Alfieri, Francesco; De Lorenzo, Antonino; Bellentani, Stefano

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. The mechanisms of the underlying disease development and progression are awaiting clarification. Insulin resistance and obesity-related inflammation status, among other possible genetic, dietary, and lifestyle factors, are thought to play the key role. There is no consensus concerning the pharmacological treatment. However, the dietary nutritional management to achieve weight loss is an essential component of any treatment strategy. On the basis of its components, the literature reports on the effectiveness of the Mediterranean diet in reducing cardiovascular risk and in preventing major chronic diseases, including obesity and diabetes. New evidence supports the idea that the Mediterranean diet, associated with physical activity and cognitive behaviour therapy, may have an important role in the prevention and the treatment of NAFLD. PMID:25492997

  3. Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia.

    PubMed

    Lee, Soo Min; Nguyen, Dara; Anand, Marie; Kant, Ritu; Köhncke, Clemens; Lisewski, Ulrike; Roepke, Torsten K; Hu, Zhaoyang; Abbott, Geoffrey W

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide, with genetic, epigenetic, and environmental components. Here, we describe the first example of NAFLD caused by genetic disruption of a mammalian potassium channel subunit. Mice with germline deletion of the KCNE2 potassium channel β subunit exhibited NAFLD as early as postnatal day 7. Using mouse genetics, histology, liver damage assays and transcriptomics we discovered that iron deficiency arising from KCNE2-dependent achlorhydria is a major factor in early-onset NAFLD in Kcne2(─/─) mice, while two other KCNE2-dependent defects did not initiate NAFLD. The findings uncover a novel genetic basis for NAFLD and an unexpected potential factor in human KCNE2-associated cardiovascular pathologies, including atherosclerosis. PMID:26984260

  4. Nonalcoholic fatty liver disease and the renin-angiotensin system: Implications for treatment

    PubMed Central

    Paschos, Paschalis; Tziomalos, Konstantinos

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in Western countries. Treatment of NAFLD is currently based on lifestyle measures and no effective pharmacologic treatment is available so far. Emerging evidence, mainly from animal studies, suggests that the renin-angiotensin-aldosterone system may be of major importance in the pathogenesis of NAFLD and indicates that angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) as a potentially useful therapeutic approach. However, data from human studies are limited and contradictory. In addition, there are few randomized controlled trials (RCTs) on the effects of ACE-I or ARB in patients with NAFLD and most data are from retrospective studies, pilot prospective studies and post hoc analyses of clinical trials. Accordingly, more and larger RCTs are needed to directly assess the effectiveness of ACE-I and ARBs in NAFLD. PMID:23355909

  5. Vitamin D: A new player in non-alcoholic fatty liver disease?

    PubMed Central

    Eliades, Myrto; Spyrou, Elias

    2015-01-01

    Vitamin D through its active form 1a-25-dihydroxyvtamin D [1,25(OH)2D] is a secosteroid hormone that plays a key role in mineral metabolism. Recent years have witnessed a significant scientific interest on vitamin D and expanded its actions to include immune modulation, cell differentiation and proliferation and inflammation regulation. As our understanding of the many functions of vitamin D has grown, the presence of vitamin D deficiency has become one of the most prevalent micronutrient deficiencies worldwide. Concomitantly, non-alcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease in western countries. NAFLD and vitamin D deficiency often coexist and epidemiologic evidence has shown that both of these conditions share several cardiometabolic risk factors. In this article we provide an overview of the epidemiology and pathophysiology linking NAFLD and vitamin D deficiency, as well as the available evidence on the clinical utility of vitamin D supplementation in NAFLD. PMID:25684936

  6. Nonalcoholic fatty liver disease epidemic and its implications for liver transplantation.

    PubMed

    Kemmer, Nyingi; Neff, Guy W; Franco, Edson; Osman-Mohammed, Hussein; Leone, John; Parkinson, Erin; Cece, Elizabeth; Alsina, Angel

    2013-11-27

    Nonalcoholic steatohepatitis (NASH) is increasingly recognized as the most common chronic liver disease worldwide. The aim of this study is to investigate the transplantation trends of liver transplant (LT) recipients with NASH. Using the United Network for Organ Sharing database, we found a steady increase in LT rate especially in those more than 65 years old. We identified differences across ethnic groups and United Network for Organ Sharing regions. This study highlights the impact of the rising prevalence of NASH on the demand for LT and provides invaluable information to healthcare policymakers and the transplant community about the target groups and geographic location for focused and early intervention. PMID:24247899

  7. Nonalcoholic Fatty Liver Disease Epidemic and Its Implications for Liver Transplantation.

    PubMed

    Kemmer, Nyingi; Neff, Guy W; Franco, Edson; Osman-Mohammed, Hussein; Leone, John; Parkinson, Erin; Cece, Elizabeth; Alsina, Angel

    2013-10-17

    Nonalcoholic steatohepatitis (NASH) is increasingly recognized as the most common chronic liver disease worldwide. The aim of this study is to investigate the transplantation trends of liver transplant (LT) recipients with NASH. Using the United Network for Organ Sharing database, we found a steady increase in LT rate especially in those more than 65 years old. We identified differences across ethnic groups and United Network for Organ Sharing regions. This study highlights the impact of the rising prevalence of NASH on the demand for LT and provides invaluable information to healthcare policymakers and the transplant community about the target groups and geographic location for focused and early intervention. PMID:24142031

  8. Ameliorative Effects of Pomegranate Peel Extract against Dietary-Induced Nonalcoholic Fatty Liver in Rats.

    PubMed

    Al-Shaaibi, Siham N K; Waly, Mostafa I; Al-Subhi, Lyutha; Tageldin, Mohamed H; Al-Balushi, Nada M; Rahman, Mohammad S

    2016-03-01

    Non-alcoholic fatty liver disease (NAFLD) is caused by fat accumulation and is associated with oxidative stress. In this study, we investigated the potential protective effect of pomegranate (Punica granatum L.) peel extract (PPE) against oxidative stress in the liver of rats with NAFLD. Sprague-Dawley rats were fed a high fat diet (HFD), 20% corn oil, or palm oil for 8 weeks in the presence or absence of PPE. The control group was fed a basal diet. The progression of NAFLD was evaluated histologically and by measuring liver enzymes (alanine transaminase and aspartate transaminase), serum lipids (triglycerides and total cholesterol), and oxidative stress markers. The HFD feeding increased the body weight and caused NAFLD, liver steatosis, hyperlipidemia, oxidative stress, and elevated liver enzymes. Administration of PPE ameliorated the hepatic morphology, reduced body weight, improved liver enzymes, and inhibited lipogenesis. Furthermore, PPE enhanced the cellular redox status in the liver tissue of rats with NAFLD. Our findings suggest that PPE could improve HFD-induced NAFLD via abolishment of hepatic oxidative damage and hyperlipidemia. PPE might be considered as a potential lead material in the treatment of NAFLD and obesity through the modulation of lipid metabolism. PMID:27069901

  9. Ameliorative Effects of Pomegranate Peel Extract against Dietary-Induced Nonalcoholic Fatty Liver in Rats

    PubMed Central

    Al-Shaaibi, Siham N. K.; Waly, Mostafa I.; Al-Subhi, Lyutha; Tageldin, Mohamed H.; Al-Balushi, Nada M.; Rahman, Mohammad S.

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is caused by fat accumulation and is associated with oxidative stress. In this study, we investigated the potential protective effect of pomegranate (Punica granatum L.) peel extract (PPE) against oxidative stress in the liver of rats with NAFLD. Sprague-Dawley rats were fed a high fat diet (HFD), 20% corn oil, or palm oil for 8 weeks in the presence or absence of PPE. The control group was fed a basal diet. The progression of NAFLD was evaluated histologically and by measuring liver enzymes (alanine transaminase and aspartate transaminase), serum lipids (triglycerides and total cholesterol), and oxidative stress markers. The HFD feeding increased the body weight and caused NAFLD, liver steatosis, hyperlipidemia, oxidative stress, and elevated liver enzymes. Administration of PPE ameliorated the hepatic morphology, reduced body weight, improved liver enzymes, and inhibited lipogenesis. Furthermore, PPE enhanced the cellular redox status in the liver tissue of rats with NAFLD. Our findings suggest that PPE could improve HFD-induced NAFLD via abolishment of hepatic oxidative damage and hyperlipidemia. PPE might be considered as a potential lead material in the treatment of NAFLD and obesity through the modulation of lipid metabolism. PMID:27069901

  10. Hydrogen peroxide impairs autophagic flux in a cell model of nonalcoholic fatty liver disease

    SciTech Connect

    Jiang, Pengtao; Huang, Zhen; Zhao, Hong; Wei, Taotao

    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 number 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.

  11. Increasing Whole Grain Intake as Part of Prevention and Treatment of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Ross, Alastair B.; Godin, Jean-Philippe; Minehira, Kaori; Kirwan, John P.

    2013-01-01

    In conjunction with the rise in rates of obesity, there has been an increase in the rate of nonalcoholic fatty liver disease (NAFLD). While NAFLD at least partially originates from poor diet, there is a lack of nutritional recommendations for patients with suspected or confirmed diagnosis of NAFLD, beyond eating a healthy diet, increasing physical activity, and emphasising weight loss. The limited current literature suggests that there may be opportunities to provide more tailored dietary advice for people diagnosed with or at risk of NAFLD. Epidemiological studies consistently find associations between whole grain intake and a reduced risk of obesity and related diseases, yet no work has been done on the potential of whole grains to prevent and/or be a part of the treatment for fatty liver diseases. In this review, we examine the potential and the current evidence for whole grains having an impact on NAFLD. Due to their nutrient and phytochemical composition, switching from consuming mainly refined grains to whole grains should be considered as part of the nutritional guidelines for patients diagnosed with or at risk for fatty liver disease. PMID:23762052

  12. Non-Alcoholic Fatty Liver Disease and Metabolic Syndrome after Liver Transplant

    PubMed Central

    Gitto, Stefano; Villa, Erica

    2016-01-01

    Liver transplant is the unique curative therapy for patients with acute liver failure or end-stage liver disease, with or without hepatocellular carcinoma. Increase of body weight, onset of insulin resistance and drug-induced alterations of metabolism are reported in liver transplant recipients. In this context, post-transplant diabetes mellitus, hyperlipidemia, and arterial hypertension can be often diagnosed. Multifactorial illnesses occurring in the post-transplant period represent significant causes of morbidity and mortality. This is especially true for metabolic syndrome. Non-alcoholic steatosis and steatohepatitis are hepatic manifestations of metabolic syndrome and after liver transplant both recurrent and de novo steatosis can be found. Usually, post-transplant steatosis shows an indolent outcome with few cases of fibrosis progression. However, in the post-transplant setting, both metabolic syndrome and steatosis might play a key role in the stratification of morbidity and mortality risk, being commonly associated with cardiovascular disease. The single components of metabolic syndrome can be treated with targeted drugs while lifestyle intervention is the only reasonable therapeutic approach for transplant patients with non-alcoholic steatosis or steatohepatitis. PMID:27049380

  13. 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

  14. Systems Biology Elucidates Common Pathogenic Mechanisms between Nonalcoholic and Alcoholic-Fatty Liver Disease

    PubMed Central

    Sookoian, Silvia; Pirola, Carlos J.

    2013-01-01

    The abnormal accumulation of fat in the liver is often related either to metabolic risk factors associated with metabolic syndrome in the absence of alcohol consumption (nonalcoholic fatty liver disease, NAFLD) or to chronic alcohol consumption (alcoholic fatty liver disease, AFLD). Clinical and histological studies suggest that NAFLD and AFLD share pathogenic mechanisms. Nevertheless, current data are still inconclusive as to whether the underlying biological process and disease pathways of NAFLD and AFLD are alike. Our primary aim was to integrate omics and physiological data to answer the question of whether NAFLD and AFLD share molecular processes that lead to disease development. We also explored the extent to which insulin resistance (IR) is a distinctive feature of NAFLD. To answer these questions, we used systems biology approaches, such as gene enrichment analysis, protein–protein interaction networks, and gene prioritization, based on multi-level data extracted by computational data mining. We observed that the leading disease pathways associated with NAFLD did not significantly differ from those of AFLD. However, systems biology revealed the importance of each molecular process behind each of the two diseases, and dissected distinctive molecular NAFLD and AFLD-signatures. Comparative co-analysis of NAFLD and AFLD clarified the participation of NAFLD, but not AFLD, in cardiovascular disease, and showed that insulin signaling is impaired in fatty liver regardless of the noxa, but the putative regulatory mechanisms associated with NAFLD seem to encompass a complex network of genes and proteins, plausible of epigenetic modifications. Gene prioritization showed a cancer-related functional map that suggests that the fatty transformation of the liver tissue is regardless of the cause, an emerging mechanism of ubiquitous oncogenic activation. In conclusion, similar underlying disease mechanisms lead to NAFLD and AFLD, but specific ones depict a particular

  15. Cross-talk between the thyroid and liver: A new target for nonalcoholic fatty liver disease treatment

    PubMed Central

    Huang, Yue-Ye; Gusdon, Aaron M; Qu, Shen

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) has been recognized as the most common liver metabolic disease, and it is also a burgeoning health problem that affects one-third of adults and is associated with obesity and insulin resistance now. Thyroid hormone (TH) and its receptors play a fundamental role in lipid metabolism and lipid accumulation in the liver. It is found that thyroid receptor and its isoforms exhibit tissue-specific expression with a variety of functions. TRβ1 is predominantly expressed in the brain and adipose tissue and TRβ2 is the major isoform in the liver, kidney and fat. They have different functions and play important roles in lipid metabolism. Recently, there are many studies on the treatment of NAFLD with TH and its analogues. We review here that thyroid hormone and TR are a potential target for pharmacologic treatments. Lipid metabolism and lipid accumulation can be regulated and reversed by TH and its analogues. PMID:24363514

  16. Nonalcoholic fatty liver disease and the heart in children and adolescents.

    PubMed

    Pacifico, Lucia; Chiesa, Claudio; Anania, Caterina; De Merulis, Antonio; Osborn, John Frederick; Romaggioli, Sara; Gaudio, Eugenio

    2014-07-21

    Over the last two decades, the rise in the prevalence rates of overweight and obesity explains the emergence of nonalcoholic fatty liver disease (NAFLD) as the leading cause of chronic liver disease worldwide. As described in adults, children and adolescents with fatty liver display insulin resistance, glucose intolerance, and dyslipidemia. Thus NAFLD has emerged as the hepatic component of the metabolic syndrome (MetS) and a strong cardiovascular risk factor even at a very early age. Several studies, including pediatric populations, have reported independent associations between NAFLD and markers of subclinical atherosclerosis including impaired flow-mediated vasodilation, increased carotid artery intima-media thickness, and arterial stiffness, after adjusting for cardiovascular risk factors and MetS. Also, it has been shown that NAFLD is associated with cardiac alterations, including abnormal left ventricular structure and impaired diastolic function. The duration of these subclinical abnormalities may be important, because treatment to reverse the process is most likely to be effective earlier in the disease. In the present review, we examine the current evidence on the association between NAFLD and atherosclerosis as well as between NAFLD and cardiac dysfunction in the pediatric population, and discuss briefly the possible biological mechanisms linking NAFLD and cardiovascular changes. We also address the approach to treatment for this increasingly prevalent disease, which is likely to have an important future global impact on the burden of ill health, to prevent not only end-stage liver disease but also cardiovascular disease. PMID:25083079

  17. Hypoxia-regulated mechanisms in the pathogenesis of obesity and non-alcoholic fatty liver disease.

    PubMed

    Lefere, Sander; Van Steenkiste, Christophe; Verhelst, Xavier; Van Vlierberghe, Hans; Devisscher, Lindsey; Geerts, Anja

    2016-09-01

    The pandemic rise in obesity has resulted in an increased incidence of metabolic complications. Non-alcoholic fatty liver disease is the hepatic manifestation of the metabolic syndrome and has become the most common chronic liver disease in large parts of the world. The adipose tissue expansion and hepatic fat accumulation characteristics of these disorders compromise local oxygen homeostasis. The resultant tissue hypoxia induces adaptive responses to restore oxygenation and tissue metabolism and cell survival. Hypoxia-inducible factors (HIFs) function as master regulators of this hypoxia adaptive response, and are in turn hydroxylated by prolyl hydroxylases (PHDs). PHDs are the main cellular oxygen sensors and regulate HIF proteasomal degradation in an oxygen-dependent manner. HIFs and PHDs are implicated in numerous physiological and pathological conditions. Extensive research using genetic models has revealed that hypoxia signaling is also a key mechanism in adipose tissue dysfunction, leading to adipose tissue fibrosis, inflammation and insulin resistance. Moreover, hypoxia affects liver lipid metabolism and deranges hepatic lipid accumulation. This review summarizes the molecular mechanisms through which the hypoxia adaptive response affects adipocyte and hepatic metabolism, and the therapeutic possibilities of modulating HIFs and PHDs in obesity and fatty liver disease. PMID:27091156

  18. Beneficial effects of neomangiferin on high fat diet-induced nonalcoholic fatty liver disease in rats.

    PubMed

    Zhou, Chengyan; Zhou, Jingjing; Han, Na; Liu, Zhihui; Xiao, Bin; Yin, Jun

    2015-03-01

    This study was carried out to determine the effect and mechanism of action of neomangiferin (NG) on high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) in rats. NAFLD rats were randomly assigned into several groups of equal number. NG (50, 25mg/kg·day(-1) BW) and lipanthyl (PT, 5mg/kg·day(-1) BW) were given to the NAFLD rats, respectively. In the study, serum lipids, metabolic rate, liver fat, liver lipids and histology were examined. To further investigate the molecular mechanism of the effect of NG on NAFLD, expression levels of mRNA and protein for peroxisome proliferator-activated receptor α (PPARα), fatty acid transport protein 2 (FATP2), long-chain-fatty-acid - CoA ligase 1 (ACSL1) and carnitine palmitoyltransferase 1a (CPT1a) in the liver were determined by Real Time-PCR and western blot analysis, respectively. NG administration significantly reduced the final body weight, liver fat accumulation, and serum triglyceride (TG), total cholesterol (TC) concentrations, low-density lipoprotein cholesterol (LDL-C), glucose (GLU) levels, and hepatic TG, TC, malondialdehyde (MDA) levels, but increased serum high-density lipoprotein cholesterol (HDL-C) and hepatic superoxide dismutase (SOD) levels. NG upregulated the mRNA and protein expression of PPARα and CPT1a, but downregulated the mRNA and protein expression of FATP2 and ACSL1 in the liver. These results suggested that NG can regulate NAFLD partly by modulating the expression levels of genes involved in FFA uptake and lipid oxidation. PMID:25661699

  19. Liver Transplantation for Alcoholic and Nonalcoholic Fatty Liver Disease: Pretransplant Selection and Posttransplant Management.

    PubMed

    Siddiqui, M Shadab; Charlton, Michael

    2016-06-01

    Alcoholic fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are common causes of chronic liver disease throughout the world. Although they have similar histologic features, a diagnosis of NAFLD requires the absence of significant alcohol use. ALD is seen commonly in patients with a long-standing history of excessive alcohol use, whereas NAFLD is encountered commonly in patients who have developed complications of obesity, such as insulin resistance, hypertension, and dyslipidemia. Lifestyle contributes to the development and progression of both diseases. Although alcohol abstinence can cause regression of ALD, and weight loss can cause regression of NAFLD, many patients with these diseases develop cirrhosis. ALD and NAFLD account for nearly 30% of liver transplants performed in the United States. Patients receiving liver transplants for ALD or NAFLD have similar survival times as patients receiving transplants for other liver disorders. Although ALD and NAFLD recur frequently after liver transplantation, graft loss from disease recurrence after transplantation is uncommon. Cardiovascular disease and de novo malignancy are leading causes of long-term mortality in liver transplant recipients with ALD or NAFLD. PMID:26971826

  20. Presence and Significance of Microvesicular Steatosis in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Tandra, Sweta; Yeh, Matthew M.; Brunt, Elizabeth M.; Vuppalanchi, Raj; Cummings, Oscar W.; Ünalp-Arida, Aynur; Wilson, Laura A.; Chalasani, Naga

    2011-01-01

    Background/Aims Liver biopsies from patients with nonalcoholic fatty liver disease (NAFLD) sometimes exhibit non-zonal aggregates of hepatocytes with microvesicular steatosis, but its prevalence and significance are unclear. In this study, we have evaluated the frequency of microvesicular steatosis and assessed its association with histological markers of disease severity in a large sample of NAFLD liver biopsies. Methods Liver biopsies from a large cohort of adults who participated in two studies conducted by the NASH Clinical Research Network (NASH CRN) were included in this cross-sectional study. Liver histology was assessed centrally and various histological features scored in a systematic fashion. The relationship between microvesicular steatosis and various histological features that characterize NAFLD was tested by multiple logistic regression, after controlling for age, gender, race, body mass index, and diabetes. Results Among 1022 liver biopsies included, 102 (10%) had microvesicular steatosis. No demographic differences were noted between patients with or without microvesicular steatosis. The presence of microvesicular steatosis was associated with higher grades of steatosis (p<0.001), ballooning cell injury (p<0.001), presence of Mallory-Denk bodies (p<0.007), presence of megamitochondria (p<0.0001), higher NAS scores (p<0.0001), more advanced fibrosis (p<0.0001) and diagnosis of borderline or definite NASH (p<0.0001). Conclusion Microvesicular steatosis correlates with more advanced histology of NAFLD. Longitudinal studies are needed to address the role of microvesicular steatosis in mediating cellular injury and disease progression in NAFLD. PMID:21172393

  1. Impaired Gallbladder Motility and Increased Gallbladder Wall Thickness in Patients with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Colak, Yasar; Bozbey, Gulcin; Erim, Tolga; Caklili, Ozge Telci; Ulasoglu, Celal; Senates, Ebubekir; Mutlu, Hasan Huseyin; Mesci, Banu; Doğan, Mehmet Sait; Tasan, Guralp; Enc, Feruze Yilmaz; Tuncer, Ilyas

    2016-01-01

    Background/Aims Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide. Along with the increase in the incidence of NAFLD and associated obesity, an increase in gallbladder disease (GD) has been noted. This has led to the identification of a new disease entity called fatty GD. There is a gap in the literature on the dynamics of gallbladder function in patients with NAFLD. Methods An observational case-control study, a total of 50 patients with biopsy proven NAFLD without gallbladder stone/sludge and 38 healthy comparison subjects were enrolled. Fasting, postprandial gallbladder volumes (PGV), gallbladder ejection fraction (GEF), and fasting gallbladder wall thickness (FGWT) were measured by real-time 2-dimensional ultrasonography. Results Fasting gallbladder wall thickness, fasting gallbladder volumes and PGV were significantly higher in patients with NAFLD than control subjects (P < 0.001, P = 0.006, and P < 0.001, respectively). Gallbladder ejection fraction was significantly lower in the NAFLD group than the controls (P = 0.008). The presence of NAFLD was an independent predictor for GEF, PGV, and FGWT. Also, steatosis grade was an independent predictor for GEF, and GEF was significantly lower in the nonalcoholic steatohepatitis (NASH) subgroup than the controls. Conclusions Gallbladder dysfunction and increase in gallbladder wall thickness exists in asymptomatic (without stone/sludge and related symptoms) patients with NAFLD and are useful in identifying fatty GD. Measurement of these variables in NAFLD patients may be useful in identifying those at higher risk for GD. PMID:26932908

  2. Non-alcoholic fatty liver disease-From the cardiologist perspective.

    PubMed

    Sîrbu, Oana; Floria, Mariana; Dăscălița, Petru; Şorodoc, Victorița; Şorodoc, Laurențiu

    2016-07-01

    Non-alcoholic fatty liver disease (NAFLD) includes a range of disorders characterized by excess accumulation of triglycerides within the liver. While simple steatosis may be clinically stable, non-alcoholic steatohepatitis (NASH) can be progressive. Inflammation is believed to be the driving force behind NASH and the progression to fibrosis and subsequent cirrhosis. NAFLD is globally considered a significant health concern not only because of its incidence but also because of its economic impact. The fact that NAFLD is associated with cardiovascular disease is widely recognized, as well as the fact that NAFLD patient mortality rises when such an association is present. In particular, NAFLD is associated with coronary and carotid atherosclerosis, endothelial dysfunction and arterial rigidity, ventricles function, valves morphology, congestive heart failure, and arrhythmias (especially atrial fibrillation). Additionally, the hypercoagulability status in NAFLD patient may be suggested by the presence of inflammatory and coagulation markers. In order to differentiate between milder forms and the more severe ones that necessitate aggressive therapy, individualized risk scores may be used. This narrative review will analyze and interpret the papers published in PubMed in the last 16 years, in an attempt to expand our understanding of the NASH as a possible cardiovascular risk factor. PMID:27389154

  3. 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. PMID:26823198

  4. Combination drug treatment in patients with non-alcoholic fatty liver disease

    PubMed Central

    Filippatos, Theodosios D; Elisaf, Moses S

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) includes simple steatosis, a benign condition, and non-alcoholic steatohepatitis, a condition that beyond TG accumulation also includes necroinflammation and fibrosis. An association between NAFLD and cardiovascular disease (CVD) has been recently suggested. NAFLD patients usually have an increased CVD risk profile. NAFLD is also associated with metabolic syndrome (MetS) and is considered as the hepatic component of MetS by some authors. Currently, the only established treatment of NAFLD is gradual weight loss. However, multifactorial treatment of NAFLD risk factors may be needed to reduce the increased CVD risk of NALFD patients. Drug combinations that include antiobesity drugs (such as orlistat and sibutramine) and target CVD risk factors may be a good approach to NAFLD patients. Our group has investigated the orlistat-fenofibrate combination treatment in obese patients with MetS and the orlistat-ezetimibe and sibutramine-antihypertensive combination treatment in obese patients with hyperlipidaemia with promising results in CVD risk factor reduction and improvement of liver function tests. Small studies give promising results but double-blind, randomized trials examining the effects of such multifactorial treatment in hard CVD endpoints in NAFLD patients are missing. PMID:21160985

  5. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease

    PubMed Central

    Kallwitz, Eric R; McLachlan, Alan; Cotler, Scott J

    2008-01-01

    Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and can result in nonalcoholic steatohepatitis (NASH) and progressive liver disease including cirrhosis and hepatocellular carcinoma. A growing body of literature implicates the peroxisome proliferators-activated receptors (PPARs) in the pathogenesis and treatment of NAFLD. These nuclear hormone receptors impact on hepatic triglyceride accumulation and insulin resistance. The aim of this review is to describe the data linking PPARα and PPARγ to NAFLD/NASH and to discuss the use of PPAR ligands for the treatment of NASH. PMID:18176957

  6. Does fructose consumption contribute to non-alcoholic fatty liver disease?

    PubMed

    Tappy, Luc; Lê, Kim-Anne

    2012-12-01

    Fructose is mainly consumed with added sugars (sucrose and high fructose corn syrup), and represents up to 10% of total energy intake in the US and in several European countries. This hexose is essentially metabolized in splanchnic tissues, where it is converted into glucose, glycogen, lactate, and, to a minor extent, fatty acids. In animal models, high fructose diets cause the development of obesity, insulin resistance, diabetes mellitus, and dyslipidemia. Ectopic lipid deposition in the liver is an early occurrence upon fructose exposure, and is tightly linked to hepatic insulin resistance. In humans, there is strong evidence, based on several intervention trials, that fructose overfeeding increases fasting and postprandial plasma triglyceride concentrations, which are related to stimulation of hepatic de novo lipogenesis and VLDL-TG secretion, together with decreased VLDL-TG clearance. However, in contrast to animal models, fructose intakes as high as 200 g/day in humans only modestly decreases hepatic insulin sensitivity, and has no effect on no whole body (muscle) insulin sensitivity. A possible explanation may be that insulin resistance and dysglycemia develop mostly in presence of sustained fructose exposures associated with changes in body composition. Such effects are observed with high daily fructose intakes, and there is no solid evidence that fructose, when consumed in moderate amounts, has deleterious effects. There is only limited information regarding the effects of fructose on intrahepatic lipid concentrations. In animal models, high fructose diets clearly stimulate hepatic de novo lipogenesis and cause hepatic steatosis. In addition, some observations suggest that fructose may trigger hepatic inflammation and stimulate the development of hepatic fibrosis. This raises the possibility that fructose may promote the progression of non-alcoholic fatty liver disease to its more severe forms, i.e. non-alcoholic steatohepatitis and cirrhosis. In humans, a

  7. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease

    PubMed Central

    Miura, Kouichi; Ohnishi, Hirohide

    2014-01-01

    Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease (NAFLD). The change in gut microbiota may alter nutritional absorption and storage. In addition, gut microbiota are a source of Toll-like receptor (TLR) ligands, and their compositional change can also increase the amount of TLR ligands delivered to the liver. TLR ligands can stimulate liver cells to produce proinflammatory cytokines. Therefore, the gut-liver axis has attracted much interest, particularly regarding the pathogenesis of NAFLD. The abundance of the major gut microbiota, including Firmicutes and Bacteroidetes, has been considered a potential underlying mechanism of obesity and NAFLD, but the role of these microbiota in NAFLD remains unknown. Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD. For instance, a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability, which allows the leakage of bacterial components. Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD. In children, the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis (NASH) compared with those in obese control. Escherichia can produce ethanol, which promotes gut permeability. Thus, normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD. In addition, TLR signaling in the liver is activated, and its downstream molecules, such as proinflammatory cytokines, are increased in NAFLD. To data, TLR2, TLR4, TLR5, and TLR9 have been shown to be associated with the pathogenesis of NAFLD. Therefore, gut microbiota and TLRs are targets for NAFLD treatment. PMID:24966608

  8. Anthropometric and Biochemical Characteristics of Patients with Nonalcoholic Fatty Liver Diagnosed by Non-Invasive Diagnostic Methods

    PubMed Central

    Novakovic, Tatjana; Mekic, Mevludin; Smilic, Ljiljana; Smilic, Tanja; Inić-Kostic, Biljana; Jovicevic, Ljiljana; Mirkovic, Zlatica; Milinic, Srbislava

    2014-01-01

    ABSTRACT Introduction: Non-alcoholic (NAFLD) encompasses a spectrum of disease states, from steatosis (fatty liver) to non-alcoholic steatohepatitis (also called NASH steatosis with inflammatory changes) followed by progression to fibrosis and cirrhosis and hepatocellular carcinoma Excess liver fat is believed to be a manifestation of the metabolic syndrome and not surprisingly NASH is associated with obesity, insulin resistance, dyslipidemia and type 2 diabetes in humans. Aim of the study: is to establish anthropometric and biochemical specificities in patients with non-alcoholic steatohepatitis diagnosed with non-invasive diagnostic methods Material and methods: Study enrolled 170 participants, 130 with NASH steatosis. The non-alcoholic group (control), consisted of 40 normal weight patients without metabolic syndrome. Alcohol intake was estimated with established protocol. Routine biochemistry analysis were performed by standard laboratory procedures; serum levels of serum levels of fasting cholesterol and triglycerides, fasting glucose and insulin, insulin resistance estimated by HOMA index (Homeostasis model assessment), biochemistry tests and a liver ultrasound examination. Results: In study participants group, patients were more obese comparing with controls p < 0, 01, waist line extent also was of greater statistical significance in the non-alcoholic group fatty liver (p < 0, 01). Comparing biochemical parameter values, significant statistical deference has been noted in glaucosis and insulin levels, total cholesterol and gama-glutamil transferase levels, between groups (p<0, 01). Fasting glucose and insulin levels, HOMA-IR were significantly greater in study cohort group patients, as was significantly positive correlation between BMI and waist line extent. Conclusion: Patients with non-alcoholic fatty liver are excessively obese, have greater waist line extent, consequently insulin resistance and impaired glucose metabolism, insulin resistance

  9. 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

  10. Risk factors and ultrasound can predict chronic hepatitis caused by nonalcoholic fatty liver disease.

    PubMed

    Riley, Thomas R; Kahn, Amin

    2006-01-01

    The diagnosis of nonalcoholic fatty liver disease (NAFLD) is under-recognized. The aim of this study was to develop a scoring system that separates NAFLD diagnosis as a cause of chronic hepatitis from controls by using clinical features and liver ultrasound. A retrospective review of consecutive NAFLD cases and other liver disease controls was undertaken selecting patients from an abnormal liver function test code. To qualify for analysis all patients had to have elevated liver injury tests for more then 6 months, a biopsy-confirmed diagnosis, and an ultrasound as part of the evaluation. There were 84 cases of NAFLD and 75 liver disease controls. The NAFLD group had a larger body mass index (BMI) (34.9 versus 26.1; P < or = 0.0001), a larger liver span (9.8 versus 8.1 cm; P < or = 0.0001), and higher triglycerides (252 versus 142.6; P < or = 0.0001). The ultrasound reports recorded features consistent with fatty infiltration in 65.5% of NAFLD cases, compared to 5.3% of other liver diseases (P < or = 0.0001). Diabetes mellitus was found in 35% of NAFLD and 6.7% of other cases (P < or = 0.0001). The BMI was >30 in 79.8% of NAFLD cases and 22.7% of other liver disease cases (P < or = 0.0001). The liver span was >8 cm in 78.6% of NAFLD cases and in only 16% of controls (P = 0.0001). On multivariate analysis using logistic regression, the odds ratio of having ultrasound report findings suggestive of fatty infiltration was 15.9 (CI, 4.1-60). The odds ratio was 9.4 (CI, 2.3-37.9) for diabetes, 5.0 (CI, 1.7-14.6) for BMI >30, and 2.3 for liver span >8 cm (CI, 1.36-3.90). A scoring system using clinical features and ultrasound was shown to reliably separate NAFLD from other cases of chronic hepatitis. PMID:16416209

  11. 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

  12. Antioxidant vitamins in the context of nonalcoholic fatty liver disease in obese children and adolescents

    PubMed Central

    Ued, Fábio da Veiga; Weffort, Virgínia Resende S.

    2013-01-01

    OBJECTIVE: To review the literature on the importance of antioxidant vitamins, analyzed in the context of dietary intake, its plasma levels, and its current use as a supplementation treatment in obese children and adolescents with nonalcoholic fatty liver disease. DATA SOURCES: The articles were identified in Lilacs, Ibecs, SciELO, PubMed/Medline, and Scopus databases. To conduct the survey, the "fatty liver" descriptor was associated to the following words: "children", "antioxidants" and "vitamins". The search was limited to articles written in Portuguese, Spanish and English, with publication date until December, 2012. DATA SYNTHESIS: Six studies were selected. The survey revealed a low dietary intake and low antioxidant vitamins serum levels in this population. The changes in lifestyle, with adequate dietary intake of vitamins, and the increase in physical activity were associated with a significant improvement in liver histology and in laboratory tests. Vitamin supplementation also improved the disease progression markers, as the alanine aminotransferase serum levels and the histological characteristics of lobular inflammation and hepatocellular damage. However, these improvements were not statistically significant in all studies. CONCLUSIONS: There is insufficient evidence to recommend or to refute antioxidant supplementation in patients with simple steatosis or steatohepatitis. The changes in lifestyle seem to be, at the present time, the more advisable therapy. PMID:24473959

  13. Insulin resistance in development and progression of nonalcoholic fatty liver disease

    PubMed Central

    Alam, Shahinul; Mustafa, Golam; Alam, Mahabubul; Ahmad, Nooruddin

    2016-01-01

    Although insulin resistance (IR) is strongly associated with nonalcoholic fatty liver disease (NAFLD), the association of IR and NAFLD is not universal and correlation between IR and severity of NAFLD is still controversial. In this review, we summarize recent evidence that partially dissociates insulin resistance from NAFLD. It has also been reported that single-nucleotide polymorphisms in the diacylglycerol acyltransferase gene, rather than IR, account for the variability in liver fat content. Polymorphisms of the patatin-like phospholipase 3 gene have also been reported to be associated with NAFLD without metabolic syndrome, which suggests that genetic conditions that promote the development of fatty changes in the liver may occur independently of IR. Moreover, environmental factors such as nutrition and physical activity as well as small intestinal bacterial overgrowth have been linked to the pathogenesis of NAFLD, although some of the data are conflicting. Therefore, findings from both genetically engineered animal models and humans with genetic conditions, as well as recent studies that have explored the role of environmental factors, have confirmed the view that NAFLD is a polygenic disease process caused by both genetic and environmental factors. Therefore, IR is not the sole predictor of the pathogenesis of NAFLD. PMID:27190693

  14. Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease

    PubMed Central

    Kim, Sokho; Park, Surim; Kim, Bumseok; Kwon, Jungkee

    2016-01-01

    Recently, a possible link between toll-like receptor 7 (TLR7) and liver disease was suggested, although it was limited to fibrosis. Based on this report, we investigated whether TLR7 has a pivotal role in non-alcoholic fatty liver disease (NAFLD). The TLR7 signaling pathway, which is activated by imiquimod (TLR7 ligand) naturally, induced autophagy and released insulin-like growth factor 1 (IGF-1) into medium from hepatocytes. Lipid accumulation induced by unsaturated fatty acid (UFA; arachidonic acid:oleic acid = 1:1) in hepatocytes, was attenuated in TLR7 and autophagy activation. Interestingly, TLR7 activation attenuated UFA-induced lipid peroxidation products, such as malondialdehyde (MDA) and 4-Hydroxy-2-Nonenal (4-HNE). To clarify a possible pathway between TLR7 and lipid peroxidation, we treated hepatocytes with MDA and 4-HNE. MDA and 4-HNE induced 2-folds lipid accumulation in UFA-treated hepatocytes via blockade of the TLR7 signaling pathway’s IGF-1 release compared to only UFA-treated hepatocytes. In vivo experiments carried out with TLR7 knockout mice produced results consistent with in vitro experiments. In conclusion, TLR7 prevents progression of NAFLD via induced autophagy and released IGF-1 from liver. These findings suggest a new therapeutic strategy for the treatment of NAFLD. PMID:27279075

  15. Insulin resistance in development and progression of nonalcoholic fatty liver disease.

    PubMed

    Alam, Shahinul; Mustafa, Golam; Alam, Mahabubul; Ahmad, Nooruddin

    2016-05-15

    Although insulin resistance (IR) is strongly associated with nonalcoholic fatty liver disease (NAFLD), the association of IR and NAFLD is not universal and correlation between IR and severity of NAFLD is still controversial. In this review, we summarize recent evidence that partially dissociates insulin resistance from NAFLD. It has also been reported that single-nucleotide polymorphisms in the diacylglycerol acyltransferase gene, rather than IR, account for the variability in liver fat content. Polymorphisms of the patatin-like phospholipase 3 gene have also been reported to be associated with NAFLD without metabolic syndrome, which suggests that genetic conditions that promote the development of fatty changes in the liver may occur independently of IR. Moreover, environmental factors such as nutrition and physical activity as well as small intestinal bacterial overgrowth have been linked to the pathogenesis of NAFLD, although some of the data are conflicting. Therefore, findings from both genetically engineered animal models and humans with genetic conditions, as well as recent studies that have explored the role of environmental factors, have confirmed the view that NAFLD is a polygenic disease process caused by both genetic and environmental factors. Therefore, IR is not the sole predictor of the pathogenesis of NAFLD. PMID:27190693

  16. A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence.

    PubMed

    Temple, Jonathan L; Cordero, Paul; Li, Jiawei; Nguyen, Vi; Oben, Jude A

    2016-01-01

    Non-Alcoholic Fatty Liver Disease (NAFLD) is now the most prevalent form of chronic liver disease, affecting 10%-20% of the general paediatric population. Within the next 10 years it is expected to become the leading cause of liver pathology, liver failure and indication for liver transplantation in childhood and adolescence in the Western world. While our understanding of the pathophysiological mechanisms underlying this disease remains limited, it is thought to be the hepatic manifestation of more widespread metabolic dysfunction and is strongly associated with a number of metabolic risk factors, including insulin resistance, dyslipidaemia, cardiovascular disease and, most significantly, obesity. Despite this, "paediatric" NAFLD remains under-studied, under-recognised and, potentially, undermanaged. This article will explore and evaluate our current understanding of NAFLD in childhood and adolescence and how it differs from adult NAFLD, in terms of its epidemiology, pathophysiology, natural history, diagnosis and clinical management. Given the current absence of definitive radiological and histopathological diagnostic tests, maintenance of a high clinical suspicion by all members of the multidisciplinary team in primary and specialist care settings remains the most potent of diagnostic tools, enabling early diagnosis and appropriate therapeutic intervention. PMID:27314342

  17. Lycopene Improves Diet-Mediated Recuperation in Rat Model of Nonalcoholic Fatty Liver Disease.

    PubMed

    Piña-Zentella, Rosa María; Rosado, Jorge L; Gallegos-Corona, Marco A; Madrigal-Pérez, Luis Alberto; García, Olga P; Ramos-Gomez, Minerva

    2016-06-01

    The aim of the present study was to evaluate the synergic effect of lycopene (LYC) treatment with a dietary control in a nonalcoholic fatty liver disease (NAFLD) model induced with a high-fat diet (HFD). Sprague-Dawley rats were fed during 4 weeks with a normal diet (ND·4w) or an HFD (HFD·4w) to produce an NAFLD model. Then, rats from the ND·4w group continued during 4 weeks with the same diet (ND·8w), and rats from HFD were fed during 4 weeks with an ND (HFD·4w+ND·4w) or an ND plus LYC (HFD·4w+ND+LYC·4w). LYC (20 mg/kg) was administered daily by gavage. ND and ND+LYC diets partially reverted the following alterations due to HFD: liver weight, serum low-density lipoproteins (LDL), hepatic total cholesterol (TC), and catalytic activity of hepatic superoxide dismutase, catalase, and glutathione peroxidase, as well as macroscopic and microscopic images of livers. A higher recuperation to reach normality was obtained with ND+LYC in: liver weight, hepatic TC, serum LDL, and, in some instances, macroscopic and microscopic images of livers. Failures to recovery with both NDs were observed for malondialdehyde level and serum aspartate aminotransferase activity. Taken together, the results from this study suggest the potentially protective role of LYC against NAFLD; however, more clinical trials are needed to support this idea. PMID:27214602

  18. The role of bariatric surgery in the management of nonalcoholic fatty liver disease and metabolic syndrome.

    PubMed

    Aguilar-Olivos, Nancy E; Almeda-Valdes, Paloma; Aguilar-Salinas, Carlos A; Uribe, Misael; Méndez-Sánchez, Nahum

    2016-08-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD is strongly associated with obesity and metabolic syndrome (MetS). Current treatment of NAFLD is based on weight reduction. Bariatric surgery is the most effective treatment for morbid obesity and its associated metabolic comorbidities. There is evidence indicating that bariatric surgery improves histological and biochemical parameters of NAFLD, but currently is not considered a treatment option for NAFLD. The aim of this work is to review the evidence for the effects of bariatric surgery on NAFLD and the MetS. We found that insulin resistance, alterations in glucose metabolism, hypertension, plasma lipids, transaminases, liver steatosis, steatohepatitis and fibrosis improve after bariatric surgery. Weight loss and improvement of NAFLD are greater after RYGB than after other interventions. These findings were obtained from retrospective or cohort studies. There are no studies designed to evaluate liver-specific mortality, liver transplantation, or quality of life. Patients with indications for bariatric surgery will benefit from the improvements in the MetS and NAFLD. PMID:26435078

  19. A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence

    PubMed Central

    Temple, Jonathan L.; Cordero, Paul; Li, Jiawei; Nguyen, Vi; Oben, Jude A.

    2016-01-01

    Non-Alcoholic Fatty Liver Disease (NAFLD) is now the most prevalent form of chronic liver disease, affecting 10%–20% of the general paediatric population. Within the next 10 years it is expected to become the leading cause of liver pathology, liver failure and indication for liver transplantation in childhood and adolescence in the Western world. While our understanding of the pathophysiological mechanisms underlying this disease remains limited, it is thought to be the hepatic manifestation of more widespread metabolic dysfunction and is strongly associated with a number of metabolic risk factors, including insulin resistance, dyslipidaemia, cardiovascular disease and, most significantly, obesity. Despite this, ”paediatric” NAFLD remains under-studied, under-recognised and, potentially, undermanaged. This article will explore and evaluate our current understanding of NAFLD in childhood and adolescence and how it differs from adult NAFLD, in terms of its epidemiology, pathophysiology, natural history, diagnosis and clinical management. Given the current absence of definitive radiological and histopathological diagnostic tests, maintenance of a high clinical suspicion by all members of the multidisciplinary team in primary and specialist care settings remains the most potent of diagnostic tools, enabling early diagnosis and appropriate therapeutic intervention. PMID:27314342

  20. Nutrition, nonalcoholic fatty liver disease and the microbiome: recent progress in the field

    PubMed Central

    Vos, Miriam B.

    2014-01-01

    Purpose of review Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and it has overlapping pathogenesis with diabetes and cardiovascular disease. Reviewed here are recent advances in understanding the contribution of diet and selected nutrients to NAFLD. Recent findings To understand the effect of diet, the microbiome must be considered because it is the interface of diet and the liver. Early studies suggest that the characteristic of the microbiota is altered in NAFLD. Fructose is a lipogenic carbohydrate that contributes to insulin resistance, hypertriglyceridemia and appears to be associated with the severity of NAFLD. Fructose absorption and malabsorption may alter the microbiota and which could be mediating effects on the liver. Lipids also have potent microbiome interactions and could contribute to the benefit of diets emphasizing lipid changes. Several new studies demonstrate that the Mediterranean diet and ‘lifestyle change’ are effective in modestly improving NAFLD. A new study of lifestyle in children showed simultaneous improvement in CVD risk measurements and hepatic steatosis. Summary Current data supports limiting sugar in the diet and ‘lifestyle change’ as a first-line treatment for NAFLD; however, the benefits from these appear to be modest. The effects of diet on the liver are mediated through the microbiome and expansion of research in this area is needed. PMID:24366230

  1. Nonalcoholic fatty liver disease: Update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine

    PubMed Central

    Noureddin, Mazen; Mato, José M; Lu, Shelly C

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide affecting over one-third of the population in the U.S. It has been associated with obesity, type 2 diabetes, hyperlipidemia, and insulin resistance and is initiated by the accumulation of triglycerides in hepatocytes. Isolated hepatic steatosis (IHS) remains a benign process, while a subset develops superimposed inflammatory activity and progression to nonalcoholic steatohepatitis (NASH) with or without fibrosis. However, the molecular mechanisms underlying NAFLD progression are not completely understood. Liver biopsy is still required to differentiate IHS from NASH as easily accessible noninvasive biomarkers are lacking. In terms of treatments for NASH, pioglitazone, vitamin E, and obeticholic acid have shown some benefit. All of these agents have potential complications associated with long-term use. Nowadays, a complex hypothesis suggests that multiple parallel hits are involved in NASH development. However, the ‘key switch’ between IHS and NASH remains to be discovered. We have recently shown that knocking out enzymes involved in S-adenosylmethionine (SAMe) metabolism, the main biological methyl donor in humans that is abundant in the liver, will lead to NASH development in mice. This could be due to the fact that a normal SAMe level is required to establish the proper ratio of phosphatidylethanolamine to phosphatidylcholine that has been found to be important in NAFLD progression. New data from humans have also suggested that these enzymes play a role in the pathogenesis of NAFLD and that some of SAMe cycle metabolites may serve as noninvasive biomarkers of NASH. In this review, we discuss the evidence of the role of SAMe in animal models and humans with NAFLD and how studying this area may lead to the discovery of new noninvasive biomarkers and possibly personalized treatment for NASH. PMID:25873078

  2. Comparison of the Phenotype and Approach to Pediatric vs Adult Patients With Nonalcoholic Fatty Liver Disease.

    PubMed

    Nobili, Valerio; Alisi, Anna; Newton, Kimberly P; Schwimmer, Jeffrey B

    2016-06-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the main chronic noncommunicable diseases in Westernized societies; its worldwide prevalence has doubled during the last 20 years. NAFLD has serious health implications not only for adults, but also for children. However, pediatric NAFLD is not only an important global problem in itself, but it is likely to be associated with increases in comorbidities, such as metabolic syndrome and cardiovascular diseases. There are several differences between NAFLD in children and adults, and it is not clear whether the disease observed in children is the initial phase of a process that progresses with age. The increasing prevalence of pediatric NAFLD has serious implications for the future adult population requiring appropriate action. Studies of NAFLD progression, pathogenesis, and management should evaluate disease phenotypes in children and follow these over the patient's lifetime. We review the similarities and differences of NAFLD between children and adults. PMID:27003600

  3. What does irritable bowel syndrome share with non-alcoholic fatty liver disease?

    PubMed Central

    Scalera, Antonella; Di Minno, Matteo Nicola Dario; Tarantino, Giovanni

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS) are two very common diseases in the general population. To date, there are no studies that highlight a direct link between NAFLD and IBS, but some recent reports have found an interesting correlation between obesity and IBS. A systematic PubMed database search was conducted highlighting that common mechanisms are involved in many of the local and systemic manifestations of NAFLD, leading to an increased cardiovascular risk, and IBS, leading to microbial dysbiosis, impaired intestinal barrier and altered intestinal motility. It is not known when considering local and systemic inflammation/immune system activation, which one has greater importance in NAFLD and IBS pathogenesis. Also, the nervous system is implicated. In fact, inflammation participates in the development of mood disorders, such as anxiety and depression, characteristics of obesity and consequently of NAFLD and, on the other hand, in intestinal hypersensitivity and dysmotility. PMID:24023483

  4. Hyperuricemia and nonalcoholic fatty liver disease: from bedside to bench and back.

    PubMed

    Xu, Chengfu

    2016-03-01

    Uric acid is the end product of dietary or endogenous purines degradation, and hyperuricemia is one of the most common metabolic disorders. It has been widely accepted that hyperuricemia increases risks of gout, cardiovascular diseases, and type 2 diabetes. A growing body of evidence, comprising a great deal of cross-sectional studies and several prospective ones, also indicates that hyperuricemia is associated with increased prevalence, incidence and disease severity of non-alcoholic fatty liver disease (NAFLD). On the contrary, NAFLD can predict hyperuricemia as well. However, no causal relationship can be drawn from this point. With a well-established relationship between uric acid and NAFLD prevalence as well as disease severity in addition to the role of potential therapeutic target, the prognostic role of uric acid is also worth investigating. Further studies should focus on the prospective role of uric acid on NAFLD progression and its underlying mechanisms, as well as its clinical implications. PMID:26671825

  5. Nonalcoholic Fatty Liver Disease: Dyslipidemia, Risk for Cardiovascular Complications, and Treatment Strategy

    PubMed Central

    Zhang, Qing-Qing; Lu, Lun-Gen

    2015-01-01

    Studies have shown that nonalcoholic fatty liver disease (NAFLD) is strongly associated with several metabolic disorders and diseases, such as obesity, type 2 diabetes mellitus, and dyslipidemia. In NAFLD, dyslipidemia is manifested as increased serum triglyceride and low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels, all of which are key risk factors for cardiovascular disease (CVD). CVD is a leading cause of mortality in NAFLD patients. Thus, implementation of an aggressive therapeutic strategy for dyslipidemia with hypolipidemic agents may mitigate the risk for CVD among NAFLD patients. Here, we provide a current review of literature regarding NAFLD, with particular emphasis on dyslipidemia and available treatment options. PMID:26357637

  6. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease

    PubMed Central

    Bradford, V; Dillon, JF; Miller, MH

    2014-01-01

    The burden of non-alcoholic fatty liver disease (NAFLD) worldwide is a significant clinical and public health issue, affecting approximately one third of the Western population. This review assesses the effect and impact lifestyle interventions have on the treatment of this common condition. We review studies comparing the effect of calorie restriction and exercise programs, as well as comparison of lifestyle intervention with pharmaceutical intervention. Both calorie restriction and exercise programs are shown to be beneficial in improving features of metabolic syndrome and surrogate markers of NAFLD. The paucity of studies using histological improvement hinders the ability to conclude a benefit on improvement of histological NAFLD, although this is shown in a small number of studies. There is a need to extend the intervention period to show a sustained improvement with intervention as most studies have a follow up period of 12 months of less. PMID:24826079

  7. The Role of Vitamins in the Pathogenesis of Non-alcoholic Fatty Liver Disease

    PubMed Central

    Li, Jiawei; Cordero, Paul; Nguyen, Vi; Oben, Jude A.

    2016-01-01

    The incidence of non-alcoholic fatty liver disease (NAFLD) is rising rapidly in parallel with obesity rates. The underlying pathogenesis of NAFLD remains an enigma but is largely influenced by individual lifestyle choices involving diet and exercise. Therefore, studies have highlighted the importance of calorie reduction and macronutrient composition (eg, carbohydrate and fat) in modifying disease outcomes. Micronutrients are also believed to play a role in disease progression. There are now an increasing number of studies linking vitamins with NAFLD, particularly vitamin E, and the supplementation of several different vitamins has been demonstrated as a promising therapeutic option in the treatment of NAFLD. This review provides a broad overview of the potential role of vitamins in NAFLD development and disease management. PMID:27147819

  8. Omega-3 fatty acids for treatment of non-alcoholic fatty liver disease: design and rationale of randomized controlled trial

    PubMed Central

    2013-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome since obesity and insulin resistance are the main pathogenic contributors for both conditions. NAFLD carries increased risk of atherosclerosis and cardiovascular diseases. There is an urgent need to find effective and safe therapy for children and adults with NAFLD. Data from research and clinical studies suggest that omega-3 fatty acids may be beneficial in metabolic syndrome-related conditions and can reduce the risk of cardiovascular disease. Methods/design We are conducting a randomized, multicenter, double-blind, placebo-controlled trial of treatment with omega-3 fatty acids in children with NAFLD. Patients are randomized to receive either omega-3 fatty acids containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or placebo for 24 weeks. The dose of omega-3 (DHA+ EPA) ranges from 450 to 1300 mg daily. Low calorie diet and increased physical activity are advised and monitored using validated questionnaires. The primary outcome of the trial is the number of patients who decreased ALT activity by ≥ 0,3 of upper limit of normal. The main secondary outcomes are improvement in the laboratory liver tests, liver steatosis on ultrasound, markers of insulin resistance and difference in fat/lean body mass composition after 6 months of intervention. Discussion Potential efficacy of omega-3 fatty acids in the treatment of NAFLD will provide needed rationale for use of this safe diet supplement together with weight reduction therapy in the growing population of children with NAFLD. Trial registration NCT01547910 PMID:23702094

  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. Visceral adipose tissue area as an independent risk factor for elevated liver enzyme in nonalcoholic fatty liver disease.

    PubMed

    Chung, Goh Eun; Kim, Donghee; Kwark, Min Sun; Kim, Won; Yim, Jeong Yoon; Kim, Yoon Jun; Yoon, Jung-Hwan

    2015-03-01

    Chronic elevations in alanine aminotransferase (ALT) levels are associated with body composition. The aim of this study was to evaluate the relationship between elevated liver enzyme levels and the visceral tissue area in subjects with and without nonalcoholic fatty liver disease (NAFLD).An observational cohort study was conducted with subjects undergoing general health examinations. To evaluate the visceral and subcutaneous abdominal adipose tissue area, a computed tomography scan was performed. NAFLD was diagnosed if a person demonstrated fatty liver on ultrasonography without a history of significant alcohol consumption or chronic liver disease. Abnormal liver enzyme levels were based on ALT elevations according to the updated Asian definition.Of the 5100 subjects, 3712 (72.8%) met the inclusion criteria, and NAFLD was found in 1185 subjects. Elevated ALT values were positively correlated with body mass index, waist circumference, and subcutaneous and visceral adipose tissue area. These relationships were attenuated, although they remained significant in a dose-dependent manner, after adjusting for multiple liver injury risk factors. In addition, when body mass index and subcutaneous and visceral tissue areas were finally considered in combination, only visceral adipose tissue remained independently associated with elevated ALT levels in the ultrasonographically diagnosed NAFLD group (P for trend <0.001 for men and women).Elevated ALT levels were independently and dose-dependently associated with visceral fat accumulation in the healthy general population, especially in ultrasonographically diagnosed NAFLD patients. These results reemphasize the importance of visceral fat in the pathogenesis of NAFLD. PMID:25738475

  11. Liver ergothioneine accumulation in a guinea pig model of non-alcoholic fatty liver disease. A possible mechanism of defence?

    PubMed

    Cheah, Irwin K; Tang, Richard; Ye, Peng; Yew, Terry S Z; Lim, Keith H S; Halliwell, Barry

    2016-01-01

    L-ergothioneine (ET), a putative antioxidant compound acquired by animals through dietary sources, has been suggested to accumulate in certain cells and tissues in the body that are predisposed to high oxidative stress. In the present study, we identified an elevation of ET in the liver of a guinea pig model of non-alcoholic fatty liver disease (NAFLD), elucidated a possible mechanism for the increased uptake and investigated the possible role for this accumulation. This increase in liver ET levels correlated with cholesterol accumulation and disease severity. We identified an increase in the transcriptional factor, RUNX1, which has been shown to upregulate the expression of the ET-specific transporter OCTN1, and could consequently lead to the observable elevation in ET. An increase was also seen in heat shock protein 70 (HSP70) which seemingly corresponds to ET elevation. No significant increase was observed in oxidative damage markers, F2-isoprostanes, and protein carbonyls, which could possibly be attributed to the increase in liver ET through direct antioxidant action, induction of HSP70, or by chelation of Fe(2+), preventing redox chemistry. The data suggest a novel mechanism by which the guinea pig fatty liver accumulates ET via upregulation of its transporter, as a possible stress response by the damaged liver to further suppress oxidative damage and delay tissue injury. Similar events may happen in other animal models of disease, and researchers should be aware of the possibility. PMID:26634964

  12. Estimation of Diagnosis and Treatment Costs of Non-Alcoholic Fatty Liver Disease: A Two-Year Observation

    PubMed Central

    Ghamar Chehreh, Mohammad Ebrahim; Vahedi, Mohsen; Pourhoseingholi, Mohammad Amin; Ashtari, Sara; Khedmat, Hossein; Amin, Mohsen; Zali, Mohammad Reza; Alavian, Seyed Moayed

    2013-01-01

    Background There are insufficient data available on utilization and health care costs of non-alcoholic fatty liver disease. The cost data for different health conditions and services is a major gap in Iranian health system. So this study is the primary or first step towards filling this gap. Objectives This study aims to estimate the diagnosis and treatment costs of Non-alcoholic Fatty Liver. Patients and Methods This cross-sectional study was conducted on 528 subjects. The subjects had been diagnosed with non-alcoholic fatty liver. All the subjects had been referred to the Tehran Fatty Liver Clinic, a clinic of the Baqiyatallah Research Center for Gastroenterology and Liver Diseases, in 2009 and they had been observed for 2 years to determine the frequency of health care utilization (physician visit, laboratory tests, medication and cost of sonography). The costs of diagnosis and treatment for each person were estimated in Purchasing Power Parity dollars (PPP$). Results The average total cost was 5,043 PPP$ per person in the 2 years of observation. Majority of these 528 patients (87.9%) had a BMI ≥ 25 (kg/m2). Also, 33.9% were diagnosed with comorbid diseases such as Diabetes Mellitus (DM), Coronary Artery Disease (CAD), hypertension (HTN) and hypothyroidism (HYPO). Conclusions The results confirmed that the total costs for non-alcoholic fatty liver among the Iranian adult urban population alone exceeded 1 billion PPP$ per year. These costs can be saved or reduced by effective disease management and early prevention. PMID:23914227

  13. Probiotics as a Novel Treatment for Non-Alcoholic Fatty Liver Disease; A Systematic Review on the Current Evidences

    PubMed Central

    Kelishadi, Roya; Farajian, Sanam; Mirlohi, Maryam

    2013-01-01

    Context Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with 5-10% of liver having extra fat. Increase in its prevalence in all age groups is linked with obesity and Type II diabetes. The treatment of NAFLD remains controversial. A growing body of evidence suggests a relation between overgrowth of gut microbiota with NAFLD and non-alcoholic steatohepatitis (NASH). The objective of this review is to provide an overview on experimental and clinical studies assessing all positive and negative effects of probiotics. Evidence Acquisition We made a critical appraisal on various types of documents published from 1999 to March 2012 in journals, electronic books, seminars, and symposium contexts including Medline, PubMed, and Cochrane Central Register of Controlled Trials databases. We used the key words: “non-alcoholic fatty liver disease, probiotics, non-alcoholic steatohepatitis, liver disease, and fatty liver”. Results Probiotics, as biological factors, control the gut microbiota and result in its progression. It is in this sense that they are suggestive of a new and a natural way of promoting liver function. Correspondingly, limited evidence suggests that probiotics could be considered as a new way of treatment for NAFLD. Conclusions Various experimental studies and clinical trials revealed promising effects of probiotics in improving NAFLD; however given the limited experience in this field, generalization of probiotics as treatment of NAFLD needs substantiation through more trials with a larger sample sizes and with longer-term follow up. PMID:23885277

  14. Spontaneous nonalcoholic fatty liver disease and ER stress in Sidt2 deficiency mice.

    PubMed

    Gao, Jialin; Zhang, Yao; Yu, Cui; Tan, Fengbiao; Wang, Lizhuo

    2016-08-01

    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(-/-) 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(-/-) mice, there were obvious fat degeneration and inflammatory changes. Almost all of 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(-/-) 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(-/-) 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(-/-) 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(-/-) mice had spontaneous nonalcoholic fatty liver disease (NAFLD) accompanied by

  15. Interleukin-18-deficient mice develop dyslipidemia resulting in nonalcoholic fatty liver disease and steatohepatitis.

    PubMed

    Yamanishi, Kyosuke; Maeda, Seishi; Kuwahara-Otani, Sachi; Watanabe, Yuko; Yoshida, Momoko; Ikubo, Kaoru; Okuzaki, Daisuke; El-Darawish, Yosif; Li, Wen; Nakasho, Keiji; Nojima, Hiroshi; Yamanishi, Hiromichi; Hayakawa, Tetsu; Okamura, Haruki; Matsunaga, Hisato

    2016-07-01

    We investigated potential pathophysiological relationships between interleukin 18 (IL-18) and dyslipidemia, nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). Compared with Il18(+/+) mice, IL-18 knockout (Il18(-/-)) mice developed hypercholesterolemia and hyper-high-density-lipoprotein-cholesterolemia as well as hypertriglyceridemia as they aged, and these disorders occurred before the manifestation of obesity and might cause secondary NASH. The analyses of molecular mechanisms involved in the onset of dyslipidemia, NAFLD, and NASH in Il18(-/-) mice identified a number of genes associated with these metabolic diseases. In addition, molecules related to circadian rhythm might affect these extracted genes. The intravenous administration of recombinant IL-18 significantly improved dyslipidemia, inhibited the body weight gain of Il18(+/+) mice, and prevented the onset of NASH. The expression of genes related to these dysfunctions was also affected by recombinant IL-18 administration. In conclusion, this study demonstrated the critical function of IL-18 in lipid metabolism and these findings might contribute to the progress of novel treatments for NAFLD or NASH. PMID:27063959

  16. Natural antioxidants for non-alcoholic fatty liver disease: molecular targets and clinical perspectives.

    PubMed

    Salomone, Federico; Godos, Justyna; Zelber-Sagi, Shira

    2016-01-01

    Non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), is emerging as a main health problem in industrialized countries. Lifestyle modifications are effective in the treatment of NAFLD; however, the long-term compliance is low. Therefore, several pharmacological treatments have been proposed but none has shown significant efficacy or long-term safety. Natural polyphenols are a heterogeneous class of polyphenolic compounds contained in vegetables, which are being proposed for the treatment of different metabolic disorders. Although the beneficial effect of these compounds has traditionally related to their antioxidant properties, they also exert several beneficial effects on hepatic and extra-hepatic glucose and lipid homeostasis. Furthermore, natural polyphenols exert antifibrogenic and antitumoural effects in animal models, which appear relevant from a clinical point of view because of the association of NASH with cirrhosis and hepatocellular carcinoma. Several polyphenols, such anthocyanins, curcumin and resveratrol and those present in coffee, tea, soy are available in the diet and their consumption can be proposed as part of a healthy diet for the treatment of NAFLD. Other phenolic compounds, such as silymarin, are commonly consumed worldwide as nutraceuticals or food supplements. Natural antioxidants are reported to have beneficial effects in preclinical models of NAFLD and in pilot clinical trials, and thus need clinical evaluation. In this review, we summarize the existing evidence regarding the potential role of natural antioxidants in the treatment of NAFLD and examine possible future clinical applications. PMID:26436447

  17. The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background.

    PubMed

    Yu, Jinsheng; Marsh, Sharon; Hu, Junbo; Feng, Wenke; Wu, Chaodong

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and it comprises a spectrum of hepatic abnormalities from simple hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, and liver cancer. While the pathogenesis of NAFLD remains incompletely understood, a multihit model has been proposed that accommodates causal factors from a variety of sources, including intestinal and adipose proinflammatory stimuli acting on the liver simultaneously. Prior cellular and molecular studies of patient and animal models have characterized several common pathogenic mechanisms of NAFLD, including proinflammation cytokines, lipotoxicity, oxidative stress, and endoplasmic reticulum stress. In recent years, gut microbiota has gained much attention, and dysbiosis is recognized as a crucial factor in NAFLD. Moreover, several genetic variants have been identified through genome-wide association studies, particularly rs738409 (Ile748Met) in PNPLA3 and rs58542926 (Glu167Lys) in TM6SF2, which are critical risk alleles of the disease. Although a high-fat diet and inactive lifestyles are typical risk factors for NAFLD, the interplay between diet, gut microbiota, and genetic background is believed to be more important in the development and progression of NAFLD. This review summarizes the common pathogenic mechanisms, the gut microbiota relevant mechanisms, and the major genetic variants leading to NAFLD and its progression. PMID:27247565

  18. Insulin sensitizers for the treatment of non-alcoholic fatty liver disease

    PubMed Central

    Ozturk, Zeynel Abidin; Kadayifci, Abdurrahman

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world and is closely associated with metabolic syndrome, which includes hypertension, central obesity, dyslipidemia and insulin resistance. NAFLD includes a wide spectrum of liver alterations, ranging from simple hepatic steatosis to variable degrees of fibrosis, cirrhosis and even hepatocellular carcinoma. Although the etiology and progression of the disorder remain poorly understood, insulin resistance is considered to play a pivotal role in the pathogenesis. Insulin sensitizers such as biguanides, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have been studied as therapeutic approaches for NAFLD in recent years. Metformin improves insulin sensitivity and serum alanine transaminase and aspartate transaminase (ALT/AST) levels in the majority of subjects; however, it has no significant effect on liver histology. TZDs improve insulin sensitivity, serum ALT/AST levels and histology in some cases, but there are some concerns about the safety of long-term therapy. Selection of appropriate patients for avoiding side effects and the treatment of underlying disease are the main points. These drugs are the best choice for the treatment of NAFLD in patients with type 2 DM who are also candidates for treatment with an insulin sensitizer. The present review provides an overview of insulin sensitizers in the treatment of NAFLD. PMID:24799988

  19. Nonalcoholic Fatty Liver: A Possible New Target for Type 2 Diabetes Prevention and Treatment

    PubMed Central

    Fruci, Barbara; Giuliano, Stefania; Mazza, Angela; Malaguarnera, Roberta; Belfiore, Antonino

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide. Several lines of evidence have indicated a pathogenic role of insulin resistance, and a strong association with type 2 diabetes (T2MD) and metabolic syndrome. Importantly, NAFLD appears to enhance the risk for T2MD, as well as worsen glycemic control and cardiovascular disease in diabetic patients. In turn, T2MD may promote NAFLD progression. The opportunity to take into account NAFLD in T2MD prevention and care has stimulated several clinical studies in which antidiabetic drugs, such as metformin, thiazolidinediones, GLP-1 analogues and DPP-4 inhibitors have been evaluated in NAFLD patients. In this review, we provide an overview of preclinical and clinical evidences on the possible efficacy of antidiabetic drugs in NAFLD treatment. Overall, available data suggest that metformin has beneficial effects on body weight reduction and metabolic parameters, with uncertain effects on liver histology, while pioglitazone may improve liver histology. Few data, mostly preclinical, are available on DPP4 inhibitors and GLP-1 analogues. The heterogeneity of these studies and the small number of patients do not allow for firm conclusions about treatment guidelines, and further randomized, controlled studies are needed. PMID:24264040

  20. Rimonabant Improves Oxidative/Nitrosative Stress in Mice with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Jorgačević, Bojan; Mladenović, Dušan; Ninković, Milica; Vesković, Milena; Dragutinović, Vesna; Vatazević, Aleksandar; Vučević, Danijela; Ješić Vukićević, Rada; Radosavljević, Tatjana

    2015-01-01

    The present study deals with the effects of rimonabant on oxidative/nitrosative stress in high diet- (HFD-) induced experimental nonalcoholic fatty liver disease (NAFLD). Male mice C57BL/6 were divided into the following groups: control group fed with control diet for 20 weeks (C; n = 6); group fed with HFD for 20 weeks (HF; n = 6); group fed with standard diet and treated with rimonabant after 18 weeks (R; n = 9); group fed with HFD and treated with rimonabant after 18 weeks (HFR; n = 10). Daily dose of rimonabant (10 mg/kg) was administered to HFR and R group by oral gavage for two weeks. Treatment induced a decrease in hepatic malondialdehyde concentration in HFR group compared to HF group (P < 0.01). The concentration of nitrites + nitrates in liver was decreased in HFR group compared to HF group (P < 0.01). Liver content of reduced glutathione was higher in HFR group compared to HF group (P < 0.01). Total liver superoxide dismutase activity in HFR group was decreased in comparison with HF group (P < 0.01). It was found that rimonabant may influence hepatic iron, zinc, copper, and manganese status. Our study indicates potential usefulness of cannabinoid receptor type 1 blockade in the treatment of HFD-induced NAFLD. PMID:26078820

  1. The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background

    PubMed Central

    Marsh, Sharon; Hu, Junbo; Feng, Wenke

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and it comprises a spectrum of hepatic abnormalities from simple hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, and liver cancer. While the pathogenesis of NAFLD remains incompletely understood, a multihit model has been proposed that accommodates causal factors from a variety of sources, including intestinal and adipose proinflammatory stimuli acting on the liver simultaneously. Prior cellular and molecular studies of patient and animal models have characterized several common pathogenic mechanisms of NAFLD, including proinflammation cytokines, lipotoxicity, oxidative stress, and endoplasmic reticulum stress. In recent years, gut microbiota has gained much attention, and dysbiosis is recognized as a crucial factor in NAFLD. Moreover, several genetic variants have been identified through genome-wide association studies, particularly rs738409 (Ile748Met) in PNPLA3 and rs58542926 (Glu167Lys) in TM6SF2, which are critical risk alleles of the disease. Although a high-fat diet and inactive lifestyles are typical risk factors for NAFLD, the interplay between diet, gut microbiota, and genetic background is believed to be more important in the development and progression of NAFLD. This review summarizes the common pathogenic mechanisms, the gut microbiota relevant mechanisms, and the major genetic variants leading to NAFLD and its progression. PMID:27247565

  2. Diet Macronutrients Composition in Nonalcoholic Fatty Liver Disease: A Review on the Related Documents

    PubMed Central

    Hashemi Kani, Ali; Alavian, Seyed Moayed; Haghighatdoost, Fahimeh; Azadbakht, Leila

    2014-01-01

    Context: Non-alcoholic fatty liver disease (NAFLD) is a growing health problem in both developed and developing countries. Metabolic abnormalities, specially insulin resistance and hyperglycemia are highly correlated with NAFLD. Lifestyle modifications including physical activity and promoting nutrient intakes are critical in prevention and treatment of NAFLD. Hence, in this article we aimed to review the evidence regarding the effects of various macronutrients on fat accumulation in hepatic cells as well as the level of liver enzymes. Evidence Acquisitions: The relevant English and non-English published papers were searched using online databases of PubMed, ISI Web of Science, SCOPUS, Science Direct and EMBASE from January 2000 to January 2013. We summarized the findings of 40 relevant studies in this review. Results: Although a hypocaloric diet could prevent the progression of fat accumulation in liver, the diet composition is another aspect which should be considered in diet therapy of patients with NAFLD. Conclusions: Several studies assessed the effects of dietary composition on fat storage in liver; however, their findings are inconsistent. Most studies focused on the quantity of carbohydrate and dietary fat; whilst there is very limited information regarding the role of protein intake. PMID:24693306

  3. Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease

    PubMed Central

    Paradies, Giuseppe; Paradies, Valeria; Ruggiero, Francesca M; Petrosillo, Giuseppe

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) is today considered the most common form of chronic liver disease, affecting a high proportion of the population worldwide. NAFLD encompasses a large spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. Obesity, hyperglycemia, type 2 diabetes and hypertriglyceridemia are the most important risk factors. The pathogenesis of NAFLD and its progression to fibrosis and chronic liver disease is still unknown. Accumulating evidence indicates that mitochondrial dysfunction plays a key role in the physiopathology of NAFLD, although the mechanisms underlying this dysfunction are still unclear. Oxidative stress is considered an important factor in producing lethal hepatocyte injury associated with NAFLD. Mitochondrial respiratory chain is the main subcellular source of reactive oxygen species (ROS), which may damage mitochondrial proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid located at the level of the inner mitochondrial membrane, plays an important role in several reactions and processes involved in mitochondrial bioenergetics as well as in mitochondrial dependent steps of apoptosis. This phospholipid is particularly susceptible to ROS attack. Cardiolipin peroxidation has been associated with mitochondrial dysfunction in multiple tissues in several physiopathological conditions, including NAFLD. In this review, we focus on the potential roles played by oxidative stress and cardiolipin alterations in mitochondrial dysfunction associated with NAFLD. PMID:25339807

  4. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer

    PubMed Central

    Asgharpour, Amon; Cazanave, Sophie C.; Pacana, Tommy; Seneshaw, Mulugeta; Vincent, Robert; Banini, Bubu A.; Kumar, Divya Prasanna; Daita, Kalyani; Min, Hae-Ki; Mirshahi, Faridoddin; Bedossa, Pierre; Sun, Xiaochen; Hoshida, Yujin; Koduru, Srinivas V.; Contaifer, Daniel; Warncke, Urszula Osinska; Wijesinghe, Dayanjan S.; Sanyal, Arun J.

    2016-01-01

    Background & Aims The lack of a preclinical model of progressive non-alcoholic steatohepatitis (NASH) that recapitulates human disease is a barrier to therapeutic development. Methods A stable isogenic cross between C57BL/6J (B6) and 129S1/SvImJ (S129) mice were fed a high fat diet with ad libitum consumption of glucose and fructose in physiologically relevant concentrations and compared to mice fed a chow diet and also to both parent strains. Results Following initiation of the obesogenic diet, B6/129 mice developed obesity, insulin resistance, hypertriglyceridemia and increased LDL-cholesterol. They sequentially also developed steatosis (4–8 weeks), steatohepatitis (16–24 weeks), progressive fibrosis (16 weeks onwards) and spontaneous hepatocellular cancer (HCC). There was a strong concordance between the pattern of pathway activation at a transcriptomic level between humans and mice with similar histological phenotypes (FDR 0.02 for early and 0.08 for late time points). Lipogenic, inflammatory and apoptotic signaling pathways activated in human NASH were also activated in these mice. The HCC gene signature resembled the S1 and S2 human subclasses of HCC (FDR 0.01 for both). Only the B6/129 mouse but not the parent strains recapitulated all of these aspects of human NAFLD. Conclusions We here describe a diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) that recapitulates the key physiological, metabolic, histologic, transcriptomic and cell-signaling changes seen in humans with progressive NASH. Lay summary We have developed a diet-induced mouse model of non-alcoholic steatohepatitis (NASH) and hepatic cancers in a cross between two mouse strains (129S1/SvImJ and C57Bl/6J). This model mimics all the physiological, metabolic, histological, transcriptomic gene signature and clinical endpoints of human NASH and can facilitate preclinical development of therapeutic targets for NASH. PMID:27261415

  5. Lipoprotein Profiles in Class III Obese Caucasian and African American Women with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Garcia, Anna E.; Kasim, Nader; Tamboli, Robyn A.; Gonzalez, Raul S.; Antoun, Joseph; Eckert, Emily A.; Marks-Shulman, Pamela A.; Dunn, Julia; Wattacheril, Julia; Wallen, Taylor; Abumrad, Naji N.; Flynn, Charles Robb

    2015-01-01

    Triglyceride content in the liver is regulated by the uptake, production and elimination of lipoproteins, and derangements in these processes contribute to nonalcoholic fatty liver disease (NAFLD). Previous studies show a direct relationship between intrahepatic fat and production of apolipoprotein B100 (apoB100) containing particles, VLDL and LDL, but little consensus exists regarding changes in lipoprotein production in the development of simple steatosis (SS) versus nonalcoholic steatohepatitis (NASH). Further, ethnic variations in lipoproteins among SS and NASH are unknown as is how such variations might contribute to the differential prevalence of disease among Caucasians versus African Americans. In this study, we assessed plasma lipoprotein profiles by nuclear magnetic resonance (NMR) spectroscopy in 70 non-diabetic class III obese females recruited from the surgical weight loss clinic. Of these, 51 females were stratified by biopsy-staged NAFLD severity (histologically normal, SS, or NASH). NASH females displayed increased circulating triglycerides and increased VLDL particle number and size relative to those with histologically normal livers, while total and large LDL concentration decreased in SS versus NASH and correlated with increased insulin resistance (via HOMA2-IR). When Caucasian women were examined alone (n = 41), VLDL and triglycerides increased between normal and SS, while total LDL and apoB100 decreased between SS and NASH along with increased insulin resistance. Compared to Caucasians with SS, African American women with SS displayed reduced triglycerides, VLDL, and small LDL and a more favorable small to large HDL ratio despite having increased BMI and HOMA2-IR. These findings suggest that ApoB100 and lipoprotein subclass particle number and size can delineate steatosis from NASH in obese Caucasian females, but should be interpreted with caution in other ethnicities as African Americans with SS display relatively improved lipoprotein profiles

  6. Non-alcoholic fatty liver disease: need for a balanced nutritional source.

    PubMed

    Veena, Jayagopalan; Muragundla, Anjaneyulu; Sidgiddi, Srinivas; Subramaniam, Swaminathan

    2014-12-14

    Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are an increasingly common chronic liver disease closely associated with diabetes and obesity that have reached epidemic proportions. Reports on the prevalence of NAFLD have suggested that 27-34% of the general population in the USA and 40-90% of the obese population worldwide have this disease. Increasing urbanisation rate and associated inappropriate lifestyle changes are not only the risk factors of diabetes, but also unmask genetic predisposition in various populations for the metabolic syndrome and its manifestations including NAFLD and NASH. Lifestyle modifications and balanced nutrition are among the foremost management strategies along with ursodeoxycholic acid, metformin, vitamin E and pentoxifylline. Although weight reduction associated with current therapeutic strategies has shown some promise, maintaining it in the long run is largely unsuccessful. With the safety of pharmacotherapy still being uncertain and can be started only after confirmation, other reasonable interventions such as nutrition hold promise in preventing disease progression. The role of dietary components including branched-chain amino acids, methionine, choline and folic acid is currently being evaluated in various clinical trials. Nutritional approaches sought to overcome the limitations of pharmacotherapy also include evaluating the effects of natural ingredients, such as silymarin and spirulina, on liver disease. Understanding the specific interaction between nutrients and dietary needs in NAFLD and maintaining this balance through either a diet or a nutritional product thus becomes extremely important in providing a more realistic and feasible alternative to treat NAFLD. A planned complete nutritional combination addressing specific needs and helping to prevent the progression of NAFLD is the need of the hour to avert people from ending up with complications. PMID:25274101

  7. The Efficacy of Pharmacological Treatment in Pediatric Nonalcoholic Fatty Liver Disease

    PubMed Central

    Cho, Taeshik; Paik, Seung Sam

    2012-01-01

    Purpose With growing number of obese children, the prevalence of nonalcoholic fatty liver disease (NAFLD) in pediatric population is increasing. Nonalcoholic steatohepatitis (NASH) is a severe form of NAFLD, and can cause morbid complications. It is important to identify patients in order to grade pathologic severities and treat those children who possibly have NASH. This study was performed to evaluate whether the pharmacological therapy is also effective as well as the body weight reduction in pediatric NAFLD. Methods Among the 52 children presenting with obesity and hepatopathy, NAFLD was diagnosed through liver biopsy in 29 children, who were 7 to 14 years of age, from January 2006 to December 2011. The patients were advised to reduce their body weight through diverse methods. Medication with Ursodeoxycholic acid (UDCA) and vitamin E was performed in children whose liver functions did not improve or their weight reductions were not successful. The therapeutic effects were monitored and assessed via the biochemical profiles and the physical measurements. Results The therapy of vitamin E and UDCA combined with body mass index (BMI) reduction showed significantly higher rate of improvement in clinical profiles, which could be seen in data of aspartate aminotransferase (AST), alanine aminotransferase (ALT), AST/ALT ratio, alkaline phosphatase, total bilirubin and γ-glutamyl transpeptidase. Children whose BMI were successfully reduced showed favorable clinical improvements without any medication, but those without BMI reduction did not show any improvement despite medications. Conclusion This study showed that the first line of therapy should be the BMI reduction in NAFLD and drug therapy combined with BMI reduction could have additive therapeutic effect in children with NAFLD. PMID:24010096

  8. Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease

    PubMed Central

    Lee, Hyun Jung; Yeon, Jong Eun; Ko, Eun Jung; Yoon, Eileen L; Suh, Sang Jun; Kang, Keunhee; Kim, Hae Rim; Kang, Seoung Hee; Yoo, Yang Jae; Je, Jihye; Lee, Beom Jae; Kim, Ji Hoon; Seo, Yeon Seok; Yim, Hyung Joon; Byun, Kwan Soo

    2015-01-01

    AIM: To evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors (PPAR)-δ agonist treatment in nonalcoholic fatty liver disease (NAFLD) models. METHODS: Male C57BL/6J mice were classified according to control or high fat diet (HFD) with or without PPAR-δ agonist (GW) over period of 12 wk [control, HFD, HFD + lipopolysaccharide (LPS), HFD + LPS + GW group]. HepG2 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of GW. RESULTS: HFD caused glucose intolerance and hepatic steatosis. In mice fed an HFD with LPS, caspase-1 and interleukin (IL)-1β in the liver were significantly increased. Treatment with GW ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In HepG2 cells, PA and LPS treatment markedly increased mRNA of several nucleotide-binding and oligomerization domain-like receptor family members (NLRP3, NLRP6, and NLRP10), caspase-1 and IL-1β. PA and LPS also exaggerated reactive oxygen species production. All of the above effects of PA and LPS were reduced by GW. GW also enhanced the phosphorylation of AMPK-α. CONCLUSION: PPAR-δ agonist reduces fatty acid-induced inflammation and steatosis by suppressing inflammasome activation. Targeting the inflammasome by the PPAR-δ agonist may have therapeutic implication for NAFLD. PMID:26668503

  9. Swimming training beneficial effects in a mice model of nonalcoholic fatty liver disease.

    PubMed

    Schultz, Alini; Mendonca, Leonardo S; Aguila, Marcia B; Mandarim-de-Lacerda, Carlos A

    2012-05-01

    The study aimed to investigate the effect of swimming training in reducing the nonalcoholic fatty liver disease (NAFLD) and associated comorbidities, including the hepatic expression of fatty acid synthesis and peroxisome proliferator receptor activity-alpha. Male C57BL/6 mice were separated into two major groups according to their nutrition and studied during 22 weeks: standard chow (10% fat, SC) or high-fat chow (60% fat, HF), characterizing the sedentary groups SC-Sed and HF-Sed. In the last 10 weeks of the experiment, half of the sedentary groups were submitted to a swimming training with a progressive increase in duration, characterizing the exercised groups: SC-Ex and HF-Ex. At the end of the experiment, considering the findings in the SC-Sed group, HF-Sed group had significantly higher body mass, hyperglycemia, hyperinsulinemia with insulin resistance, hypertrophy of the adipocytes (with inflammatory infiltrate), hypertrophy of the pancreatic islets, dyslipidemia, altered liver enzymes and inflammatory cytokines, and NAFLD with changes in gene expression of hepatic lipogenic and oxidative proteins. The swimming program, even concomitant with the high-fat diet, reduced overweight and all the other worst findings, especially NAFLD. In conclusion, the swimming training can attenuate the morbid effects of a high-fat diet combined with sedentary lifestyle in mice. These data reinforce the notion that swimming exercise can be considered an efficient nonpharmacologic therapy in the treatment of NAFLD, obesity and insulin resistance. PMID:20869214

  10. Diets and nonalcoholic fatty liver disease: the good and the bad.

    PubMed

    Asrih, Mohamed; Jornayvaz, François R

    2014-04-01

    Nonalcoholic fatty liver disease (NAFLD) is now described as the hepatic manifestation of the metabolic syndrome and is the most frequent chronic liver disease, affecting about one out of three people in the western world. NAFLD is strongly linked to insulin resistance, which represents a key risk factor for the development of type 2 diabetes. To date, there are no reliable and efficient pharmacotherapies in the treatment of NAFLD. However, obesity, which represents one of the main features of the metabolic syndrome, is strongly associated with NAFLD. Therefore, lifestyle modifications, i.e. weight loss and increased physical activity, are the very first clinical approaches aiming at treating NAFLD. However, although weight loss is beneficial in NAFLD, certain diets known to induce weight loss can actually cause or exacerbate this disease, and therefore induce insulin resistance, such as very low carbohydrate, high fat diets. Moreover, macronutrient diet composition can impact NAFLD without any change in body weight. Indeed, diets rich in fatty acids, particularly saturated, or in refined carbohydrates such as those found in soft drinks, can actually exacerbate NAFLD. The aim of this review is to discuss the role of weight loss and macronutrients modifications, particularly the role of fat and carbohydrate diet composition, in the treatment of NAFLD. PMID:24262589

  11. Effect of chronic alcohol consumption on the development and progression of non-alcoholic fatty liver disease (NAFLD)

    PubMed Central

    Mueller, Sebastian; Hellerbrand, Claus; Liangpunsakul, Suthat

    2015-01-01

    A number of epidemiologic studies show a protective effect of light to moderate daily alcohol consumption on the development of non-alcoholic fatty liver disease (NAFLD). Although these small amounts of ethanol may prevent fatty liver, they may also be a risk factor for other diseases such as breast and colon cancer. Those individuals who have underlying hepatic steatosis or non-alcoholic steatohepatitis (NASH) should not use ethanol chronically since the data available at present do not support a beneficial effect of alcohol in this situation. Especially overweight and obese individuals may be more susceptible towards alcohol even at moderate doses. Animal experiments show a negative effect of ethanol on liver histology in either dietary or genetic NASH models. In addition, patients with NASH reveal a significant increased risk for hepatocellular cancer (HCC) even with social alcohol consumption. Thus, subjects with underlying NASH should abstain from alcohol at any amounts. PMID:26151054

  12. Increased circulating zonulin in children with biopsy-proven nonalcoholic fatty liver disease

    PubMed Central

    Pacifico, Lucia; Bonci, Enea; Marandola, Lidia; Romaggioli, Sara; Bascetta, Stefano; Chiesa, Claudio

    2014-01-01

    AIM: To investigate the potential association of circulating zonulin with the stage of liver disease in obese children with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD). METHODS: A case-control study was performed. Cases were 40 obese children with NAFLD. The diagnosis of NAFLD was based on magnetic resonance imaging (MRI) with high hepatic fat fraction (HFF ≥ 5%), and confirmed by liver biopsy with ≥ 5% of hepatocytes containing macrovesicular fat. Controls were selected from obese children with normal levels of aminotransferases, and without MRI evidence of fatty liver as well as of other causes of chronic liver diseases. Controls were matched (1-to 1) with the cases on age, gender, pubertal stage and as closely as possible on body mass index- standard deviation score. All participants underwent clinical examination, laboratory tests including zonulin, inflammatory and metabolic parameters, and MRI for measurement of HFF and visceral adipose tissue. RESULTS: Zonulin values were significantly greater in obese subjects with NAFLD than in those without NAFLD [median (interquartile range), 4.23 (3.18-5.89) vs 3.31 (2.05-4.63), P < 0.01]. In patients with NAFLD, zonulin concentrations increased significantly with the severity of steatosis and the Spearman’s coefficient revealed a positive correlation between zonulin values and steatosis (r = 0.372, P < 0.05); however, we did not find a significant correlation between zonulin and lobular inflammation (P = 0.23), ballooning (P = 0.10), fibrosis score (P = 0.18), or presence of nonalcoholic steatohepatitis (P = 0.17). Within the entire study population, zonulin levels were positively associated with gamma-glutamyl transferase, 2-h insulin, HFF, and negatively associated with whole-body insulin sensitivity index (WBISI), after adjustment for age, gender and pubertal status. When the associations were restricted to the group of NAFLD patients, 2-h insulin, hepatic fat, and WBISI retained statistical

  13. Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease.

    PubMed

    Mao, Jing-Wei; Tang, Hai-Ying; Zhao, Ting; Tan, Xiao-Yan; Bi, Jian; Wang, Bing-Yuan; Wang, Ying-De

    2015-01-01

    Intestinal mucosal barrier dysfunction is closely related to liver diseases, which implies impaired gut-liver axis may play a role in the pathogenesis of NAFLD. In our study, rats were divided into three groups: normal chow diet (NCD) group, high-fat diet (HFD) group and TNBS-induced colitis with high-fat diet (C-HFD) group. Liver tissues were obtained for histological observation and TNF-α, IL-6 mRNA determination and blood samples were collected for liver enzymes and LPS analysis. Ultrastructural changes of jejuna epithelium, SIBO and amounts of CD103(+)MHCII(+)DCs and CD4(+)CD25(+)FoxP3(+)T-regs in terms of percentage in mesenteric lymph nodes (MLN) were observed by electron microscope, bacterial cultivation and flow cytometry, respectively. The results demonstrated the pathological characteristics accorded with nonalcoholic simple fatty liver (NAFL) and NASH in HFD group by week 8 and 12, respectively. Besides, the degree of hepatic steatosis and steatohepatitis was more severe in C-HFD group compared with HFD-group at the same time point. NAFLD activity score (NAS), liver enzymes, concentration of LPS and mRNA expressions of TNF-α, IL-6 were higher significantly in C-HFD group compared with HFD and NCD group at week 4, 8 and 12, respectively. In HFD group, epithelium microvilli atrophy, disruptive tight junctions and SIBO were present, and these changes were more severe in NASH compared with NAFL. The percentage of CD103+MHCII+DCs and CD4+CD25+FoxP3+T-regs decreased significantly in NAFL and NASH compared with NCD group. Our conclusion was that gut-liver axis was impaired in NAFLD, which played crucial role in the pathogenesis of NAFLD. PMID:26097546

  14. Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease

    PubMed Central

    Mao, Jing-Wei; Tang, Hai-Ying; Zhao, Ting; Tan, Xiao-Yan; Bi, Jian; Wang, Bing-Yuan; Wang, Ying-De

    2015-01-01

    Intestinal mucosal barrier dysfunction is closely related to liver diseases, which implies impaired gut-liver axis may play a role in the pathogenesis of NAFLD. In our study, rats were divided into three groups: normal chow diet (NCD) group, high-fat diet (HFD) group and TNBS-induced colitis with high-fat diet (C-HFD) group. Liver tissues were obtained for histological observation and TNF-α, IL-6 mRNA determination and blood samples were collected for liver enzymes and LPS analysis. Ultrastructural changes of jejuna epithelium, SIBO and amounts of CD103+MHCII+DCs and CD4+CD25+FoxP3+T-regs in terms of percentage in mesenteric lymph nodes (MLN) were observed by electron microscope, bacterial cultivation and flow cytometry, respectively. The results demonstrated the pathological characteristics accorded with nonalcoholic simple fatty liver (NAFL) and NASH in HFD group by week 8 and 12, respectively. Besides, the degree of hepatic steatosis and steatohepatitis was more severe in C-HFD group compared with HFD-group at the same time point. NAFLD activity score (NAS), liver enzymes, concentration of LPS and mRNA expressions of TNF-α, IL-6 were higher significantly in C-HFD group compared with HFD and NCD group at week 4, 8 and 12, respectively. In HFD group, epithelium microvilli atrophy, disruptive tight junctions and SIBO were present, and these changes were more severe in NASH compared with NAFL. The percentage of CD103+MHCII+DCs and CD4+CD25+FoxP3+T-regs decreased significantly in NAFL and NASH compared with NCD group. Our conclusion was that gut-liver axis was impaired in NAFLD, which played crucial role in the pathogenesis of NAFLD. PMID:26097546

  15. Association of the serum uric acid level with liver histology in biopsy-proven non-alcoholic fatty liver disease

    PubMed Central

    Huang, Qian; Yu, Jianhua; Zhang, Xiantu; Liu, Shourong; Ge, Yanyan

    2016-01-01

    Hyperuricemia is significantly associated with and independently predicts the risk for non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to examine the association of serum uric acid (SUA) levels with liver histology in patients with biopsy-proven NAFLD. Data were collected from 158 adults aged >18 years, and diagnosed with biopsy-proven NAFLD. The differences in liver histology were assessed between hyperuricemic and normal SUA groups with NAFLD to determine the possible risk factors. The SUA level was closely associated with the degree of steatosis (correlation coefficient 0.177, P=0.027). A higher proportion of patients with hyperuricemia showed increased severity of lobular inflammation (lobular inflammation score ≥2) compared with patients exhibiting normal SUA (75 vs. 52.7%; χ2=8.548, P=0.003). Hyperuricemic groups had higher non-alcoholic steatosis (≥5) compared to the normal SUA groups with NAFLD (48.8 vs. 31.1%; χ2=5.131, P=0.024). Hyperuricemia was independently associated with advanced lobular inflammation (odds ratio, 2.79; 95% confidence interval, 1.250–6.257; P=0.012) using a logistic regression model controlling for ferritin, serum alanine aminotransferase and aspartate aminotransferase. In conclusion, hyperuricemia is associated with histologically severe NAFLD. Hyperuricemia was independently associated with greater odds of advanced lobular inflammation of NAFLD. PMID:27446539

  16. 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

  17. Effects of Eating Fast and Eating Before Bedtime on the Development of Nonalcoholic Fatty Liver Disease.

    PubMed

    Nishi, Takumi; Babazono, Akira; Maeda, Toshiki; Imatoh, Takuya; Une, Hiroshi

    2016-08-01

    Few studies have evaluated the effects of lifestyle habits, such as eating behaviors, on the development of nonalcoholic fatty liver disease (NAFLD). It is known that NAFLD increases the risk of type 2 diabetes, prediabetes, cardiovascular disease, and chronic kidney disease. Therefore, a retrospective cohort study was conducted to evaluate the effect of eating behaviors and interactions between these behaviors on the development of NAFLD among health insurance beneficiaries without NAFLD. Study subjects were 2254 male and female insurance beneficiaries without NAFLD who had attended specific health checkups during fiscal years 2009 and 2012 among health insurance societies located in Fukuoka and Shizuoka Prefectures (Japan). The incidence of NAFLD was defined as Fatty Liver Index scores ≥60 or visiting medical organizations for fatty liver disease treatment according to claims data. Eating behaviors, including eating speed and eating before bedtime, were evaluated by a self-administered questionnaire. During the study period, 52 (2.3%) subjects progressed to NAFLD. Subjects who ate before bedtime but did not eat fast had a higher risk of NAFLD (adjusted odds ratio [AOR] = 2.15; 95% confidence interval [CI]: 1.03-4.46). Those with both negative eating habits had a significantly higher risk of NAFLD (AOR = 2.48; 95% CI: 1.09-5.63). Subjects who habitually ate before bedtime, and those who ate fast and before bedtime, tended to have an increased risk of NAFLD. Earlier intervention to modify these poor eating behaviors could be useful to prevent NAFLD. (Population Health Management 2016;19:279-283). PMID:26565781

  18. 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

  19. Pentoxifylline ameliorates non-alcoholic fatty liver disease in hyperglycaemic and dyslipidaemic mice by upregulating fatty acid β-oxidation.

    PubMed

    Ye, Jia-Hung; Chao, Jung; Chang, Ming-Ling; Peng, Wen-Huang; Cheng, Hao-Yuan; Liao, Jiunn-Wang; Pao, Li-Heng

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD), which includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis, is characterised by abnormal fat accumulation in the liver in the absence of excessive alcohol intake. In patients with type 2 diabetes (T2D), concurrent NAFLD might increase the risk of chronic kidney disease and the mortality rate. Although several studies have examined the effectiveness of pentoxifylline (PTX) in NAFLD treatment, no results are available to verify the effectiveness of PTX in treating T2D associated with NAFLD. In this study, we developed a combined high-fat diet-induced obesity and low-dose streptozocin-induced hyperglycaemia mouse model to mimic the concurrent NAFLD and T2D pathological condition. By combining physiological assessments, pathological examinations, metabolomics studies on blood, urine, and liver, and measurements of gene and protein expression, we elucidated the effectiveness and the underlying mechanism of action of PTX in the hyperglycaemic and dyslipidaemic mice. Our results revealed that PTX ameliorated NAFLD in the hyperglycaemic and dyslipidaemic mice by upregulating fatty acid β-oxidation. Furthermore, the glycolysis pathway and branched-chain amino acid-related pathways in these mice were restored by PTX. PMID:27612024

  20. Pentoxifylline ameliorates non-alcoholic fatty liver disease in hyperglycaemic and dyslipidaemic mice by upregulating fatty acid β-oxidation

    PubMed Central

    Ye, Jia-Hung; Chao, Jung; Chang, Ming-Ling; Peng, Wen-Huang; Cheng, Hao-Yuan; Liao, Jiunn-Wang; Pao, Li-Heng

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD), which includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis, is characterised by abnormal fat accumulation in the liver in the absence of excessive alcohol intake. In patients with type 2 diabetes (T2D), concurrent NAFLD might increase the risk of chronic kidney disease and the mortality rate. Although several studies have examined the effectiveness of pentoxifylline (PTX) in NAFLD treatment, no results are available to verify the effectiveness of PTX in treating T2D associated with NAFLD. In this study, we developed a combined high-fat diet-induced obesity and low-dose streptozocin-induced hyperglycaemia mouse model to mimic the concurrent NAFLD and T2D pathological condition. By combining physiological assessments, pathological examinations, metabolomics studies on blood, urine, and liver, and measurements of gene and protein expression, we elucidated the effectiveness and the underlying mechanism of action of PTX in the hyperglycaemic and dyslipidaemic mice. Our results revealed that PTX ameliorated NAFLD in the hyperglycaemic and dyslipidaemic mice by upregulating fatty acid β-oxidation. Furthermore, the glycolysis pathway and branched-chain amino acid-related pathways in these mice were restored by PTX. PMID:27612024

  1. Quality of Life in Adults with Nonalcoholic Fatty Liver Disease: Baseline Data from the NASH CRN

    PubMed Central

    David, Kristin; Kowdley, Kris V.; Unalp, Aynur; Kanwal, Fasiha; Brunt, Elizabeth M.; Schwimmer, Jeffrey B.

    2009-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. The association between NAFLD and quality of life (QOL) remains unclear. These data are important to estimate the burden of illness in NAFLD. The aim was to report QOL scores of adults with NAFLD, and examine the association between NAFLD severity and QOL. QOL data were collected from adults with NAFLD enrolled in the NASH Clinical Research Network using the SF-36 survey and scores were compared to normative U.S. population scores. Liver biopsy histology was reviewed by a central pathology committee. A total of 713 subjects with NAFLD (M=269, F=444) were included. Mean age of subjects was 48.3 years; 61% had definite NASH, and 28% had bridging fibrosis or cirrhosis. Diabetes was present in 27% of subjects. Subjects with NAFLD had worse physical (mean=45.2) and mental health scores (mean=47.6) compared to the U.S. population with (mean=50) and without (physical: 55.8, mental: 52.5) chronic illness. Subjects with NASH reported lower physical health compared to subjects with fatty liver disease without NASH (44.5 vs. 47.1, p=.02). Subjects with cirrhosis had significantly (P<0.001) poorer physical health scores (38.4) vs. subjects with no (47.6), mild (46.2), moderate (44.6) or bridging fibrosis (44.6). Cirrhosis was associated with poorer physical health after adjusting for potential confounders. Mental health scores did not differ between participants with and without NASH or by degree of fibrosis. Conclusion Adults with NAFLD have a significant decrement in QOL. Treatment of NAFLD should incorporate strategies to improve QOL, especially physical health. PMID:19434741

  2. Treatment of Nonalcoholic Fatty Liver Disease: Where do we Stand? An Overview

    PubMed Central

    Dajani, Asad; AbuHammour, Adnan

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide, the prevalence of which had progressively increased over the past 10 years where other liver diseases remained at the same prevalence rates or are expected to decrease as in the case of hepatitis C virus (HCV). The treatment of NAFLD is of prime concern to health care professionals and patients due to the significant mortality and morbidity it implies; the problem is further escalated by the fact that standard of care medications targeting NAFLD remain experimental and without evidence base. Treatment nowadays is focused on lifestyle modification and managing the comorbid associated diseases, with a possible role for some hepatic protective agents. This review presents all the medications that had been proposed and used for the treatment of NAFLD with or without scientific rationale and includes agents for weight loss, insulin sensitizers, drugs that reduce blood lipids, glucagon-mimetics, drugs that may reduce fibrosis, angiotensin receptor blockers, and medicines believed to reduce endoplasmic reticular stress such as vitamin E, ursodeoxycholic acid, and S-adenosyl methionine. A quick review of the newer agents that proved to be promising such as obeticholic acid and GFT505 and the medicines that are still in the pipeline is also presented. PMID:26997214

  3. Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease

    PubMed Central

    Ferolla, Silvia Marinho; Armiliato, Geyza Nogueira de Almeida; Couto, Cláudia Alves; Ferrari, Teresa Cristina Abreu

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is currently recognized as one of the most common causes of chronic liver disease. It involves a spectrum of conditions that include pure steatosis without inflammation, steatohepatitis, fibrosis and cirrhosis. The key factor in the pathophysiology of NAFLD is insulin resistance that determines lipid accumulation in the hepatocytes and, thus, oxidative stress, which is followed by inflammatory response. However, NAFLD pathogenesis is still largely unknown and has been extensively investigated. Although life style modification with the aim of losing weight has been advocated to treat this disorder, its effectiveness is limited; additionally, there is no specific pharmacologic treatment until nowadays. Recent evidence suggests that the gut microbiota may play a role in the development of insulin resistance, hepatic steatosis, necroinflammation and fibrosis. Differences in gut microbiota between NAFLD patients and lean individuals as well as presence of small intestinal bacterial overgrowth in NAFLD subjects have been demonstrated. Furthermore, some data indicate that the immunoregulatory effects of probiotics may be beneficial in NAFLD treatment as they modulate the intestinal microbiota; improve epithelial barrier function and strengthen the intestinal wall decreasing its permeability; reduce bacterial translocation and endotoxemia; improve intestinal inflammation; and reduce oxidative and inflammatory liver damage. In this article, we review the clinical trials on the use of probiotics in the treatment of NAFLD and discuss the effects of these agents and their efficacy as an emerging therapeutic resource to treat NAFLD patients. PMID:25848479

  4. Recent Advances in the Herbal Treatment of Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Xiao, Jia; Fai So, Kwok; Liong, Emily C.; Tipoe, George L.

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver injury across the world. It is also strongly related to other pathological conditions, including obesity, diabetes, cardiovascular diseases, and symptoms of metabolic syndrome. Pathogenesis of NAFLD remains not fully characterized but is generally attributed to the occurrence of insulin resistance, lipid metabolism dysfunction,0 oxidative stress, inflammation, and necro-apoptosis. Every potential therapeutic strategy should target one or some of these pathological events in the liver. Over the past decades, application of herbal treatment for NAFLD has received increasing attention due to its wide availability, low side effects, and proven therapeutic mechanisms and benefits. In recent years, some monomers and certain functional mixtures of herbs have been extensively examined for their potential uses in NAFLD treatment. In the present review, we selected several herbal derivatives under intense basic and/or clinical investigations by carrying out a PubMed search of English language articles relevant to herbal derivatives and NAFLD, such as polysaccharide portion of wolfberry, garlic-derived monomers, red grape–derived resveratrol, and milk thistle–derived substances. They have been shown to target the pathological events during NAFLD initiation and progression both in pre-clinical studies and clinical trials. Although more detailed mechanistic researches and long-term clinical evaluations are needed for their future applications, they offer unanticipated and great health benefits without obvious adverse effects in NAFLD therapy. PMID:24716162

  5. ZJU index: a novel model for predicting nonalcoholic fatty liver disease in a Chinese population

    PubMed Central

    Wang, Jinghua; Xu, Chengfu; Xun, Yunhao; Lu, Zhenya; Shi, Junping; Yu, Chaohui; Li, Youming

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an important health issue worldwide. We aimed to develop a simple model to determine the presence of NAFLD in a Chinese population. A cross-sectional study with 9602 subjects was conducted. Potential predictors were entered into a stepwise logistic regression analysis to obtain the model. We used 148 patients with liver biopsy to validate this model. The model, named the ZJU index, was developed based on body mass index (BMI), fasting plasma glucose (FPG), triglycerides (TG), and the serum alanine aminotransferase (ALT) to serum aspartate transaminase (AST) ratio. The area under the receiver operating characteristic curve (AUROC) of the ZJU index to detect NAFLD was 0.822. At a value of <32.0, the ZJU index could rule out NAFLD with a sensitivity of 92.2%, and at a value of >38.0, the ZJU index could detect NAFLD with a specificity of 93.4%. In patients with liver biopsy, the ZJU index could detect steatosis with good accuracy, with an AUROC of 0.896. This study revealed that the ZJU index is a helpful model to detect NAFLD for community physicians in China. It was validated not only by a validation cohort but also by pathological data. PMID:26568423

  6. Lifestyle Interventions Including Nutrition, Exercise, and Supplements for Nonalcoholic Fatty Liver Disease in Children.

    PubMed

    Africa, Jonathan A; Newton, Kimberly P; Schwimmer, Jeffrey B

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease among children. Lifestyle interventions, such as diet and exercise, are frequently recommended. Children with NAFLD have a distinct physiology that is different from obesity alone and has the potential to influence lifestyle treatments. Studies of diet alone in the treatment of pediatric NAFLD have focused on sugar and carbohydrate, but did not indicate any one dietary approach that was superior to another. For children who are obese and have NAFLD, weight loss may have a beneficial effect regardless of the diet used. Exercise is widely believed to improve NAFLD because a sedentary lifestyle, poor aerobic fitness, and low muscle mass are all risk factors for NAFLD. However, there have been no randomized controlled trials of exercise as a treatment for children with NAFLD. Studies of the combination of diet and exercise suggest a potential for improvement in serum alanine aminotransferase activity and/or magnetic resonance imaging liver fat fraction with intervention. There is also enthusiasm for the use of dietary supplements; however, studies in children have shown inconsistent effects of vitamin E, fish oil, and probiotics. This review presents the available data from studies of lifestyle intervention and dietary supplements published to date and highlights challenges that must be addressed in order to advance the evidence base for the treatment of pediatric NAFLD. PMID:27041377

  7. Recurrent hepatitis C and non-alcoholic fatty liver disease in transplanted patients: a review.

    PubMed

    Testino, G; Sumberaz, A; Leone, S; Borro, P

    2013-04-01

    Non-alcoholic fatty liver disease (NAFLD) is a common occurrence after orthotopic liver transplantation (OLT). The association steatosis/HCV determines important implications for clinical practice: steatosis accelerates the progression of fibrosis and reduces the likelihood of obtaining a sustained virological response (SVR) with antiviral therapy. In post-transplant HCV patients we have evidenced a strong correlation between body mass index (BMI), cholesterol, triglycerides (TGC) and hepatic percentage of steatosis. In subjects with BMI <25 and TGC <160 ng/mL, the chance of SVR was 48 times higher than that of non response. The chances of SVR and sustained biochemical response for patients with percentage of steatosis <15 were 12 times higher than that with higher percentage of steatosis. We can conclude how the amount of steatosis be noted specifically in biopsy examination reports of patients with relapse chronic hepatitis C and how the management of dismetabolism, diet and exercise therapy can improve BMI, liver histology and the response to antiviral therapy. PMID:23514999

  8. 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. PMID:23538296

  9. Effect of oleoylethanolamide on diet-induced nonalcoholic fatty liver in rats.

    PubMed

    Li, Long; Li, Lei; Chen, Ling; Lin, Xiaoyu; Xu, Yaping; Ren, Jie; Fu, Jin; Qiu, Yan

    2015-03-01

    Oleoylethanolamine (OEA), an endogenous high-affinity agonist of peroxisome proliferator-activated receptor alpha (PPAR-α), has revealed the pharmacological properties in the treatment of obesity, atherosclerosis and other diseases through the modulation of lipid metabolism. To assess whether OEA can also regulate non-alcoholic fatty liver disease (NAFLD) caused by fat accumulation, we administrated OEA or fenofibrate in Sprague Dawley (SD) rats fed with a high fat diet (HFD). After 6 or 17 weeks treatment, OEA (5 mg/kg/day, i.p.) relieved the development of NAFLD compared with control groups by regulating the levels of plasma TG, TC, ALT and AST and liver inflammatory cytokines. Gene expression analysis of liver tissue and plasma from the animal models showed that OEA and fenofibrate both promoted the lipid β-oxidation by activating PPAR-α. Detailed research revealed that OEA inhibited the mRNA expression of lipogenesis in a PPAR-α-independant manner, while fenofibrate expressed an opposite effection. In summary, our research results suggested that as a potential lead compound, OEA could improve HFD-induced NAFLD with higher efficacy and safety than fenofibrate. PMID:25837920

  10. Choline and Fructooligosaccharide: Non-alcoholic Fatty Liver Disease, Cardiac Fat Deposition, and Oxidative Stress Markers

    PubMed Central

    Borges Haubert, Nadia Juliana Beraldo Goulart; Marchini, Julio Sergio; Carvalho Cunha, Selma Freire; Suen, Vivian Marques Miguel; Padovan, Gilberto Joao; Jordao, Alceu Afonso; Marchini Alves, Claudia Maria Meirelles; Marchini, Julio Flavio Meirelles; Vannucchi, Helio

    2015-01-01

    This study investigates the treatment of non-alcoholic fatty liver disease (NAFLD) in rats with choline and fructooligosaccharide (FOS). The healthy control group received standard diet. The other three groups consisted of animals with NAFLD. Group Estr received standard diet; group Echo received standard diet plus choline (3 g/100 g diet); and group Efos received standard diet plus FOS (10 g/100 g diet). Food intake, weight, urinary nitrogen, urinary ammonia, total cholesterol, serum triacylglyceride, liver and heart weights, tissue nitrogen, tissue fat, vitamin E, TBARS, and reduced glutathione (GSH) were measured in hepatic and heart tissue. Choline and FOS treatments resulted in total mean fat reduction in liver and heart tissue of 0.2 and 1.7 g, respectively. Both treatments were equally effective in reducing hepatic and cardiac steatosis. There were no differences in the TBARS level among experimental and control groups, indicating that the proposed treatments had no added protection against free radicals. While all experimental groups had increased vitamin E and GSH levels, choline treatment led to a significant increase compared to control. PMID:25987847

  11. 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. PMID:23576797

  12. Altered Fatty Acid Metabolism-Related Gene Expression in Liver from Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Auguet, Teresa; Berlanga, Alba; Guiu-Jurado, Esther; Martinez, Salomé; Porras, José Antonio; Aragonès, Gemma; Sabench, Fátima; Hernandez, Mercé; Aguilar, Carmen; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

    2014-01-01

    Lipid accumulation in the human liver seems to be a crucial mechanism in the pathogenesis and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate gene expression of different fatty acid (FA) metabolism-related genes in morbidly obese (MO) women with NAFLD. Liver expression of key genes related to de novo FA synthesis (LXRα, SREBP1c, ACC1, FAS), FA uptake and transport (PPARγ, CD36, FABP4), FA oxidation (PPARα), and inflammation (IL6, TNFα, CRP, PPARδ) were assessed by RT-qPCR in 127 MO women with normal liver histology (NL, n = 13), simple steatosis (SS, n = 47) and non-alcoholic steatohepatitis (NASH, n = 67). Liver FAS mRNA expression was significantly higher in MO NAFLD women with both SS and NASH compared to those with NL (p = 0.003, p = 0.010, respectively). Hepatic IL6 and TNFα mRNA expression was higher in NASH than in SS subjects (p = 0.033, p = 0.050, respectively). Interestingly, LXRα, ACC1 and FAS expression had an inverse relation with the grade of steatosis. These results were confirmed by western blot analysis. In conclusion, our results indicate that lipogenesis seems to be downregulated in advanced stages of SS, suggesting that, in this type of extreme obesity, the deregulation of the lipogenic pathway might be associated with the severity of steatosis. PMID:25474087

  13. Effects of pentoxifylline on nonalcoholic fatty liver disease: A meta-analysis

    PubMed Central

    Du, Juan; Ma, Yan-Yan; Yu, Chao-Hui; Li, You-Ming

    2014-01-01

    AIM: To evaluate the effects of pentoxifylline therapy in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We searched PubMed, Medline, Google Scholar, Embase, Web of Science, the Cochrane Library and the Chinese Biomedicine Database for all relevant controlled trials of pentoxifylline in patients with NAFLD from 1997 to July 2013. Five studies (3 randomized, double-blind, placebo-controlled trials and 2 prospective cohort studies with concurrent controls) were included in this meta-analysis. Statistical analysis was performed using RevMan 5.0 software. RESULTS: Five randomized trials of 147 patients with NAFLD/nonalcoholic steatohepatitis (NASH) were included. The results showed that compared to placebo, pentoxifylline therapy resulted in a significant decrease in body weight (P = 0.04), alanine aminotransferase (P < 0.00001), aspartate transaminase (P = 0.0006), glucose (P = 0.0008) and tumor necrosis factor-α (P = 0.007), but did not significantly affect body mass index (P = 0.28), total cholesterol (P = 0.80), triglyceride (P = 0.98), alkaline phosphatase (P = 0.29), γ-glutamyl transferase (P = 0.39) and interleukin-6 (P = 0.38). With regard to histological changes, pentoxifylline only reduced the NAFLD activity score (P < 0.00001) and improved lobular inflammation (P < 0.0001). Improvements in steatosis grade (P = 0.11), ballooning (P = 0.10) and fibrosis (P = 0.50) were not obvious. CONCLUSION: Pentoxifylline therapy results in weight loss, improved liver function and histological changes in patients with NAFLD/NASH. Therefore, pentoxifylline may be a new treatment option for NAFLD. PMID:24574727

  14. Management of nonalcoholic fatty liver disease: An evidence-based clinical practice review

    PubMed Central

    Arab, Juan P; Candia, Roberto; Zapata, Rodrigo; Muñoz, Cristián; Arancibia, Juan P; Poniachik, Jaime; Soza, Alejandro; Fuster, Francisco; Brahm, Javier; Sanhueza, Edgar; Contreras, Jorge; Cuellar, M Carolina; Arrese, Marco; Riquelme, Arnoldo

    2014-01-01

    AIM: To build a consensus among Chilean specialists on the appropriate management of patients with nonalcoholic fatty liver disease (NAFLD) in clinical practice. METHODS: NAFLD has now reached epidemic proportions worldwide. The optimal treatment for NAFLD has not been established due to a lack of evidence-based recommendations. An expert panel of members of the Chilean Gastroenterological Society and the Chilean Hepatology Association conducted a structured analysis of the current literature on NAFLD therapy. The quality of the evidence and the level of recommendations supporting each statement were assessed according to the recommendations of the United States Preventive Services Task Force. A modified three-round Delphi technique was used to reach a consensus among the experts. RESULTS: A group of thirteen experts was established. The survey included 17 open-ended questions that were distributed among the experts, who assessed the articles associated with each question. The levels of agreement achieved by the panel were 93.8% in the first round and 100% in the second and third rounds. The final recommendations support the indication of lifestyle changes, including diet and exercise, for all patients with NAFLD. Proven pharmacological therapies include only vitamin E and pioglitazone, which can be used in nondiabetic patients with biopsy-proven nonalcoholic steatohepatitis (the progressive form of NAFLD), although the long-term safety and efficacy of these therapies have not yet been established. CONCLUSION: Current NAFLD management is rapidly evolving, and new pathophysiology-based therapies are expected to be introduced in the near future. All NAFLD patients should be evaluated using a three-focused approach that considers the risks of liver disease, diabetes and cardiovascular events. PMID:25232252

  15. The expanding role of fish models in understanding non-alcoholic fatty liver disease

    PubMed Central

    Asaoka, Yoichi; Terai, Shuji; Sakaida, Isao; Nishina, Hiroshi

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a condition in which excessive fat accumulates in the liver of an individual who has not consumed excessive alcohol. Non-alcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to hepatic cirrhosis and/or hepatocellular carcinoma (HCC). NAFLD is considered to be a hepatic manifestation of metabolic syndrome, and its incidence has risen worldwide in lockstep with the increased global prevalence of obesity. Over the last decade, rodent studies have yielded an impressive list of molecules associated with NAFLD and NASH pathogenesis. However, the identification of currently unknown metabolic factors using mammalian model organisms is inefficient and expensive compared with studies using fish models such as zebrafish (Danio rerio) and medaka (Oryzias latipes). Substantial advances in unraveling the molecular pathogenesis of NAFLD have recently been achieved through unbiased forward genetic screens using small fish models. Furthermore, these easily manipulated organisms have been used to great advantage to evaluate the therapeutic effectiveness of various chemical compounds for the treatment of NAFLD. In this Review, we summarize aspects of NAFLD (specifically focusing on NASH) pathogenesis that have been previously revealed by rodent models, and discuss how small fish are increasingly being used to uncover factors that contribute to normal hepatic lipid metabolism. We describe the various types of fish models in use for this purpose, including those generated by mutation, transgenesis, or dietary or chemical treatment, and contrast them with rodent models. The use of small fish in identifying novel potential therapeutic agents for the treatment of NAFLD and NASH is also addressed. PMID:23720231

  16. Histopathological differences utilizing the nonalcoholic fatty liver disease activity score criteria in diabetic (type 2 diabetes mellitus) and non-diabetic patients with nonalcoholic fatty liver disease

    PubMed Central

    Puchakayala, Bharat K; Verma, Siddharth; Kanwar, Pushpjeet; Hart, John; Sanivarapu, Raghavendra R; Mohanty, Smruti R

    2015-01-01

    AIM: To study clinical and histopathological features of nonalcoholic fatty liver disease (NAFLD) in patients with and without type 2 diabetes mellitus (T2DM) using updated nonalcoholic steatohepatitis clinical research network (NASH-CRN) grading system. METHODS: We retrospectively analyzed data of 235 patients with biopsy proven NAFLD with and without T2DM. This database was utilized in the previously published study comparing ethnicity outcomes in NAFLD by the same corresponding author. The pathology database from University of Chicago was utilized for enrolling consecutive patients who met the criteria for NAFLD and their detailed clinical and histopathology findings were obtained for comparison. The relevant clinical profile of patients was collected from the Electronic Medical Records around the time of liver biopsy and the histology was read by a single well-trained histopathologist. The updated criteria for type 2 diabetes have been utilized for analysis. Background data of patients with NASH and NAFLD has been included. The mean differences were compared using χ2 and t-test along with regression analysis to evaluate the predictors of NASH and advanced fibrosis. RESULTS: Patients with NAFLD and T2DM were significantly older (49.9 vs 43.0, P < 0.01), predominantly female (71.4 vs 56.3, P < 0.02), had higher rate of metabolic syndrome (88.7 vs 36.4, P < 0.01), had significantly higher aspartate transaminase (AST)/alanine transaminase (ALT) ratio (0.94 vs 0.78, P < 0.01) and Fib-4 index (1.65 vs 1.06, P < 0.01) as markers of NASH, showed higher mean NAFLD activity score (3.5 vs 3.0, P = 0.03) and higher mean fibrosis score (1.2 vs 0.52, P < 0.01) compared to patients with NAFLD without T2DM. Furthermore, advanced fibrosis (32.5 vs 12.0, P < 0.01) and ballooning (27.3 vs 13.3, P < 0.01) was significantly higher among patients with NAFLD and T2DM compared to patients with NAFLD without T2DM. On multivariate analysis, T2DM was independently associated with NASH

  17. 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

  18. Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease.

    PubMed

    Mardinoglu, Adil; Agren, Rasmus; Kampf, Caroline; Asplund, Anna; Uhlen, Mathias; Nielsen, Jens

    2014-01-01

    Several liver disorders result from perturbations in the metabolism of hepatocytes, and their underlying mechanisms can be outlined through the use of genome-scale metabolic models (GEMs). Here we reconstruct a consensus GEM for hepatocytes, which we call iHepatocytes2322, that extends previous models by including an extensive description of lipid metabolism. We build iHepatocytes2322 using Human Metabolic Reaction 2.0 database and proteomics data in Human Protein Atlas, which experimentally validates the incorporated reactions. The reconstruction process enables improved annotation of the proteomics data using the network centric view of iHepatocytes2322. We then use iHepatocytes2322 to analyse transcriptomics data obtained from patients with non-alcoholic fatty liver disease. We show that blood concentrations of chondroitin and heparan sulphates are suitable for diagnosing non-alcoholic steatohepatitis and for the staging of non-alcoholic fatty liver disease. Furthermore, we observe serine deficiency in patients with NASH and identify PSPH, SHMT1 and BCAT1 as potential therapeutic targets for the treatment of non-alcoholic steatohepatitis. PMID:24419221

  19. Monounsaturated fat decreases hepatic lipid content in non-alcoholic fatty liver disease in rats

    PubMed Central

    Hussein, Osamah; Grosovski, Masha; Lasri, Etti; Svalb, Sergio; Ravid, Uzi; Assy, Nimer

    2007-01-01

    AIM: To evaluate the effects of different types of dietary fats on the hepatic lipid content and oxidative stress parameters in rat liver with experimental non-alcoholic fatty liver disease (NAFLD). METHODS: A total of 32 Sprague-Dawley rats were randomly divided into five groups. The rats in the control group (n = 8) were on chow diet (Group 1), rats (n = 6) on methionine choline-deficient diet (MCDD) (Group 2), rats (n = 6) on MCDD enriched with olive oil (Group 3), rats (n = 6) on MCDD with fish oil (Group 4) and rats (n = 6) on MCDD with butter fat (Group 5). After 2 mo, blood and liver sections were examined for lipids composition and oxidative stress parameters. RESULTS: The liver weight/rat weight ratio increased in all treatment groups as compared with the control group. Severe fatty liver was seen in MCDD + fish oil and in MCDD + butter fat groups, but not in MCDD and MCDD + olive oil groups. The increase in hepatic triglycerides (TG) levels was blunted by 30% in MCDD + olive oil group (0.59 ± 0.09) compared with MCDD group (0.85 ± 0.04, p < 0.004), by 37% compared with MCDD + fish oil group (0.95 ± 0.07, p < 0.001), and by 33% compared with MCDD + butter group (0.09 ± 0.1, p < 0.01). The increase in serum TG was lowered by 10% in MCDD + olive oil group (0.9 ± 0.07) compared with MCDD group (1.05 ± 0.06). Hepatic cholesterol increased by 15-fold in MCDD group [(0.08 ± 0.02, this increment was blunted by 21% in MCDD + fish oil group (0.09 ± 0.02)]. In comparison with the control group, ratio of long-chain polyunsaturated fatty acids omega-6/omega-3 increased in MCDD + olive oil, MCDD + fish oil and MCDD + butter fat groups by 345-, 30- and 397-fold, respectively. In comparison to MCDD group (1.58 ± 0.08), hepatic MDA contents in MCDD + olive oil (3.3 ± 0.6), MCDD + fish oil (3.0 ± 0.4), and MCDD + butter group (2.9 ± 0.36) were increased by 108%, 91% and 87%, respectively (p < 0.004). Hepatic paraoxonase activity decreased significantly in all

  20. Large-scale analysis of factors influencing nonalcoholic fatty liver disease and its relationship with liver enzymes.

    PubMed

    Bi, W R; Yang, C Q; Shi, Q; Xu, Y; Cao, C P; Ling, J; Wang, X Y

    2014-01-01

    Serum liver enzyme levels are often used effectively for the evaluation of nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the associations between serum liver enzyme levels and risks for NAFLD in over 8000 cases in a large-scale analysis. A cross-sectional survey with multiple stages and random samplings was performed from May 2007 to May 2009 on 8102 workers at Tongji University. A questionnaire was given, assessments of physical measurements, plasma glucose, lipid profiles, and liver enzymes were made, and real-time liver ultrasounds conducted. The prevalence of NAFLD in Tongji University was 22.2%. It was higher in males than in females (P = 0.0023). The body mass index, waist-to-hip ratio, serum total triglycerides, serum total cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) values were all higher in the NAFLD group than in the control group. For moderate and severe NAFLD patients, the ALT, AST and GGT values were significantly increased, high density lipoprotein cholesterol was decreased, and drinking much, heavy entertainment and less exercise were more prevalent (P < 0.001). There were strong correlations between serum liver enzyme levels and NAFLD (P < 0.001), with GGT being a more sensitive marker for NAFLD than ALT or AST. ALT and GGT were independent predictors for NAFLD, and GGT was a better predictor than ALT for NAFLD. PMID:25117346

  1. The pediatric NAFLD fibrosis index: a predictor of liver fibrosis in children with non-alcoholic fatty liver disease

    PubMed Central

    Nobili, Valerio; Alisi, Anna; Vania, Andrea; Tiribelli, Claudio; Pietrobattista, Andrea; Bedogni, Giorgio

    2009-01-01

    Background Liver fibrosis is a stage of non-alcoholic fatty liver disease (NAFLD) which is responsible for liver-related morbidity and mortality in adults. Accordingly, the search for non-invasive markers of liver fibrosis has been the subject of intensive efforts in adults with NAFLD. Here, we developed a simple algorithm for the prediction of liver fibrosis in children with NAFLD followed at a tertiary care center. Methods The study included 136 male and 67 female children with NAFLD aged 3.3 to 18.0 years; 141 (69%) of them had fibrosis at liver biopsy. On the basis of biological plausibility, readily availability and evidence from adult studies, we evaluated the following potential predictors of liver fibrosis at bootstrapped stepwise logistic regression: gender, age, body mass index, waist circumference, alanine transaminase, aspartate transaminase, gamma-glutamyl-transferase, albumin, prothrombin time, glucose, insulin, triglycerides and cholesterol. A final model was developed using bootstrapped logistic regression with bias-correction. We used this model to develop the 'pediatric NAFLD fibrosis index' (PNFI), which varies between 0 and 10. Results The final model was based on age, waist circumference and triglycerides and had a area under the receiver operating characteristic curve of 0.85 (95% bootstrapped confidence interval (CI) with bias correction 0.80 to 0.90) for the prediction of liver fibrosis. A PNFI ≥ 9 (positive likelihood ratio = 28.6, 95% CI 4.0 to 201.0; positive predictive value = 98.5, 95% CI 91.8 to 100.0) could be used to rule in liver fibrosis without performing liver biopsy. Conclusion PNFI may help clinicians to predict liver fibrosis in children with NAFLD, but external validation is needed before it can be employed for this purpose. PMID:19409076

  2. Hugan Qingzhi Exerts Anti-Inflammatory Effects in a Rat Model of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Tang, WaiJiao; Zeng, Lu; Yin, JinJin; Yao, YuFa; Feng, LiJuan; Yao, XiaoRui; Sun, XiaoMin; Zhou, BenJie

    2015-01-01

    Ethnopharmacological Relevance. The Hugan Qingzhi tablet (HQT) is a traditional Chinese medicine used for treating NAFLD (nonalcoholic fatty liver disease). The present study evaluated the anti-inflammatory effects of HQT in rats with NAFLD. Materials and Methods. HQT was administered daily to the NAFLD experimental groups. Biochemical markers, histopathological data, and oxidative stress/antioxidant biomarkers were determined. Proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) were detected by enzyme-linked immunoassay. Expressions of silent information regulator 1 (SIRT1) and acetylated-nuclear-factor kappaB-p65 (Ac-NF-κB-p65) were performed by western blotting. Results. At high and moderate doses, HQT was highly effective in decreasing serum alanine aminotransferase (P < 0.01), aspartate aminotransferase (P < 0.01), hepatic total cholesterol (P < 0.01), triglycerides (P < 0.01), and free fatty acid levels (P < 0.01). Moreover, high and moderate doses of HQT reduced hepatic levels of the proinflammatory cytokines TNF-α (P < 0.01), IL-1β (P < 0.01), and IL-6 (P < 0.01), enhanced SIRT1 expression, and depressed Ac-NF-κB-p65 expression at protein level. Conclusions. In our NAFLD rat model, HQT exerted substantial anti-inflammatory and antioxidant activities, possibly involving the regulation of SIRT1 and Ac-NF-κB-p65 expression. PMID:26146507

  3. miR-149 controls non-alcoholic fatty liver by targeting FGF-21.

    PubMed

    Xiao, Junjie; Lv, Dongchao; Zhao, Yingying; Chen, Xiaoyu; Song, Meiyi; Liu, Jingqi; Bei, Yihua; Wang, Fei; Yang, Wenzhuo; Yang, Changqing

    2016-08-01

    Non-alcoholic fatty liver disease (NAFLD), a lipid metabolism disorder characterized by the accumulation of intrahepatic fat, has emerged as a global public health problem. However, its underlying molecular mechanism remains unclear. We previously have found that miR-149 was elevated in NAFLD induced by high-fat diet mice model, whereas decreased by a 16-week running programme. Here, we reported that miR-149 was increased in HepG2 cells treated with long-chain fatty acid (FFA). In addition, miR-149 was able to promote lipogenesis in HepG2 cells in the absence of FFA treatment. Moreover, inhibition of miR-149 was capable of inhibiting lipogenesis in HepG2 cells in the presence of FFA treatment. Meanwhile, fibroblast growth factor-21 (FGF-21) was identified as a target gene of miR-149, which was demonstrated by the fact that miR-149 could negatively regulate the protein expression level of FGF-21, and FGF-21 was also responsible for the effect of miR-149 inhibitor in decreasing lipogenesis in HepG2 cells in the presence of FFA treatment. These data implicate that miR-149 might be a novel therapeutic target for NAFLD. PMID:27061435

  4. Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease

    PubMed Central

    Galloway, Chad A.; Lee, Hakjoo; Brookes, Paul S.

    2014-01-01

    Mitochondria produce the majority of cellular ATP through oxidative phosphorylation, and their capacity to do so is influenced by many factors. Mitochondrial morphology is recently suggested as an important contributor in controlling mitochondrial bioenergetics. Mitochondria divide and fuse continuously, which is affected by environmental factors, including metabolic alterations. Underscoring its bioenergetic influence, altered mitochondrial morphology is reported in tissues of patients and in animal models of metabolic dysfunction. In this study, we found that mitochondrial fission plays a vital role in the progression of nonalcoholic fatty liver disease (NAFLD). The development of hepatic steatosis, oxidative/nitrative stress, and hepatic tissue damage, induced by a high-fat diet, were alleviated in genetically manipulated mice suppressing mitochondrial fission. The alleviation of steatosis was recapitulated in primary hepatocytes with the inhibition of mitochondrial fission. Mechanistically, our study indicates that fission inhibition enhances proton leak under conditions of free fatty acid incubation, implicating bioenergetic change through manipulating mitochondrial fission. Taken together, our results suggest a mechanistic role for mitochondrial fission in the etiology of NAFLD. The efficacy of decreasing mitochondrial fission in the suppression of NAFLD suggests that mitochondrial fission represents a novel target for therapeutic treatment of NAFLD. PMID:25080922

  5. Genetic factors that affect nonalcoholic fatty liver disease: A systematic clinical review

    PubMed Central

    Severson, Tyler J; Besur, Siddesh; Bonkovsky, Herbert L

    2016-01-01

    AIM: To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease (NAFLD) onset, severity, and outcome through systematic literature review. METHODS: The authors conducted both systematic and specific searches of PubMed through December 2015 with special emphasis on more recent data (from 2012 onward) while still drawing from more historical data for background. We identified several specific genetic polymorphisms that have been most researched and, at this time, appear to have the greatest clinical significance on NAFLD and similar hepatic diseases. These were further investigated to assess their specific effects on disease onset and progression and the mechanisms by which these effects occur. RESULTS: We focus particularly on genetic polymorphisms of the following genes: PNPLA3, particularly the p. I148M variant, TM6SF2, particularly the p. E167K variant, and on variants in FTO, LIPA, IFNλ4, and iron metabolism, specifically focusing on HFE, and HMOX-1. We discuss the effect of these genetic variations and their resultant protein variants on the onset of fatty liver disease and its severity, including the effect on likelihood of progression to cirrhosis and hepatocellular carcinoma. While our principal focus is on NAFLD, we also discuss briefly effects of some of the variants on development and severity of other hepatic diseases, including hepatitis C and alcoholic liver disease. These results are briefly discussed in terms of clinical application and future potential for personalized medicine. CONCLUSION: Polymorphisms and genetic factors of several genes contribute to NAFLD and its end results. These genes hold keys to future improvements in diagnosis and management. PMID:27547017

  6. Anthropometric and metabolic characteristics in children with clinically diagnosed nonalcoholic fatty liver disease

    PubMed Central

    Mager, Diana R; Ling, Simon; Roberts, Eve A

    2008-01-01

    BACKGROUND Childhood obesity is currently approaching epidemic proportions worldwide. Various chronic diseases are associated with obesity, but nonalcoholic fatty liver disease (NAFLD) has received little attention from paediatricians. AIM To examine anthropometric and metabolic variables relevant to NAFLD disease mechanism and severity. METHODS A retrospective review of 53 consecutive paediatric patients clinically diagnosed with NAFLD was performed between 1997 and 2004. Variables studied included ethnicity, body mass index, acanthosis nigricans, aspartate aminotransferase and alanine amino-transferase levels, and fasting levels of glucose, insulin and lipids. Insulin resistance was quantified by validated models (the homeostasis model of insulin resistance [HOMA-IR] and the quantitative insulin-sensitivity check index [QUICKI]). RESULTS The cohort was comprised of 34 boys and 19 girls; there was a 2:1 male predominance. The mean age of the children was 13.5 years (median 14.2 years; range 5.6 to 18.9 years), and 13 were 11 years of age or younger. Forty-five per cent were Caucasian, 30% Asian and 21% Hispanic. Thirty-eight children (72%) were classified as obese and 11 children (21%) were classified as overweight, with a mean ideal body weight percentage of 150.9±4.2 (range 67% to 226%) and a BMI Z score of 1.9±0.1 (range −1.2 to 3.2). Hyperinsulinemia was present in 35 children (66%). Insulin resistance (HOMA-IR 9.8±2.6, abnormal if greater than 3) was associated with increased plasma triglyceride (P=0.03) and total cholesterol (P=0.04) levels. These parameters were significant irrespective of alanine aminotransferase or aspartate aminotransferase levels. CONCLUSIONS Hyperlipidemia with hyperinsulinemia and insulin resistance in overweight and obese children with fatty liver may be important signs of liver dysfunction in childhood NAFLD, irrespective of serum aminotransferases. In overweight or obese children with hyperlipidemia or insulin resistance

  7. Carbohydrate intake and nonalcoholic fatty liver disease: fructose as a weapon of mass destruction.

    PubMed

    Basaranoglu, Metin; Basaranoglu, Gokcen; Bugianesi, Elisabetta

    2015-04-01

    Excessive accumulation of triglycerides (TG) in liver, in the absence of significant alcohol consumption is nonalcoholic fatty liver disease (NAFLD). NAFLD is a significant risk factor for developing cirrhosis and an independent predictor of cardiovascular disease. High fructose corn syrup (HFCS)-containing beverages were associated with metabolic abnormalities, and contributed to the development of NAFLD in human trials. Ingested carbohydrates are a major stimulus for hepatic de novo lipogenesis (DNL) and are more likely to directly contribute to NAFLD than dietary fat. Substrates used for the synthesis of newly made fatty acids by DNL are primarily glucose, fructose, and amino acids. Epidemiological studies linked HFCS consumption to the severity of fibrosis in patients with NAFLD. New animal studies provided additional evidence on the role of carbohydrate-induced DNL and the gut microbiome in NAFLD. The excessive consumption of HFCS-55 increased endoplasmic reticulum stress, activated the stress-related kinase, caused mitochondrial dysfunction, and increased apoptotic activity in the liver. A link between dietary fructose intake, increased hepatic glucose transporter type-5 (Glut5) (fructose transporter) gene expression and hepatic lipid peroxidation, MyD88, TNF-α levels, gut-derived endotoxemia, toll-like receptor-4, and NAFLD was reported. The lipogenic and proinflammatory effects of fructose appear to be due to transient ATP depletion by its rapid phosphorylation within the cell and from its ability to raise intracellular and serum uric acid levels. However, large prospective studies that evaluated the relationship between fructose and NAFLD were not performed yet. PMID:26005677

  8. Insulin sensitizers in treatment of nonalcoholic fatty liver disease: Systematic review

    PubMed Central

    Chavez-Tapia, Norberto C; Barrientos-Gutierrez, Tonatiuh; Tellez-Ávila, Felix I; Sánchez-Ávila, Francisco; Montaño-Reyes, Maria Antonieta; Uribe, Misael

    2006-01-01

    AIM: To summarize the evidence available for the clinical effectiveness of insulin sensitizers in the treatment of nonalcoholic fatty liver disease (NAFLD) systematically. METHODS: Relevant articles were located using computer-assisted searches of Medline (1966-March 2006), EMBASE (1988-March 2006), CINAHL (1982-March 2003), Educational Resource Information Center (1966-March 2006), Library, Information Science & Technology Abstracts (1967-March 2006), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (1994-2006), dissertations in ProQuest and FirstSearch databases. Manual searches were made in the abstracts from meetings of the American Gastroenterological Association (1999-2006), and the American Association for the Study of Liver Diseases (2003-2005). Studies were retrieved using the following selection criteria: (1) clinical trials using insulin sensitizers in subjects with NAFLD, (2) adult patients, (3) published as full manuscripts or abstracts, and (4) English, Spanish, German, and French languages only. Data were abstracted independently by two reviewers following standardized procedures. A face-to-face comparison of data was conducted to ensure the completeness and reliability of the abstraction process. RESULTS: Nine studies were included, six using metformin and three using thiazolidinediones. Only two studies were placebo-controlled trials. The median sample size for all studies was 18 subjects. In the placebo-controlled trials, metformin improved insulin resistance markers and liver function tests, but not histological scores. In the single-arm trials, metformin and thiazolidinediones improved insulin resistance markers and liver function tests, and beneficial histological changes were reported. There is limited high-quality information available from which to draw categorical conclusions about the clinical use of insulin sensitizers in NAFLD. CONCLUSION: Current information indicates that the use of insulin

  9. Coffee enhances the expression of chaperones and antioxidant proteins in rats with nonalcoholic fatty liver disease.

    PubMed

    Salomone, Federico; Li Volti, Giovanni; Vitaglione, Paola; Morisco, Filomena; Fogliano, Vincenzo; Zappalà, Agata; Palmigiano, Angelo; Garozzo, Domenico; Caporaso, Nicola; D'Argenio, Giuseppe; Galvano, Fabio

    2014-06-01

    Coffee consumption is inversely related to the degree of liver injury in patients with nonalcoholic fatty liver disease (NAFLD). Molecular mediators contributing to coffee's beneficial effects in NAFLD remain to be elucidated. In this study, we administrated decaffeinated espresso coffee or vehicle to rats fed an high-fat diet (HFD) for 12 weeks and examined the effects of coffee on liver injury by using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) proteomic analysis combined with mass spectrometry. Rats fed an HFD and water developed panacinar steatosis, lobular inflammation, and mild fibrosis, whereas rats fed an HFD and coffee exhibited only mild steatosis. Coffee consumption increased liver expression of the endoplasmic reticulum chaperones glucose-related protein 78 and protein disulfide-isomerase A3; similarly, coffee drinking enhanced the expression of the mitochondrial chaperones heat stress protein 70 and DJ-1. Furthermore, in agreement with reduced hepatic levels of 8-isoprostanes and 8-hydroxy-2'-deoxyguanosine, proteomic analysis showed that coffee consumption induces the expression of master regulators of redox status (i.e., peroxiredoxin 1, glutathione S-transferase α2, and D-dopachrome tautomerase). Last, proteomics revealed an association of coffee intake with decreased expression of electron transfer flavoprotein subunit α, a component of the mitochondrial respiratory chain, involved in de novo lipogenesis. In this study, we were able to identify by proteomic analysis the stress proteins mediating the antioxidant effects of coffee; moreover, we establish for the first time the contribution of specific coffee-induced endoplasmic reticulum and mitochondrial chaperones ensuring correct protein folding and degradation in the liver. PMID:24365744

  10. Psoriasis, non-alcoholic fatty liver disease, and cardiovascular disease: Three different diseases on a unique background

    PubMed Central

    Ganzetti, Giulia; Campanati, Anna; Molinelli, Elisa; Offidani, Annamaria

    2016-01-01

    Psoriasis is a chronic inflammatory immune-mediated skin disease, frequently associated with systemic comorbidities. According to recent data, patients with psoriasis show a greater prevalence of metabolic syndrome, which confers a higher cardiovascular risk. The link between these pathological conditions appears to be a chronic low-grade inflammatory status. The aim of this review is to focus on the multiple epidemiological and physio-pathogenetic aspects linking non-alcoholic fatty liver disease, psoriasis, and cardiovascular disease. PMID:26981209

  11. Psoriasis, non-alcoholic fatty liver disease, and cardiovascular disease: Three different diseases on a unique background.

    PubMed

    Ganzetti, Giulia; Campanati, Anna; Molinelli, Elisa; Offidani, Annamaria

    2016-02-26

    Psoriasis is a chronic inflammatory immune-mediated skin disease, frequently associated with systemic comorbidities. According to recent data, patients with psoriasis show a greater prevalence of metabolic syndrome, which confers a higher cardiovascular risk. The link between these pathological conditions appears to be a chronic low-grade inflammatory status. The aim of this review is to focus on the multiple epidemiological and physio-pathogenetic aspects linking non-alcoholic fatty liver disease, psoriasis, and cardiovascular disease. PMID:26981209

  12. Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease

    PubMed Central

    Ballestri, Stefano; Lonardo, Amedeo; Bonapace, Stefano; Byrne, Christopher D; Loria, Paola; Targher, Giovanni

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) has emerged as a public health problem of epidemic proportions worldwide. Accumulating clinical and epidemiological evidence indicates that NAFLD is not only associated with liver-related morbidity and mortality but also with an increased risk of coronary heart disease (CHD), abnormalities of cardiac function and structure (e.g., left ventricular dysfunction and hypertrophy, and heart failure), valvular heart disease (e.g., aortic valve sclerosis) and arrhythmias (e.g., atrial fibrillation). Experimental evidence suggests that NAFLD itself, especially in its more severe forms, exacerbates systemic/hepatic insulin resistance, causes atherogenic dyslipidemia, and releases a variety of pro-inflammatory, pro-coagulant and pro-fibrogenic mediators that may play important roles in the pathophysiology of cardiac and arrhythmic complications. Collectively, these findings suggest that patients with NAFLD may benefit from more intensive surveillance and early treatment interventions to decrease the risk for CHD and other cardiac/arrhythmic complications. The purpose of this clinical review is to summarize the rapidly expanding body of evidence that supports a strong association between NAFLD and cardiovascular, cardiac and arrhythmic complications, to briefly examine the putative biological mechanisms underlying this association, and to discuss some of the current treatment options that may influence both NAFLD and its related cardiac and arrhythmic complications. PMID:24587651

  13. Flaxseed supplementation in non-alcoholic fatty liver disease: a pilot randomized, open labeled, controlled study.

    PubMed

    Yari, Zahra; Rahimlou, Mehran; Eslamparast, Tannaz; Ebrahimi-Daryani, Naser; Poustchi, Hossein; Hekmatdoost, Azita

    2016-06-01

    A two-arm randomized open labeled controlled clinical trial was conducted on 50 patients with non-alcoholic fatty liver disease (NAFLD). Participants were assigned to take either a lifestyle modification (LM), or LM +30 g/day brown milled flaxseed for 12 weeks. At the end of the study, body weight, liver enzymes, insulin resistance and hepatic fibrosis and steatosis decreased significantly in both groups (p< 0.05); however, this reduction was significantly greater in those who took flaxseed supplementation (p < 0.05). The significant mean differences were reached in hepatic markers between flaxseed and control group, respectively: ALT [-11.12 compared with -3.7 U/L; P< 0.001], AST [-8.29 compared with -4 U/L; p < 0.001], GGT [-15.7 compared with -2.62 U/L; p < 0.001], fibrosis score [-1.26 compared with -0.77 kPa; p = 0.013] and steatosis score [-47 compared with -15.45 dB/m; p = 0.022]. In conclusion, flaxseed supplementation plus lifestyle modification is more effective than lifestyle modification alone for NAFLD management. PMID:26983396

  14. Relationship between non-alcoholic fatty liver disease and MIA syndrome.

    PubMed

    Mikolasevic, Ivana; Stimac, Davor; Racki, Sanjin; Zaputovic, Luka; Devcic, Bosiljka; Jelic, Ita; Lukenda, Vesna; Radic, Mladen; Orlic, Lidija

    2015-07-01

    Non-alcoholic fatty liver disease (NAFLD) is an important factor in the pathogenesis of cardiovascular diseases in the general population. Recently, it has been shown that NAFLD is highly prevalent in chronic kidney disease (CKD) patients. Ninety-four hemodialysis (HD) patients were followed for a time period of 18 months or until death. Patient's survival rate was determined in relation to their nutritional and inflammatory state, and the presence of NAFLD. We also investigated the association between the presence of NAFLD and the patients' nutritional and inflammatory state. We did not find any significant association between the clinical parameters of nutritional status and the mortality rate. However, the mortality rate was statistically significantly higher in patients with low serum albumin and high high-sensitive C-reactive protein (hs-CRP) levels and in those who had NAFLD. Surprisingly, patients who had received enteral nutrition did not have a better survival rate. The severity of liver steatosis was negatively correlated with the serum albumin levels, while it was positively correlated with hs-CRP values. Furthermore, serum albumin levels showed a negative correlation with hs-CRP levels. We did not find any significant association between the presence of NAFLD and clinical parameters of nutrition. We have shown that NAFLD could be one more possible example of reverse epidemiology in patients undergoing HD. NAFLD may be the missing link that causally ties malnutrition, inflammation, and atherosclerosis syndrome to the morbidity and mortality in patients undergoing HD. PMID:25688578

  15. Nuclear Receptor Modulation for the Treatment of Nonalcoholic Fatty Liver Disease.

    PubMed

    Fuchs, Claudia D; Traussnigg, Stefan A; Trauner, Michael

    2016-02-01

    Nuclear receptors (NRs) are ligand-activated transcriptional regulators of several key metabolic processes including hepatic lipid and glucose metabolism, bile acid homeostasis, and energy expenditure as well as inflammation, fibrosis, and cellular proliferation in the liver. Dysregulation of these processes contributes to the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD). This places NRs at the forefront of novel therapeutic approaches for NAFLD. Some NRs are already pharmacologically targeted in metabolic disorders such as hyperlipidemia (peroxisomal proliferator-activated receptor α [PPARα], fibrates) and diabetes (PPARγ, glitazones) with potential applications for NAFLD. Other NRs with potential therapeutic implications are the vitamin D receptor (VDR) and xenobiotic sensors such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Further new perspectives include combined ligands for NR isoforms such as PPARα/δ ligands. Other novel key players represent the nuclear bile acid receptor farnesoid X receptor (FXR; targeted by synthetic FXR ligands such as obeticholic acid) and RAR-related orphan receptor gamma two (RORγt). In this review the authors provide an overview of the preclinical and clinical evidence of current and future treatment strategies targeting NRs in metabolism, inflammation, and fibrogenesis of NAFLD. PMID:26870934

  16. Assessment of Cardiovascular Parameters in Obese Children and Adolescents with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Eklioğlu, Beray Selver; Atabek, Mehmet Emre; Akyürek, Nesibe; Alp, Hayrullah

    2015-01-01

    Objective: The aim of this study was to evaluate the periaortic fat thickness (PAFT) using conventional echocardiography in obese children and adolescents with non-alcoholic fatty liver disease (NAFLD). Methods: Two hundred and ninety-seven obese children and adolescents were included in the study. Anthropometric measurements were made in all subjects, and fasting venous blood samples were taken for determination of glucose, insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Ultrasonography of the liver was used for assessment of NAFLD and the subjects were grouped as NAFLD and non-NAFLD. Echocardiography was performed in all subjects. Results: PAFT was higher in patients with NAFLD compared with the non-NAFLD group. In patients with NAFLD, PAFT was positively correlated with waist circumference and with total cholesterol levels. In multiple regression analysis, waist circumference (β=0.28, p=<0.001) was found to be the best predictor of PAFT. Conclusion: Conventional echocardiography may be used to determine increased PAFT at an early stage in obese children and adolescents with NAFLD for careful monitoring of cardiovascular risk. PMID:26831557

  17. Ursolic acid inhibits the development of nonalcoholic fatty liver disease by attenuating endoplasmic reticulum stress.

    PubMed

    Li, Jian-Shuang; Wang, Wen-Jun; Sun, Yu; Zhang, Yu-Hao; Zheng, Ling

    2015-05-01

    Ursolic acid (UA) is a natural pentacyclic triterpenoid compound, which is enriched with many herbs and plants, such as apple, cranberry and olive. UA performs multiple biological activities including anti-oxidation, anti-inflammation, anti-cancer and hepatoprotection. However, the exact mechanism underlying the hepatoprotective activity of UA remains unclear. In this study, the effects of UA on the development of nonalcoholic fatty liver disease (NAFLD) were investigated. In vivo, UA treatment (0.14%, w/w) significantly decreased the liver weight, serum levels of ALT/AST and hepatic steatosis in db/db mice (a type 2 diabetic mouse model). In vitro, UA treatment (10-30 μg ml(-1)) significantly decreased palmitic acid induced intracellular lipid accumulation in L02 cells. Our results suggested that the beneficial effects of UA on NAFLD may be due to its ability to increase lipid β-oxidation and to inhibit the hepatic endoplasmic reticulum (ER) stress. Together, UA may be further considered as a natural compound for NAFLD treatment. PMID:25892149

  18. Bioinformatics-Driven Identification and Examination of Candidate Genes for Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Banasik, Karina; Justesen, Johanne M.; Hornbak, Malene; Krarup, Nikolaj T.; Gjesing, Anette P.; Sandholt, Camilla H.; Jensen, Thomas S.; Grarup, Niels; Andersson, Åsa; Jørgensen, Torben; Witte, Daniel R.; Sandbæk, Annelli; Lauritzen, Torsten; Thorens, Bernard; Brunak, Søren; Sørensen, Thorkild I. A.; Pedersen, Oluf; Hansen, Torben

    2011-01-01

    Objective Candidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes. Research Design and Methods By integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs) which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D), central obesity, and WHO-defined metabolic syndrome (MetS). Results 273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P<0.05) to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations. Conclusions Using a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS. PMID:21339799

  19. Histopathologic Evaluation of Nonalcoholic Fatty Liver Disease in Hypothyroidism-Induced Rats

    PubMed Central

    Demir, Şule; Ünübol, Mustafa; Aypak, Serap Ünübol; İpek, Emrah; Aktaş, Serdar; Ekren, Gamze Sevri; Yılmaz, Murat; Tunca, Recai; Güney, Engin

    2016-01-01

    It is speculated that thyroid hormones may be involved in nonalcoholic fatty liver disease (NAFLD) pathogenesis. A literature scan, however, demonstrated conflicting results from studies investigating the relationship between hypothyroidism and NAFLD. Therefore, our study aims to evaluate NAFLD, from the histopathologic perspective, in hypothyroidism-induced rats. Wistar rats were divided into 2 groups: the experimental group consumed water containing methimazole 0.025% (MMI, Sigma, USA) for 12 weeks and the control group consumed tap water. At the end of week 12, serum glucose, ALT, AST, triglyceride, HDL, LDL, TSH, fT4, fT3, visfatin, and insulin assays were performed. Sections were stained with hematoxylin-eosin and “Oil Red-O” for histopathologic examination of the livers. In our study, we detected mild hepatosteatosis in all hypothyroidism-induced rats. There was statistically significant difference with respect to obesity between the two groups (p < 0.001). The mean fasting blood glucose was 126.25 ± 23.4 mg/dL in hypothyroidism-induced group and 102.63 ± 15.51 mg/dL in the control group, with a statistically significant difference between the groups (p = 0.032). The two groups did not differ statistically significantly with respect to visfatin levels (p > 0.05). In conclusion, we found that hypothyroidism-induced rats had mild hepatosteatosis as opposed to the control group histopathologically. Our study indicates that hypothyroidism can cause NAFLD. PMID:27143968

  20. Multi-omic profiles of human non-alcoholic fatty liver disease tissue highlight heterogenic phenotypes.

    PubMed

    Wruck, Wasco; Kashofer, Karl; Rehman, Samrina; Daskalaki, Andriani; Berg, Daniela; Gralka, Ewa; Jozefczuk, Justyna; Drews, Katharina; Pandey, Vikash; Regenbrecht, Christian; Wierling, Christoph; Turano, Paola; Korf, Ulrike; Zatloukal, Kurt; Lehrach, Hans; Westerhoff, Hans V; Adjaye, James

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a consequence of sedentary life style and high fat diets with an estimated prevalence of about 30% in western countries. It is associated with insulin resistance, obesity, glucose intolerance and drug toxicity. Additionally, polymorphisms within, e.g., APOC3, PNPLA3, NCAN, TM6SF2 and PPP1R3B, correlate with NAFLD. Several studies have already investigated later stages of the disease. This study explores the early steatosis stage of NAFLD with the aim of identifying molecular mechanisms underlying the etiology of NAFLD. We analyzed liver biopsies and serum samples from patients with high- and low-grade steatosis (also pre-disease states) employing transcriptomics, ELISA-based serum protein analyses and metabolomics. Here, we provide a detailed description of the various related datasets produced in the course of this study. These datasets may help other researchers find new clues for the etiology of NAFLD and the mechanisms underlying its progression to more severe disease states. PMID:26646939

  1. Multi-omic profiles of human non-alcoholic fatty liver disease tissue highlight heterogenic phenotypes

    PubMed Central

    Wruck, Wasco; Kashofer, Karl; Rehman, Samrina; Daskalaki, Andriani; Berg, Daniela; Gralka, Ewa; Jozefczuk, Justyna; Drews, Katharina; Pandey, Vikash; Regenbrecht, Christian; Wierling, Christoph; Turano, Paola; Korf, Ulrike; Zatloukal, Kurt; Lehrach, Hans; Westerhoff, Hans V.; Adjaye, James

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a consequence of sedentary life style and high fat diets with an estimated prevalence of about 30% in western countries. It is associated with insulin resistance, obesity, glucose intolerance and drug toxicity. Additionally, polymorphisms within, e.g., APOC3, PNPLA3, NCAN, TM6SF2 and PPP1R3B, correlate with NAFLD. Several studies have already investigated later stages of the disease. This study explores the early steatosis stage of NAFLD with the aim of identifying molecular mechanisms underlying the etiology of NAFLD. We analyzed liver biopsies and serum samples from patients with high- and low-grade steatosis (also pre-disease states) employing transcriptomics, ELISA-based serum protein analyses and metabolomics. Here, we provide a detailed description of the various related datasets produced in the course of this study. These datasets may help other researchers find new clues for the etiology of NAFLD and the mechanisms underlying its progression to more severe disease states. PMID:26646939

  2. Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease.

    PubMed

    Hyötyläinen, Tuulia; Jerby, Livnat; Petäjä, Elina M; Mattila, Ismo; Jäntti, Sirkku; Auvinen, Petri; Gastaldelli, Amalia; Yki-Järvinen, Hannele; Ruppin, Eytan; Orešič, Matej

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD. PMID:26839171

  3. Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease

    PubMed Central

    Hyötyläinen, Tuulia; Jerby, Livnat; Petäjä, Elina M.; Mattila, Ismo; Jäntti, Sirkku; Auvinen, Petri; Gastaldelli, Amalia; Yki-Järvinen, Hannele; Ruppin, Eytan; Orešič, Matej

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD. PMID:26839171

  4. Phenotype, Body Composition, and Prediction Equations (Indian Fatty Liver Index) for Non-Alcoholic Fatty Liver Disease in Non-Diabetic Asian Indians: A Case-Control Study

    PubMed Central

    Bhatt, Surya Prakash; Misra, Anoop; Nigam, Priyanka; Guleria, Randeep; Pasha, M. A. Qadar

    2015-01-01

    Objective In this study, we have attempted comparison of detailed body composition phenotype of Asian Indians with non-alcoholic fatty liver disease (NAFLD) vs. those without, in a case controlled manner. We also aim to analyse prediction equations for NAFLD for non-diabetic Asian Indians, and compare performance of these with published prediction equations researched from other populations. Methods In this case-control study, 162 cases and 173 age-and sex-matched controls were recruited. Clinical, anthropometric, metabolic, and body composition profiles, and liver ultrasound were done. Fasting insulin levels, value of homeostasis model assessment of insulin resistance (HOMA-IR), and serum high sensitive C-reactive protein (hs-CRP) levels were evaluated. Multivariate logistic and linear regression analyses were used to arrive at prediction equations for fatty liver [Indian fatty liver index (IFLI)]. Results As compared to those without fatty liver, those with fatty liver exhibited the following; Excess dorsocervical fat (‘Buffalo hump’), skin tags, xanthelasma, ‘double chin’, arcus; excess total, abdominal and subcutaneous adiposity, and high blood pressure, blood glucose, measures of insulin resistance (fasting insulin and HOMA-IR values), lipids and hs-CRP levels. Two prediction equations were developed; Clinical [Indian Fatty Liver Index-Clinical; IFLI-C]: 1(double chin) +15.5 (systolic blood pressure) +13.8 (buffalo hump); and IFLI-Clinical and Biochemical (CB): serum triglycerides+12 (insulin)+1(systolic blood pressure) +18 (buffalo hump). On ROC Curve analysis, IFLI performed better than all published prediction equations, except one. Conclusion Non-diabetic Asian Indians with NAFLD researched by us were overweight/obese, had excess abdominal and subcutaneous fat, multiple other phenotypic markers, had higher insulin resistance, glycemia, dyslipidemia and subclinical inflammation than those without. Prediction score developed by us for NAFLD; IFLI

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

    PubMed

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

    2015-08-01

    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. PMID:26051164

  6. Treatment of Nonalcoholic Fatty Liver Disease in Children: TONIC Trial Design

    PubMed Central

    2010-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) in children can lead to steatohepatitis, cirrhosis, and end-stage liver disease. The cause of NAFLD is unknown, but it is commonly associated with obesity, insulin resistance, and dyslipidemia. Objectives TONIC is conducted to test whether treatment with metformin, an insulin sensitizer, or vitamin E, a naturally available antioxidant, will lead to improvements in biochemical and histological features of nondiabetic children with biopsy-proven NAFLD. Design TONIC is a randomized, multicenter, double-masked, placebo-controlled trial of 96 weeks of treatment with metformin or vitamin E. The primary outcome measure chosen for the trial is improvement in serum alanine aminotransferase (ALT) levels with treatment as compared to placebo. An improvement in ALT is defined as reduction in serum ALT levels to below 50% of the baseline values or into the normal range (40 U/L or less) during the last 48 weeks of treatment. Histological improvement is defined by changes in liver histology between a baseline and end-of-treatment liver biopsy in regards to (1) steatohepatitis, (2) NAFLD Activity Score, consisting of scores for steatosis, lobular inflammation, and hepatocellular injury (ballooning), and (3) fibrosis score. Methods Between September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States. Participants were randomized to receive either metformin (500 mg b.i.d.), vitamin E (400 IU b.i.d.), or placebo for 96 weeks. This protocol was approved by all participating center Institutional Review Boards (IRBs) and an independent Data and Safety Monitoring Board (DSMB). (ClinicalTrials.gov number, NCT00063635.) PMID:19761871

  7. Association between nonalcoholic fatty liver disease and coronary artery calcification in postmenopausal women

    PubMed Central

    Kim, Min Kyung; Ahn, Chul Woo; Nam, Ji Sun; MD, Shinae Kang; Park, Jong Suk; Kim, Kyung Rae

    2015-01-01

    Abstract Objective: Cardiovascular disease is a leading cause of death in postmenopausal women, and nonalcoholic fatty liver disease (NAFLD) has been known to be associated with cardiovascular disease. However, little information regarding the relationship between NAFLD and coronary artery calcification (CAC) in postmenopausal women is available. The aim of this study was to investigate the association between NAFLD and CAC in postmenopausal women. Methods: Among 4,377 participants who underwent cardiac computed tomography in a health promotion center, 919 postmenopausal women were enrolled. Anthropometric profiles and multiple cardiovascular risk factors were measured. NAFLD was measured by ultrasonography, and CAC was evaluated by cardiac computed tomography. Odds ratios and 95% CI for the presence of CAC, by severity of fatty liver disease, were estimated using logistic regression. Results: Women were stratified into three groups by severity of NAFLD. There were significant differences in cardiovascular parameters among the groups, and prevalence of CAC significantly increased with severity of NAFLD. On logistic regression analysis after adjustment for multiple risk factors, the odds ratios for the prevalence of CAC were as follows (P < 0.05): no NAFLD, 1.0; mild NAFLD, 1.34 (95% CI, 0.92-2.16); moderate to severe NAFLD, 1.83 (95% CI, 1.06-3.16). However, this association was attenuated after adjustment for insulin resistance (P = 0.16). Conclusions: There is a significant correlation between NAFLD and prevalence of CAC, but NAFLD is not an independent factor for coronary atherosclerosis in postmenopausal women. PMID:26154274

  8. Novel hepatic microRNAs upregulated in human nonalcoholic fatty liver disease.

    PubMed

    Soronen, Jarkko; Yki-Järvinen, Hannele; Zhou, You; Sädevirta, Sanja; Sarin, Antti-Pekka; Leivonen, Marja; Sevastianova, Ksenia; Perttilä, Julia; Laurila, Pirkka-Pekka; Sigruener, Alexander; Schmitz, Gerd; Olkkonen, Vesa M

    2016-01-01

    MicroRNAs (miRNAs) control gene expression by reducing mRNA stability and translation. We aimed to identify alterations in human liver miRNA expression/function in nonalcoholic fatty liver disease (NAFLD). Subjects with the highest (median liver fat 30%, n = 15) and lowest (0%, n = 15) liver fat content were selected from >100 obese patients for miRNA profiling of liver biopsies on microarrays carrying probes for 1438 human miRNAs (a cross-sectional study). Target mRNAs and pathways were predicted for the miRNAs most significantly upregulated in NAFLD, their cell-type-specific expression was investigated by quantitative PCR (qPCR), and the transcriptome of immortalized human hepatocytes (IHH) transfected with the miRNA with the highest number of predicted targets, miR-576-5p, was studied. The screen revealed 42 miRNAs up- and two downregulated in the NAFLD as compared to non-NAFLD liver. The miRNAs differing most significantly between the groups, miR-103a-2*, miR-106b, miR-576-5p, miRPlus-I137*, miR-892a, miR-1282, miR-3663-5p, and miR-3924, were all upregulated in NAFLD liver. Target pathways predicted for these miRNAs included ones involved in cancer, metabolic regulation, insulin signaling, and inflammation. Consistent transcriptome changes were observed in IHH transfected with miR-576-5p, and western analysis revealed a marked reduction of the RAC1 protein belonging to several miR-576-5p target pathways. To conclude, we identified 44 miRNAs differentially expressed in NAFLD versus non-NAFLD liver, 42 of these being novel in the context of NAFLD. The study demonstrates that by applying a novel study set-up and a broad-coverage array platform one can reveal a wealth of previously undiscovered miRNA dysregulation in metabolic disease. PMID:26733244

  9. Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis

    PubMed Central

    Ma, Yan-Yan; Li, Lin; Yu, Chao-Hui; Shen, Zhe; Chen, Li-Hua; Li, You-Ming

    2013-01-01

    AIM: To investigate the relationship between the gut-liver axis and nonalcoholic fatty liver disease (NAFLD), we performed a meta-analysis to evaluate the effects of probiotic therapy in NAFLD. METHODS: We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library and Chinese Biomedicine Database for all relevant randomized controlled trials on probiotics in patients with NAFLD/nonalcoholic steatohepatitis (NASH). A statistical analysis was performed using RevMan 5.0 software. RESULTS: Four randomized trials involving 134 NAFLD/NASH patients were included. The results showed that probiotic therapy significantly decreased alanine aminotransferase (ALT), aspartate transaminase (AST), total-cholesterol (T-chol), high density lipoprotein (HDL), tumor necrosis factor (TNF)-α and homeostasis model assessment of insulin resistance (HOMA-IR) [ALT: weighted mean difference (WMD) -23.71, 95%CI: -33.46--13.95, P < 0.00001; AST: WMD -19.77, 95%CI: -32.55--7.00, P = 0.002; T-chol: WMD -0.28, 95%CI: -0.55--0.01, P = 0.04; HDL: WMD -0.09, 95%CI: -0.16-0.01, P = 0.03; TNF-α: WMD -0.32, 95%CI: -0.48--0.17, P < 0.0001; HOMA-IR: WMD -0.46, 95%CI: -0.73--0.19, P = 0.0008]. However, the use of probiotics was not associated with changes in body mass index (BMI), glucose (GLU) and low density lipoprotein (LDL) (BMI: WMD 0.05, 95%CI: -0.18-0.29, P = 0.64; GLU: WMD 0.05, 95%CI: -0.25-0.35, P = 0.76; LDL: WMD -0.38, 95%CI: -0.78-0.02, P = 0.06). CONCLUSION:Probiotic therapies can reduce liver aminotransferases, total-cholesterol, TNF-α and improve insulin resistance in NAFLD patients. Modulation of the gut microbiota represents a new treatment for NAFLD. PMID:24187469

  10. Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease.

    PubMed

    Polyzos, Stergios A; Anastasilakis, Athanasios D; Kountouras, Jannis; Makras, Polyzois; Papatheodorou, Athanasios; Kokkoris, Panagiotis; Sakellariou, Grigorios T; Terpos, Evangelos

    2016-07-01

    There is increasing evidence for bone-liver interplay. The main aim of this study was to determine serum sclerostin and Dickkopf (DKK)-1 levels in patients with nonalcoholic fatty liver disease (NAFLD) and their association with the disease severity. Patients with biopsy-proven NAFLD, 13 with nonalcoholic simple steatosis (SS) and 14 with steatohepatitis (NASH), and 20 gender-, age-, body mass index- and waist circumference-matched controls were enrolled. Serum sclerostin, DKK-1, bone turnover markers, vitamin D, insulin and standard biochemical and hematologic parameters were measured; lumbar spinal dual-energy X-ray absorptiometry was performed. We observed that there was a progressive decline in serum sclerostin levels from the controls (76.1 ± 6.8) to SS (53.5 ± 6.4) and NASH (46.0 ± 8.1 pmol/l) patients (p = 0.009); in adjusted pairwise comparisons, sclerostin was significantly higher in the controls than in NASH patients (p = 0.012). Although serum DKK-1 did not differ between groups (p = 0.135), there was a trend toward U-shaped distribution (controls 35.8 ± 2.8; SS 27.3 ± 2.9; NASH 36.8 ± 4.4 pmol/l). Higher DKK-1 levels were independently associated with NASH. Regarding specific histological lesions, DKK-1 levels were marginally lower in NAFLD patients with lower (≤33 %) than higher (>33 %) steatosis grade (27.7 ± 3.1 and 38.8 ± 4.7 pmol/l, respectively; p = 0.049). No other significant difference was observed within histological lesions. In conclusion, serum sclerostin levels were lower in NASH patients than in controls. DKK-1 levels were independently associated with NASH in NAFLD patients. The potential importance of these findings indicates a possible bone-liver interaction and warrants further investigation. PMID:26056025

  11. Nonalcoholic Fatty Liver Disease Progression in Rats is Accelerated by Splenic Regulation of Liver PTEN/AKT

    PubMed Central

    Wang, Ziming; Li, Naishu; Wang, Biao; Lin, Jianhua

    2015-01-01

    Background/Aim: The spleen has been reported to participate in the development of nonalcoholic fatty liver disease (NAFLD), but the mechanism has not been fully characterized. This study aims to elucidate how the spleen affects the development of NAFLD in a rat model. Materials and Methods: Following either splenectomy or sham operation, male Sprague–Dawley (SD) rats were fed a high-fat diet to drive the development of NAFLD; animals fed a normal diet were used as controls. Two months after surgery, livers and blood samples were collected. Serum lipids were measured; liver histology, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) gene expression, and the ratio of pAkt/Akt were determined. Results: Splenectomy increased serum lipids, except triglyceride (TG) and high-density lipoprotein (HDL), in animals fed either a high-fat or normal diet. Furthermore, splenectomy significantly accelerated hepatic steatosis. Western blot analysis and real-time polymerase chain reaction showed splenectomy induced significant downregulation of PTEN expression and a high ratio of pAkt/Akt in the livers. Conclusions: The spleen appears to play a role in the development of NAFLD, via a mechanism involving downregulation of hepatic PTEN expression. PMID:26228367

  12. Non-alcoholic fatty liver disease is not associated with a lower health perception

    PubMed Central

    Mlynarsky, Liat; Schlesinger, Dalit; Lotan, Roni; Webb, Muriel; Halpern, Zamir; Santo, Erwin; Shibolet, Oren; Zelber-Sagi, Shira

    2016-01-01

    AIM: To examine the association between non-alcoholic fatty liver disease (NAFLD) and general health perception. METHODS: 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. RESULTS: 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

  13. Non-alcohol fatty liver disease in Asia: Prevention and planning

    PubMed Central

    Ashtari, Sara; Pourhoseingholi, Mohamad Amin; Zali, Mohamad Reza

    2015-01-01

    AIM: To review all of epidemiological aspects of non-alcoholic fatty liver disease (NAFLD) and also prevent this disease is examined. METHODS: We conducted a systematic review according to the PRISMA guidelines. All searches for writing this review is based on the papers was found in PubMed (MEDLINE), Cochrane database and Scopus in August and September 2014 for topic of NAFLD in Asia and the way of prevention of this disease, with no language limitations. All relevant articles were accessed in full text and all relevant materials was evaluated and reviewed. RESULTS: NAFLD is the most common liver disorder in worldwide, with an estimated with 20%-30% prevalence in Western countries and 2%-4% worldwide. The prevalence of NAFLD in Asia, depending on location (urban vs rural), gender, ethnicity, and age is variable between 15%-20%. According to the many studies in the world, the relationship between NAFLD, obesity, diabetes mellitus, and metabolic syndrome (MS) is quiet obvious. Prevalence of NAFLD in Asian countries seems to be lower than the Western countries but, it has increased recently due to the rise of obesity, type 2 diabetes and MS in this region. One of the main reasons for the increase in obesity, diabetes and MS in Asia is a lifestyle change and industrialization. Today, NAFLD is recognized as a major chronic liver disease in Asia. Therefore, prevention of this disease in Asian countries is very important and the best strategy for prevention and control of NAFLD is lifestyle modifications. Lifestyle modification programs are typically designed to change bad eating habits and increase physical activity that is associated with clinically significant improvements in obesity, type 2 diabetes and MS. CONCLUSION: Prevention of NAFLD is very important in Asian countries particularly in Arab countries because of high prevalence of obesity, diabetes and MS. PMID:26167252

  14. Helicobacter pylori infection is not associated with nonalcoholic fatty liver disease

    PubMed Central

    Baeg, Myong Ki; Yoon, Seung Kew; Ko, Sun-Hye; Noh, Yong-Sun; Lee, In-Seok; Choi, Myung-Gyu

    2016-01-01

    AIM: To determine whether Helicobacter pylori (H. pylori) infection confers a higher risk of Nonalcoholic fatty liver disease (NAFLD). METHODS: Healthy people who underwent health screening were analyzed retrospectively. Inclusion criteria were age ≥ 20 years, history of H. pylori infection, and recorded insulin level. Participants were classified as H. pylori positive or negative according to 13C urea breath tests. NAFLD was defined using the hepatic steatosis index (HSI) and NAFLD liver fat score (NAFLD-LFS). Those with an HSI > 36 or NAFLD-LFS > -0.640 were considered to have NAFLD. Multivariable logistic regression was performed to identify risk factors for NAFLD. RESULTS: Three thousand six hundred and sixty-three people were analyzed and 1636 (44.7%) were H. pylori positive. H. pylori infection was associated with older age, male gender, hypertension, higher body mass index, and a dyslipidemic profile. HSI differed significantly between H. pylori positive and negative subjects (median 33.2, interquartile range (IQR) 30.0-36.2 for H. pylori-positive vs median 32.6, IQR 29.8-36.0 for negative participants, P = 0.005), but NAFLD-LSF did not [median -1.7, IQR -2.4 - -0.7 vs median -1.8, IQR -2.4-(-0.7), respectively, P = 0.122]. The percentage of people with NAFLD did not differ between infected and uninfected groups: HIS, 26.9% vs 27.1%, P = 0.173; NAFLD-LFS, 23.5% vs 23.1%, P = 0.778. H. pylori infection was not a risk factor, but C-reactive protein concentration and smoking were significant risk factors for NAFLD. CONCLUSION: H. pylori infection is not a risk factor for NAFLD as indicated by HSI or NAFLD-LFS. Prospective, large-scale studies involving liver biopsies should be considered. PMID:26937147

  15. Diet-induced dyslipidemia leads to nonalcoholic fatty liver disease and oxidative stress in guinea pigs.

    PubMed

    Tveden-Nyborg, Pernille; Birck, Malene M; Ipsen, David H; Thiessen, Tina; Feldmann, Linda de Bie; Lindblad, Maiken M; Jensen, Henrik E; Lykkesfeldt, Jens

    2016-02-01

    Chronic dyslipidemia imposed by a high-fat and high-caloric dietary regime leads to debilitating disorders such as obesity, nonalcoholic fatty liver disease (NAFLD), and insulin resistance. As disease rates surge, so does the need for high validity animal models to effectively study the causal relationship between diet and disease progression. The dyslipidemic guinea pig displays a high similarity with the human lipoprotein profile and may in this aspect be superior to other rodent models. This study investigated the effects of 2 long-term Westernized diets (0.35% cholesterol, 18.5% vegetable oil and either 15% or 20% sucrose) compared with isocaloric standard chow in adult guinea pigs. Biochemical markers confirmed dyslipidemia in agreement with dietary regimens; however, both high-fat groups displayed a decreased tissue fat percentage compared with controls. Macroscopic appearance, histopathologic evaluation, and plasma markers of liver function confirmed NAFLD in high-fat groups, supported by liver redox imbalance and markers suggesting hepatic endothelial dysfunction. Plasma markers indicated endothelial dysfunction in response to a high-fat diet, although atherosclerotic lesions were not evident. Evaluation of glucose tolerance showed no indication of insulin resistance. The 5% increase in sucrose between the 2 high-fat diets did not lead to significant differences between groups. In conclusion, we find the dyslipidemic guinea pig to be a valid model of diet imposed dyslipidemia, particularly with regards to hepatic steatosis and endothelial dysfunction. Furthermore, the absence of obesity supports the present study setup as targeting NAFLD in nonobese individuals. PMID:26518991

  16. Relationship Between the Methylome and Transcriptome in Patients with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Murphy, Susan K.; Yang, Hyuna; Moylan, Cynthia A.; Pang, Herbert; Dellinger, Andrew; Abdelmalek, Manal F.; Garrett, Melanie E.; Ashley-Koch, Allison; Suzuki, Ayako; Tillmann, Hans L.; Hauser, Michael A.; Mae Diehl, Anna

    2013-01-01

    Background & Aims Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting non-invasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression. Methods We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0–1 (mild) and F3–4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome. Results Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P<.05). Methylation at FGFR2, MAT1A, and CASP1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, whereas genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and under-expressed. Conclusions Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate

  17. Treatment of Non-alcoholic Fatty Liver Disease with Curcumin: A Randomized Placebo-controlled Trial.

    PubMed

    Rahmani, Sepideh; Asgary, Sedigheh; Askari, Gholamreza; Keshvari, Mahtab; Hatamipour, Mahdi; Feizi, Awat; Sahebkar, Amirhossein

    2016-09-01

    Non-alcoholic fatty liver disease (NAFLD) is a global health problem. Although many aspects of NAFLD pathogenesis have been understood, there is a paucity of effective treatments to be used as the second line when lifestyle modification is insufficient. Curcumin, a natural polyphenol from turmeric, has been shown to be effective against development of hepatic steatosis and its progression to steatohepatitis, yet these beneficial effects have not been explored in clinical practice. The aim of this study is to investigate the effects of curcumin on hepatic fat content as well as biochemical and anthropometric features of patients with NAFLD. In this randomized double-blind placebo-controlled trial, patients with ultrasonographic evidence of NAFLD were randomly assigned to receive an amorphous dispersion curcumin formulation (500 mg/day equivalent to 70-mg curcumin) or matched placebo for a period of 8 weeks. Liver fat content (assessed through ultrasonography), glycemic and lipid profile, transaminase levels, and anthropometric indices were evaluated at baseline and at the end of follow-up period. The clinical trial protocol was registered under the Iranian Registry of Clinical Trials ID: IRCT2014110511763N18. Compared with placebo, curcumin was associated with a significant reduction in liver fat content (78.9% improvement in the curcumin vs 27.5% improvement in the placebo group). There were also significant reductions in body mass index and serum levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, glucose, and glycated hemoglobin compared with the placebo group. Curcumin was safe and well tolerated during the course of trial. Findings of the present proof-of-concept trial suggested improvement of different features of NAFLD after a short-term supplementation with curcumin. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27270872

  18. SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease

    PubMed Central

    Colak, Yasar; Ozturk, Oguzhan; Senates, Ebubekir; Tuncer, Ilyas; Yorulmaz, Elif; Adali, Gupse; Doganay, Levent; Enc, Feruze Yilmaz

    2011-01-01

    Summary Sirtuins are members of the silent information regulator 2 (Sir2) family, a group of Class III histone/protein deacetylases. There are 7 different sirtuins in mammals (SIRT1-7), of which SIRT1 is the best known and most studied. SIRT1 is responsible for the regulation of protein activation by means of deacetylating a variety of proteins that play important roles in the pathophysiology of metabolic diseases. Recently, it has been shown that SIRT1 plays key roles in the regulation of lipid and glucose homeostasis, control of insulin secretion and sensitivity, antiinflammatory effects, control of oxidative stress and the improvements in endothelial function that result due to increased mitochondrial biogenesis and β-oxidation capacity. Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease, and it has been accepted as the hepatic component of metabolic syndrome. Recent studies have shown that SIRT expression in the liver is significantly decreased in an NAFLD model of rats fed a high-fat diet, and moderate SIRT1 overexpression protects mice from developing NAFLD. In addition to resveratrol, a natural SIRT1 activator, small-molecule pharmacologic SIRT1 activators have positive effects on metabolic diseases. These effects are particularly promising in the case of diabetes mellitus, for which phase studies are currently being performed. With this information, we hypothesized that the pharmacologic activation of SIRT1, which has been implicated in the pathogenesis of NAFLD, will be a potential therapeutic target for treating NAFLD. In this paper, we review the metabolic effects of SIRT1 and its association with the pathophysiology of NAFLD. PMID:21525818

  19. Metabolomic analysis of the effects of polychlorinated biphenyls in nonalcoholic fatty liver disease.

    PubMed

    Shi, Xue; Wahlang, Banrida; Wei, Xiaoli; Yin, Xinmin; Falkner, K Cameron; Prough, Russell A; Kim, Seong Ho; Mueller, Eugene G; McClain, Craig J; Cave, Matthew; Zhang, Xiang

    2012-07-01

    Polychlorinated biphenyls (PCBs) are persistent organic pollutants and have been associated with abnormal liver enzymes and suspected nonalcoholic fatty liver disease (NAFLD), obesity, and the metabolic syndrome in epidemiological studies. In epidemiological surveys of human PCB exposure, PCB 153 has the highest serum levels among PCB congeners. To determine the hepatic effects of PCB 153 in mice, C57BL/6J mice were fed either a control diet (CD) or a high fat diet (HFD) for 12 weeks, with or without PCB 153 coexposure. The metabolite extracts from mouse livers were analyzed using linear trap quadrupole-Fourier transform ion cyclotron resonance mass spectrometer (LTQ-FTICR MS) via direct infusion nanoelectrospray ionization (DI-nESI) mass spectrometry. The metabolomics analysis indicated no difference in the metabolic profile between mice fed the control diet with PCB 153 exposure (CD+PCB 153) and mice fed the control diet (CD) without PCB 153 exposure. However, compared with CD group, levels of 10 metabolites were increased and 15 metabolites were reduced in mice fed HFD. Moreover, compared to CD+PCB 153 group, the abundances of 6 metabolites were increased and 18 metabolites were decreased in the mice fed high fat diet with PCB 153 exposure (HFD+PCB 153). Compared with HFD group, the abundances of 2 metabolites were increased and of 12 metabolites were reduced in HFD+PCB 153 group. These observations agree with the histological results and indicate that the metabolic effects of PCB 153 were highly dependent on macronutrient interactions with HFD. Antioxidant depletion is likely to be an important consequence of this interaction, as this metabolic disturbance has previously been implicated in obesity and NAFLD. PMID:22686559

  20. Activation of Proteinase 3 Contributes to Nonalcoholic Fatty Liver Disease and Insulin Resistance

    PubMed Central

    Toonen, Erik JM; Mirea, Andreea-Manuela; Tack, Cees J; Stienstra, Rinke; Ballak, Dov B; van Diepen, Janna A; Hijmans, Anneke; Chavakis, Triantafyllos; Dokter, Wim H; Pham, Christine TN; Netea, Mihai G; Dinarello, Charles A; Joosten, Leo AB

    2016-01-01

    Activation of inflammatory pathways is known to accompany development of obesity-induced nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive proinflammatory mediators interleukin (IL)-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In this study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human α-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin-resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3-deficient mice showed strongly reduced levels of lipids in the liver after being fed a high-fat diet. Moreover, these mice were resistant to high–fat–diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1–/– mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with α-1 antitrypsin during the last 10 d of a 16-wk high-fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential. PMID:27261776

  1. Elevated citrate levels in non-alcoholic fatty liver disease: the potential of citrate to promote radical production.

    PubMed

    van de Wier, Bregje; Balk, Jiska M; Haenen, Guido R M M; Giamouridis, Dimosthenis; Bakker, Jaap A; Bast, Bertine C; den Hartog, Gertjan J M; Koek, Ger H; Bast, Aalt

    2013-08-01

    Plasma citrate levels were found to be elevated in non-alcoholic fatty liver disease (NAFLD) patients. Cellular experiments indicated that increased citrate levels might originate from an excess of fatty acids. The impact of elevated citrate levels on oxidative stress was examined. It was found that citrate stimulated hydrogen peroxide induced intracellular oxidative stress in HepG2 cells. This was related to the promotion of iron mediated hydroxyl radical formation from hydrogen peroxide by citrate. The stimulating effect of citrate on the reactivity of iron promotes oxidative stress, a crucial process in the progression of NAFLD. PMID:23792160

  2. Healthy dietary pattern is inversely associated with non-alcoholic fatty liver disease in elderly.

    PubMed

    Adriano, Lia Silveira; Sampaio, Helena Alves de Carvalho; Arruda, Soraia Pinheiro Machado; Portela, Clarissa Lima de Melo; Melo, Maria Luisa Pereira de; Carioca, Antônio Augusto Ferreira; Soares, Nadia Tavares

    2016-06-01

    The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising, an increase that may be associated with changes in lifestyle such as unhealthy dietary patterns. Although advanced age is a risk factor for NAFLD, no studies reporting this association in the elderly population were found. In the present study, the association between dietary patterns and NAFLD in the elderly was assessed. A study including 229 older adults was conducted. NAFLD diagnosis was defined as individuals whose ultrasound examination disclosed hepatic steatosis at any stage, in the absence of excess intake of alcoholic beverages. Dietary patterns were obtained by principal components analysis. Mean scores and standard errors of each dietary pattern were calculated for the groups with and without NAFLD, and mean scores of the two groups were compared using the Mann-Whitney U test. The prevalence ratios and 95 % CI were estimated for each tertile of the dietary pattern adherence scores using Poisson multiple regression models with robust variance. A total of 103 (45 %) elderly with NAFLD and four dietary patterns were identified: traditional, regional snacks, energy dense and healthy. Mean scores for adherence to the healthy pattern in the groups with and without NAFLD differed. NAFLD was inversely associated with greater adherence to the healthy pattern and directly associated with the regional snacks, after adjustment for confounders. In conclusion, healthy dietary pattern is inversely associated with NAFLD in elderly. PMID:27102566

  3. Oral Fructose Absorption in Obese Children with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Sullivan, Jillian S; Le, MyPhuong T; Pan, Zhaoxing; Rivard, Christopher; Love-Osborne, Kathryn; Robbins, Kristen; Johnson, Richard J; Sokol, Ronald J; Sundaram, Shikha S

    2014-01-01

    Background Fructose intake is associated with NAFLD (Non-Alcoholic Fatty Liver Disease) development. Objective To measure fructose absorption/metabolism in pediatric NAFLD compared to obese and lean controls. Methods Children with histologically proven NAFLD, and obese and lean controls received oral fructose (1 gm/kg ideal body weight). Serum glucose, insulin, uric acid, and fructose, urine uric acid, urine fructose, and breath hydrogen levels were measured at baseline and multiple points until 360 minutes after fructose ingestion. Results Nine NAFLD (89% Hispanic, mean age 14.3 years, mean BMI 35.3 kg/m2), 6 Obese Controls (67% Hispanic, mean age 12.7 years, mean BMI 31.0 kg/m2), and 9 Lean Controls (44% Hispanic, mean age 14.3 years, mean BMI 19.4 kg/m2) were enrolled. Following fructose ingestion, NAFLD vs. Lean Controls had elevated serum glucose, insulin, and uric acid (p<0.05), higher urine uric acid (p=0.001) but lower fructose excretion (p=0.002) and lower breath hydrogen 180-min AUC (p=0.04). NAFLD vs. Obese Controls had similar post-fructose serum glucose, insulin, urine uric acid, and breath hydrogen, but elevated serum uric acid (p<0.05) and lower urine fructose excretion (p=0.02). Conclusions Children with NAFLD absorb and metabolize fructose more effectively than lean subjects, associated with an exacerbated metabolic profile following fructose ingestion. PMID:24961681

  4. Integrative Genomic Signatures Of Hepatocellular Carcinoma Derived from Nonalcoholic Fatty Liver Disease

    PubMed Central

    Frades, Itziar; Andreasson, Erik; Mato, Jose Maria; Alexandersson, Erik; Matthiesen, Rune; Martínez-Chantar, Mª Luz

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a risk factor for Hepatocellular carcinoma (HCC), but he transition from NAFLD to HCC is poorly understood. Feature selection algorithms in human and genetically modified mice NAFLD and HCC microarray data were applied to generate signatures of NAFLD progression and HCC differential survival. These signatures were used to study the pathogenesis of NAFLD derived HCC and explore which subtypes of cancers that can be investigated using mouse models. Our findings show that: (I) HNF4 is a common potential transcription factor mediating the transcription of NAFLD progression genes (II) mice HCC derived from NAFLD co-cluster with a less aggressive human HCC subtype of differential prognosis and mixed etiology (III) the HCC survival signature is able to correctly classify 95% of the samples and gives Fgf20 and Tgfb1i1 as the most robust genes for prediction (IV) the expression values of genes composing the signature in an independent human HCC dataset revealed different HCC subtypes showing differences in survival time by a Logrank test. In summary, we present marker signatures for NAFLD derived HCC molecular pathogenesis both at the gene and pathway level. PMID:25993042

  5. Relationship between Non-Alcoholic Fatty Liver Disease and Psoriasis: A Novel Hepato-Dermal Axis?

    PubMed Central

    Mantovani, Alessandro; Gisondi, Paolo; Lonardo, Amedeo; Targher, Giovanni

    2016-01-01

    Over the past 10 years, it has become increasingly evident that nonalcoholic fatty liver disease (NAFLD) is a multisystem disease that affects multiple extra-hepatic organ systems and interacts with the regulation of several metabolic and immunological pathways. In this review we discuss the rapidly expanding body of clinical and epidemiological evidence supporting a strong association between NAFLD and chronic plaque psoriasis. We also briefly discuss the possible biological mechanisms underlying this association, and discuss treatment options for psoriasis that may influence NAFLD development and progression. Recent observational studies have shown that the prevalence of NAFLD (as diagnosed either by imaging or by histology) is remarkably higher in psoriatic patients (occurring in up to 50% of these patients) than in matched control subjects. Notably, psoriasis is associated with NAFLD even after adjusting for metabolic syndrome traits and other potential confounding factors. Some studies have also suggested that psoriatic patients are more likely to have the more advanced forms of NAFLD than non-psoriatic controls, and that psoriatic patients with NAFLD have more severe psoriasis than those without NAFLD. In conclusion, the published evidence argues for more careful evaluation and surveillance of NAFLD among patients with psoriasis. PMID:26861300

  6. The role of dietary sugars and de novo lipogenesis in non-alcoholic fatty liver disease.

    PubMed

    Moore, J Bernadette; Gunn, Pippa J; Fielding, Barbara A

    2014-12-01

    Dietary sugar consumption, in particular sugar-sweetened beverages and the monosaccharide fructose, has been linked to the incidence and severity of non-alcoholic fatty liver disease (NAFLD). Intervention studies in both animals and humans have shown large doses of fructose to be particularly lipogenic. While fructose does stimulate de novo lipogenesis (DNL), stable isotope tracer studies in humans demonstrate quantitatively that the lipogenic effect of fructose is not mediated exclusively by its provision of excess substrates for DNL. The deleterious metabolic effects of high fructose loads appear to be a consequence of altered transcriptional regulatory networks impacting intracellular macronutrient metabolism and altering signaling and inflammatory processes. Uric acid generated by fructose metabolism may also contribute to or exacerbate these effects. Here we review data from human and animal intervention and stable isotope tracer studies relevant to the role of dietary sugars on NAFLD development and progression, in the context of typical sugar consumption patterns and dietary recommendations worldwide. We conclude that the use of hypercaloric, supra-physiological doses in intervention trials has been a major confounding factor and whether or not dietary sugars, including fructose, at typically consumed population levels, effect hepatic lipogenesis and NAFLD pathogenesis in humans independently of excess energy remains unresolved. PMID:25514388

  7. The Role of Dietary Sugars and De novo Lipogenesis in Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Moore, J. Bernadette; Gunn, Pippa J.; Fielding, Barbara A.

    2014-01-01

    Dietary sugar consumption, in particular sugar-sweetened beverages and the monosaccharide fructose, has been linked to the incidence and severity of non-alcoholic fatty liver disease (NAFLD). Intervention studies in both animals and humans have shown large doses of fructose to be particularly lipogenic. While fructose does stimulate de novo lipogenesis (DNL), stable isotope tracer studies in humans demonstrate quantitatively that the lipogenic effect of fructose is not mediated exclusively by its provision of excess substrates for DNL. The deleterious metabolic effects of high fructose loads appear to be a consequence of altered transcriptional regulatory networks impacting intracellular macronutrient metabolism and altering signaling and inflammatory processes. Uric acid generated by fructose metabolism may also contribute to or exacerbate these effects. Here we review data from human and animal intervention and stable isotope tracer studies relevant to the role of dietary sugars on NAFLD development and progression, in the context of typical sugar consumption patterns and dietary recommendations worldwide. We conclude that the use of hypercaloric, supra-physiological doses in intervention trials has been a major confounding factor and whether or not dietary sugars, including fructose, at typically consumed population levels, effect hepatic lipogenesis and NAFLD pathogenesis in humans independently of excess energy remains unresolved. PMID:25514388

  8. Ceramide as a Mediator of Non-Alcoholic Fatty Liver Disease and Associated Atherosclerosis

    PubMed Central

    Kasumov, Takhar; Li, Ling; Li, Min; Gulshan, Kailash; Kirwan, John P.; Liu, Xiuli; Previs, Stephen; Willard, Belinda; Smith, Jonathan D.; McCullough, Arthur

    2015-01-01

    Cardiovascular disease (CVD) is a serious comorbidity in nonalcoholic fatty liver disease (NAFLD). Since plasma ceramides are increased in NAFLD and sphingomyelin, a ceramide metabolite, is an independent risk factor for CVD, the role of ceramides in dyslipidemia was assessed using LDLR-/- mice, a diet-induced model of NAFLD and atherosclerosis. Mice were fed a standard or Western diet (WD), with or without myriocin, an inhibitor of ceramide synthesis. Hepatic and plasma ceramides were profiled and lipid and lipoprotein kinetics were quantified. Hepatic and intestinal expression of genes and proteins involved in insulin, lipid and lipoprotein metabolism were also determined. WD caused hepatic oxidative stress, inflammation, apoptosis, increased hepatic long-chain ceramides associated with apoptosis (C16 and C18) and decreased very-long-chain ceramide C24 involved in insulin signaling. The plasma ratio of ApoB/ApoA1 (proteins of VLDL/LDL and HDL) was increased 2-fold due to increased ApoB production. Myriocin reduced hepatic and plasma ceramides and sphingomyelin, and decreased atherosclerosis, hepatic steatosis, fibrosis, and apoptosis without any effect on oxidative stress. These changes were associated with decreased lipogenesis, ApoB production and increased HDL turnover. Thus, modulation of ceramide synthesis may lead to the development of novel strategies for the treatment of both NAFLD and its associated atherosclerosis. PMID:25993337

  9. Physical activity as a treatment of non-alcoholic fatty liver disease: A systematic review

    PubMed Central

    Whitsett, Maureen; VanWagner, Lisa B

    2015-01-01

    AIM: To review the effectiveness of exercise as a therapy for nonalcoholic fatty liver disease (NAFLD) and potential benefits in treating insulin resistance and atherosclerosis. METHODS: Medline (EBSCOhost) and PubMed were searched for English-language randomized controlled trials and prospective cohort studies in human adults aged ≥ 18 which investigated the various effects of exercise alone, a combination of exercise and diet, or exercise and diet coupled with behavioral modification on NAFLD from 2010 to Feburary 2015. RESULTS: Eighteen of 2298 available studies were chosen for critical review, which included 6925 patients. Nine (50%) studies were randomized controlled trials. Five (27.8%) studies utilized biopsy to examine the effects of physical activity on hepatic histology. The most commonly employed imaging modality to determine change in hepatic steatosis was hydrogen-magnetic resonance spectroscopy. Only two studies examined the effects of low impact physical activity for patients with significant mobility limitations and one compared the efficacy of aerobic and resistance exercise. No studies examined the exact duration of exercise required for hepatic and metabolic improvement in NAFLD. CONCLUSION: While exercise improved hepatic steatosis and underlying metabolic abnormalities in NAFLD, more studies are needed to define the most beneficial form and duration of exercise treatment. PMID:26261693

  10. The Global Nonalcoholic Fatty Liver Disease Epidemic: What a Radiologist Needs to Know

    PubMed Central

    Pereira, Keith; Salsamendi, Jason; Casillas, Javier

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disorders from a benign steatosis to hepatocellular carcinoma (HCC). Metabolic syndrome, mainly obesity, plays an important role, both as an independent risk factor and in the pathogenesis of NAFLD. With the progressive epidemics of obesity and diabetes mellitus, the prevalence of NAFLD and its associated complications is expected to increase dramatically. Therapeutic strategies for treating NAFLD and metabolic syndrome, particularly obesity, are continuously being refined. Their goal is the prevention of NAFLD by the management of risk factors, prevention of progression of the disease, as well as management of complications, ultimately preventing morbidity and mortality. Optimal management of NAFLD and metabolic syndrome requires a multidisciplinary collaboration between the government as well as the health system including the nutritionist, primary care physician, radiologist, hepatologist, oncologist, and transplant surgeon. An awareness of the clinical presentation, risk factors, pathogenesis, diagnosis, and management is of paramount importance to a radiologist, both from the clinical perspective as well as from the imaging standpoint. With expertise in imaging modalities as well as minimally invasive percutaneous endovascular therapies, radiologists play an essential role in the comprehensive management, which is highlighted in this article, with cases from our practice. We also briefly discuss transarterial embolization of the left gastric artery (LGA), a novel method that promises to have an enormous potential in the minimally invasive management of obesity, with details of a case from our practice. PMID:26167390

  11. Extracellular Vesicles: A New Frontier in Biomarker Discovery for Non-Alcoholic Fatty Liver Disease.

    PubMed

    Ban, Linda A; Shackel, Nicholas A; McLennan, Susan V

    2016-01-01

    In recent years, the global burden of obesity and diabetes has seen a parallel rise in other metabolic complications, such as non-alcoholic fatty liver disease (NAFLD). This condition, once thought to be a benign accumulation of hepatic fat, is now recognized as a serious and prevalent disorder that is conducive to inflammation and fibrosis. Despite the rising incidence of NAFLD, there is currently no reliable method for its diagnosis or staging besides the highly invasive tissue biopsy. This limitation has resulted in the study of novel circulating markers as potential candidates, one of the most popular being extracellular vesicles (EVs). These submicron membrane-bound structures are secreted from stressed and activated cells, or are formed during apoptosis, and are known to be involved in intercellular communication. The cargo of EVs depends upon the parent cell and has been shown to be changed in disease, as is their abundance in the circulation. The role of EVs in immunity and epigenetic regulation is widely attested, and studies showing a correlation with disease severity have made these structures a favorable target for diagnostic as well as therapeutic purposes. This review will highlight the research that is available on EVs in the context of NAFLD, the current limitations, and projections for their future utility in a clinical setting. PMID:26985892

  12. Extracellular Vesicles: A New Frontier in Biomarker Discovery for Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Ban, Linda A.; Shackel, Nicholas A.; McLennan, Susan V.

    2016-01-01

    In recent years, the global burden of obesity and diabetes has seen a parallel rise in other metabolic complications, such as non-alcoholic fatty liver disease (NAFLD). This condition, once thought to be a benign accumulation of hepatic fat, is now recognized as a serious and prevalent disorder that is conducive to inflammation and fibrosis. Despite the rising incidence of NAFLD, there is currently no reliable method for its diagnosis or staging besides the highly invasive tissue biopsy. This limitation has resulted in the study of novel circulating markers as potential candidates, one of the most popular being extracellular vesicles (EVs). These submicron membrane-bound structures are secreted from stressed and activated cells, or are formed during apoptosis, and are known to be involved in intercellular communication. The cargo of EVs depends upon the parent cell and has been shown to be changed in disease, as is their abundance in the circulation. The role of EVs in immunity and epigenetic regulation is widely attested, and studies showing a correlation with disease severity have made these structures a favorable target for diagnostic as well as therapeutic purposes. This review will highlight the research that is available on EVs in the context of NAFLD, the current limitations, and projections for their future utility in a clinical setting. PMID:26985892

  13. Hemochromatosis gene and nonalcoholic fatty liver disease: a systematic review and meta-analysis

    PubMed Central

    Hernaez, Ruben; Yeung, Edwina; Clark, Jeanne M.; Kowdley, Kris V.; Brancati, Frederick L.; Kao, Wen Hong Linda

    2011-01-01

    Background and aims Previous studies examining the relationship between the C282Y and H63D HFE mutations and presence of nonalcoholic fatty liver disease (NAFLD) have yielded conflicting results. The goal of this study was to systematically evaluate and summarize data on the association between these two variants and the presence of NAFLD. Methods The authors searched EMBASE and PUBMED from August 1, 1996 to August 12, 2010. Two investigators independently conducted data abstraction. Ethnic specific weighted prevalence was calculated, and pooled odds ratios were estimated using random effects model. Results From 2,542 references, the authors included 16 case-control studies and 14 case-only studies, or 2,610 cases and 7,298 controls. The majority of the studies came from Caucasian populations (2,287 cases and 4,275 controls). The weighted prevalence of HFE mutations in cases was comparable to controls. The meta-analysis was restricted to Caucasians only because the small sample size of non Caucasian participants. The pooled odds ratio for the presence of any HFE genetic variant in cases was 1.03 (95% CI: 0.90, 1.17; I2: 65.8%, 95% CI: 38.5, 81.0). The presence of other genotypes, and secondary analyses yielded similar non significant findings. Conclusion Our systematic review does not support an association between the HFE genetic variants and the presence of NAFLD. PMID:21354231

  14. Waist circumference as a marker for screening nonalcoholic fatty liver disease in obese adolescents

    PubMed Central

    Clemente, Ana Paula Grotti; Dal Molin, Bárbara; de Carvalho-Ferreira, Joana Pereira; Campos, Raquel Munhoz da Silveira; Ganen, Aline de Piano; Tock, Lian; de Mello, Marco Túlio; Dâmaso, Ana Raimunda

    2016-01-01

    Abstract Objective: To assess the relationship between the degree of waist circumference (WC) and nonalcoholic fatty liver disease (NAFLD) in obese adolescents of both genders, analyzed according to quartiles of WC. Methods: Cross-sectional study that involved 247 obese adolescents aged 12–19 years. Mean values of the nutritional parameters and serum analyses were compared with the groups using the independent t-test. Pearson correlation coefficient was used to determine the relationship of the parameters studied. Chi-square test for trend was used to determine the relationship between the prevalence of the NAFLD and WC quartile by gender. Results: NAFLD were presented in 60% of the study participants. Obese adolescents in the 3rd and 4th quartiles of WC presented higher prevalence of NAFLD when compared with that in the 1st quartile in both genders. The NAFLD patients had significantly higher values for body weight, BMI (body mass index), BAZ-score (BMI-for-age z-scores), total fat (% and kg), WC, visceral fat, insulin, insulin resistance index (HOMA-IR), aspartate aminotransferase and alanine aminotransferase, when compared with non-NAFLD obese adolescents. Conclusions: In conclusion, the results presented here suggest that an increase in WC can reliably predict the risk of NAFLD in obese adolescents. This is a low cost and easy-to-use tool that can help in screening in adolescents. PMID:26830602

  15. Liver glycerol permeability and aquaporin-9 are dysregulated in a murine model of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Gena, Patrizia; Mastrodonato, Maria; Portincasa, Piero; Fanelli, Elena; Mentino, Donatella; Rodríguez, Amaia; Marinelli, Raúl A; Brenner, Catherine; Frühbeck, Gema; Svelto, Maria; Calamita, Giuseppe

    2013-01-01

    One form of liver steatosis, namely Non-Alcoholic Fatty Liver Disease (NAFLD), is a worrisome health problem worldwide characterized by intrahepatic triacylglycerol (TG) overaccumulation. NAFLD is a common feature of metabolic syndrome being often associated with obesity, dyslipidemia and diabetes and mostly closely linked to insulin resistance. The mechanism of NAFLD pathogenesis is object of intense investigation especially regarding complex systems ultimately resulting in excessive TG deposition in hepatocytes. However, scarce is the attention about the relevance of hepatic import of glycerol, the other primary source (as glycerol-3-phosphate) of increased TG in hepatocytes. Obese leptin-deficient (ob/ob) mice, an animal model of NAFLD, were used to evaluate the functional involvement of Aquaporin-9 (AQP9), the major pathway of liver glycerol entry, in hepatosteatosis. By RT-PCR and qPCR, the level of Aqp9 mRNA in the liver of starved obese mice was comparable with the corresponding control lean littermates. By immunoblotting, the AQP9 protein at the hepatocyte sinusoidal plasma membrane of obese mice was markedly lower (33%) than lean mice, a finding fully confirmed by immunohistochemistry. By stopped-flow light scattering, the liver glycerol permeability of ob/ob mice was significantly lower (53%) than lean mice, a finding consistent with both the observed down-regulation of AQP9 protein and increased level of plasma glycerol characterizing obese mice. In summary, our results suggest implication of AQP9 in liver steatosis. The reduction of hepatocyte AQP9 and, consequently, glycerol permeability might be a defensive mechanism to counteract further fat infiltration in liver parenchyma. PMID:24205128

  16. Potential for dietary ω-3 fatty acids to prevent nonalcoholic fatty liver disease and reduce the risk of primary liver cancer.

    PubMed

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

    2015-11-01

    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

  17. Visceral Obesity Predicts Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

    PubMed Central

    Yu, Su Jong; Kim, Won; Kim, Donghee; Yoon, Jung-Hwan; Lee, Kyoungbun; Kim, Jung Ho; Cho, Eun Ju; Lee, Jeong-Hoon; Kim, Hwi Young; Kim, Yoon Jun; Kim, Chung Yong

    2015-01-01

    Abstract Nonalcoholic fatty liver disease (NAFLD) is associated with visceral obesity. However, the association between visceral adipose tissue (VAT) area and fibrosis in NAFLD patients has not been completely established. This study was aimed to determine the relationship between the computed tomography-measured VAT area and significant fibrosis in NAFLD patients. A total of 324 NAFLD patients and 132 controls were evaluated by liver biopsy. NAFLD was diagnosed based on histological examinations and alcohol consumption <20 g/day. The NAFLD patients showed a higher age and gender-adjusted VAT area than the control group (86.1 ± 2.3 vs 56.7 ± 3.7, P < 0.001). The VAT area increased across the control, NAFLD without significant fibrosis, and NAFLD with significant fibrosis groups (54.9 ± 3.5, 80.6 ± 2.4, and 123.4 ± 6.4, P < 0.001). This association persisted after adjusting for multiple confounders (P for trend = 0.028). A multivariate regression analysis demonstrated the VAT area was independently associated with NAFLD with significant fibrosis (F2–F4) (odds ratio [OR] 1.21 95% confidence interval [CI] 1.07–1.37 per 10 cm2 increase of VAT area; OR 2.62 [per 1 – standard deviation (SD)] 95% CI 1.41–4.86). Moreover, a multivariate logistic regression analysis revealed the VAT area was independently associated with nonalcoholic steatohepatitis (NASH) in NAFLD (OR 1.17 95% CI 1.05–1.32 per 10 cm2 increase of VAT area; OR 2.21 [per 1 – SD] 95% CI 1.25–3.89). Increased VAT area is independently associated with NASH or significant fibrosis and VAT might be a central target for lifestyle modifications in NAFLD patients. PMID:26632897

  18. Non-Alcoholic Fatty Liver Disease: Current Perspectives and Future Direction in Disease pathogenesis, Treatment and Diagnosis

    PubMed Central

    Athinarayanan, Shaminie; Liu, Wanqing

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the world. An important implication of this disease is the progression of the disease to a more complicated condition called non-alcoholic steatohepatitis (NASH) and the wide variety of clinical presentations. Over the past 5 years, remarkable progresses have been made in understanding the genetic basis for the disease. Recent clinical trials in pharmacotherapy for the disease have been encouraging as well. It is anticipated that the integration of the wide spectrum information retrieved from genomics, transcriptomics and proteomics studies conducted in NAFLD and NASH will mediate a better understanding of the disease pathogenesis and facilitate the postulation of disease pathobiology pathways. Genetic and biological markers identified from the omics studies may hold promise for diagnosis, personalized treatment, early prevention and new drug development. PMID:24660114

  19. S-Allyl cysteine improves nonalcoholic fatty liver disease in type 2 diabetes Otsuka Long-Evans Tokushima Fatty rats via regulation of hepatic lipogenesis and glucose metabolism

    PubMed Central

    Takemura, Shigekazu; Minamiyama, Yukiko; Kodai, Shintaro; Shinkawa, Hiroji; Tsukioka, Takuma; Okada, Shigeru; Azuma, Hideki; Kubo, Shoji

    2013-01-01

    It is important to prevent and improve diabetes mellitus and its complications in a safe and low-cost manner. S-Allyl cysteine, an aged garlic extract with antioxidant activity, was investigated to determine whether S-allyl cysteine can improve type 2 diabetes in Otsuka Long-Evans Tokushima Fatty rats with nonalcoholic fatty liver disease. Male Otsuka Long-Evans Tokushima Fatty rats and age-matched Long-Evans Tokushima Otsuka rats were used and were divided into two groups at 29 weeks of age. S-Allyl cysteine (0.45% diet) was administered to rats for 13 weeks. Rats were killed at 43 weeks of age, and detailed analyses were performed. S-Allyl cysteine improved hemoglobinA1c, blood glucose, triglyceride, and low-density lipoprotein cholesterol levels. Furthermore, S-allyl cysteine normalized plasma insulin levels. S-Allyl cysteine activated the mRNA and protein expression of both peroxisome proliferator-activated receptor α and γ, as well as inhibiting pyruvate dehydrogenase kinase 4 in Otsuka Long-Evans Tokushima Fatty rat liver. Sterol regulatory element-binding protein 1c and forkhead box O1 proteins were normalized by S-allyl cysteine in Otsuka Long-Evans Tokushima Fatty rat liver. In conclusions, these findings support the hypothesis that S-allyl cysteine has diabetic and nonalcoholic fatty liver disease therapeutic potential as a potent regulating agent against lipogenesis and glucose metabolism. PMID:24062606

  20. The Effect of Green Tea Extract Supplementation on Liver Enzymes in Patients with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Pezeshki, Ali; Safi, Sara; Feizi, Awat; Askari, Gholamreza; Karami, Fatemeh

    2016-01-01

    Background: Green tea is one of the most popular beverages in the world. It is believed to have beneficial effects in the prevention and treatment of many diseases, one of which is nonalcoholic fatty liver disease (NAFLD). The present study investigated the effects of consumption of green tea in NAFLD patients. Methods: This study was a double-blind, placebo-controlled, randomized clinical trial. Ultrasonography was used to diagnose fatty liver in patients with alanine aminotransferase (ALT) >31 mg/dl and 41 mg/dl and aspartate aminotransferase (AST) >31 mg/dl and 47 g/dl in women and men, respectively and without other hepatic diseases. A total of 80 participants (20–50 years) with NAFLD were randomly allocated into two groups to receive either green tea extract (GTE) supplement (500 mg GTE tablet per day) or placebo for 90 days. At baseline and at the end of the intervention weight, serum ALT, AST, and alkaline phosphatase (ALP) were measured in fasting state, and dietary data were collected at baseline and end of the study. Results: Green tea group showed significant reductions in ALT and AST levels after 12 weeks period (P < 0.001). The placebo group showed a reduction in ALT and AST levels at the end of the study, but it was no significant. ALP levels showed significant reductions in both groups after 12 weeks period (P < 0.001). Conclusions: According to the findings of this study, GTE supplementation decrease liver enzymes in patients with NAFLD. It can be claimed that GTE prescribed can be considered as a treatment to improve serum levels of liver enzymes in NAFLD patients. PMID:26955458

  1. Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY)

    PubMed Central

    Tomita, Kengo; Kawai, Toshihide; Yokoyama, Hirokazu; Shimada, Akira; Kikuchi, Masahiro; Hirose, Hiroshi; Ebinuma, Hirotoshi; Irie, Junichiro; Ojiro, Keisuke; Oikawa, Yoichi; Itoh, Hiroshi; Hibi, Toshifumi

    2013-01-01

    Aim. This study compared the effects of telmisartan and losartan on nonalcoholic fatty liver disease (NAFLD) and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus. Methods. This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to receive telmisartan at a dose of 20 mg once a day (n = 12) or losartan at a dose of 50 mg once a day (n = 7) for 12 months. Body fat area as determined by CT scanning and hepatic fat content based on the liver-to-spleen (L/S) ratio, as well as several parameters of glycemic and lipid metabolism, were compared before and after 12 months. Results. The telmisartan group showed a significant decline in serum free fatty acid (FFA) level (from 0.87 ± 0.26 to 0.59 ± 0.22 mEq/L (mean ± SD), P = 0.005) and a significant increase in L/S ratio (P = 0.049) evaluated by CT scan, while these parameters were not changed in the losartan group. Conclusion. Although there was no significant difference in improvement in liver enzymes with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months, it is suggested that telmisartan may exert beneficial effects by improving fatty liver. PMID:23997767

  2. Diabetes Mellitus Predicts Occurrence of Cirrhosis and Hepatocellular Cancer in Alcoholic Liver and Non-alcoholic Fatty Liver Diseases

    PubMed Central

    Raff, Evan J.; Kakati, Donny; Bloomer, Joseph R.; Shoreibah, Mohamed; Rasheed, Khalid; Singal, Ashwani K.

    2015-01-01

    Background and Aims Alcohol abuse and nonalcoholic fatty liver disease (NAFLD) are common causes of liver disease. Diabetes mellitus (DM) is a common comorbidity among NAFLD patients. We performed this study with the specific aim to examine the impact of DM on progression of alcoholic liver disease (ALD) liver and NAFLD. Methods Medical charts of 480 patients with ALD or NAFLD (2004–2011) managed at a tertiary center were retrospectively reviewed. NAFLD was diagnosed based on exclusion of other causes of liver disease and alcohol use of <10 g/d. ALD was diagnosed based on alcohol use of >40 g/d in women or >60 g/d in men for >5 years. Results Of 480 patients (307 NAFLD), 200 diabetics differed from nondiabetics for: age (52±11 vs. 49±11 years; p=0.004); male gender (48% vs. 57%; p=0.03); metabolic syndrome (49% vs. 30%; p=0.0002); NAFLD (80% vs. 56%; p<0.0001); cirrhosis (70% vs. 59%; p=0.005); and hepatocellular carcinoma (HCC; 8% vs. 3%; p=0.009). Over a 3 year median follow-up period, diabetics relative to nondiabetics had a higher probability to develop cirrhosis (60% vs. 41%; p=0.022) and HCC (27% vs. 10%; p=0.045). There was a trend for increased development of hepatic encephalopathy in diabetics compared to nondiabetics (55% vs. 39%; p=0.053), and there was no difference between the two groups in survival or other liver disease complications. Conclusions DM increased risk for cirrhosis and HCC among patients with ALD and NAFLD. Prospective studies with longer follow-up periods are needed to examine the impact of DM on survival and the role of aggressive HCC screening in diabetic cirrhotics. PMID:26356325

  3. Insulin sensitisers in the treatment of non-alcoholic fatty liver disease: a systematic review.

    PubMed Central

    Shyangdan, D; Clar, C; Ghouri, N; Henderson, R; Gurung, T; Preiss, D; Sattar, N; Fraser, A; Waugh, N

    2011-01-01

    BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is closely linked with obesity and the prevalence of NAFLD is about 17% to 33% in the Western world. There is a strong association of NAFLD with insulin resistance and, hence, insulin sensitisers have been tried. This systematic review examined the clinical effectiveness of insulin sensitisers in patients with NAFLD, to help decide whether or not a trial or trials of the insulin sensitisers was necessary and also to explore whether or not non-invasive alternatives to liver biopsy were available that could be used in a large trial of the insulin sensitisers. OBJECTIVE To review the use of insulin sensitisers in the treatment of NAFLD. REVIEW METHODS A systematic review of the clinical effectiveness of metformin, rosiglitazone and pioglitazone was carried out, including reviews and randomised controlled trials (RCTs). Databases searched were MEDLINE, 1950 to June 2010; EMBASE, 1980 to June 2010; Science Citation Index Expanded, June 2010; Conference Proceedings Citation Index - Science June 2010; The Cochrane Library 2005-10. Abstracts were screened independently by two researchers. A narrative review of diagnostic methods was conducted. RESULTS Clinical effectiveness. We identified 15 RCTs (one available as abstract). Four papers explored efficacy of pioglitazone, one rosiglitazone, eight metformin; two compared metformin and rosiglitazone, although one used both metformin and rosiglitazone. The duration of most trials was between 6 and 12 months. Many trials had a small number of participants and the quality of the studies was mixed. Pioglitazone improved all parameters of liver histology. Metformin showed mixed results, with ultrasound changes in two studies showing some improvement in steatosis, whereas there were no changes in the other two. Metformin, however, showed no improvement in non-alcoholic steatohepatitis (NASH) stages. Metformin showed greater reduction in glycosylated haemoglobin (-0.23% to -1

  4. Gestational Diabetes Mellitus is Strongly Associated with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Ajmera, Veeral H.; Gunderson, Erica P.; VanWagner, Lisa B.; Lewis, Cora E.; Carr, John J.; Terrault, Norah A.

    2016-01-01

    Insulin resistance is central to the development of non-alcoholic fatty liver disease (NAFLD), and gestational diabetes mellitus (GDM) is an early marker of insulin resistance. We hypothesized that a history of GDM would identify women at higher risk of NAFLD in middle age. Women from the multicenter Coronary Artery Risk Development in Young Adults (CARDIA) cohort study who delivered ≥ 1 birth, were free of diabetes prior to pregnancy(ies), and underwent CT quantification of hepatic steatosis 25 years following cohort entry (Y25: 2010–2011) were included (n = 1115). History of GDM by self-report, validated in a subsample by review of antenatal glucose testing, and metabolic risk factors were assessed prospectively. NAFLD was defined by liver attenuation (LA) ≤ 40 Hounsfield Units on CT scan after exclusion of other causes of hepatic steatosis. Of 1,115 women meeting selection criteria (57% black, 43% white, median age 25 years at baseline), 124 (11%) reported a history of GDM and 75 (7%) met the CT definition for NAFLD at year 25. The crude risk of NAFLD at the 25-year visit was significantly higher in women with GDM compared to those without (14% vs. 5.8%, OR: 2.56, 95% CI: 1.44–4.55, p<0.01). History of GDM remained associated with NAFLD (OR: 2.29, 95% CI: 1.23–4.27, p=0.01) after adjustment for covariates in multivariable logistic regression. Addition of incident diabetes mellitus (DM) into the final model attenuated the association between GDM and NAFLD (OR: 1.48, 95% CI: 0.73 – 3.02, p=0.28). Conclusion GDM is a risk marker for NAFLD and represents an opportunity to identify women at risk for NAFLD at a young age and may be mediated by the development of incident DM. PMID:27002796

  5. Perceptions of non-alcoholic fatty liver disease – an Asian community-based study

    PubMed Central

    Goh, George B.B.; Kwan, Clarence; Lim, Sze Ying; Venkatanarasimha, Nanda KK; Abu-Bakar, Rafidah; Krishnamoorthy, Thinesh L; Shim, Hang Hock; Tay, Kiang Hiong; Chow, Wan Cheng

    2016-01-01

    Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is closely related to metabolic syndrome and its risk factors. Worldwide, epidemiological studies have reported NAFLD prevalence rates of 5% to 30% depending on geographical variations. While epidemiological data suggest a progressively increasing prevalence of metabolic risk factors in Singapore, there are limited data about NAFLD per se in the community. We aim to explore the prevalence and perceptions of NAFLD in Singapore. Methods: Attendees at a gastroenterology public forum were enrolled in a cross-sectional observational study evaluating demographic, anthropometric and clinical information. The diagnosis of NAFLD was based on sonographic criteria. Metabolic syndrome was defined according to International Diabetes Federation guidelines. Perceptions of NAFLD were explored using a self-administered survey questionnaire. Results: A total of 227 subjects were recruited, with NAFLD being diagnosed in 40% of the cohort. Relative to those without NAFLD, subjects with NAFLD had higher male preponderance, older age, higher body mass index, waist circumference and more metabolic syndrome (all P < 0.05). Although 71.2% subjects had heard about NAFLD before, only 25.4% of them felt that they were at risk of NAFLD. Comparable responses were observed in subjects with no metabolic risk factors relative to subjects with one or more metabolic risk factors (P > 0.05). Of note, 75.6% of subjects with one or more metabolic risk factors did not think that they were at risk of NAFLD. Conclusion: Our study suggests a significant local prevalence of NAFLD in the community including non-obese individuals. Considering the tendency to underestimate risk of NAFLD, enhanced public education about NAFLD is warranted to improve understanding. PMID:26463276

  6. [Retinoids as promising treatment for non-alcoholic fatty liver disease].

    PubMed

    Tsuchiya, Hiroyuki

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is frequently associated with insulin resistance, suggesting its crucial role in the development and progression of NAFLD. We used a mouse model of high-fat, high-fructose (HFHFr) diet-induced NAFLD to examine the effects of retinoids on insulin resistance. Dietary administration of all-trans-retinoic acid (ATRA) significantly improved insulin sensitivity in C57BL/6J mice fed the HFHFr diet, and in KK-Ay mice but not in the leptin-deficient ob/ob mice. ATRA treatment significantly upregulated hepatic leptin receptor (LEPR) expression. In agreement with these observations, in vitro experiments showed ATRA directly induced LEPR gene expression through RARα. In the livers of C57BL/6J mice administered ATRA, insulin receptor substrate-1 (IRS1) was activated concomitantly with the phosphorylation of Janus kinase-2 and signal transducer and activator of transcription-3 (STAT3). STAT3 phosphorylation was also observed in KK-Ay but not in ob/ob mice. In in vitro experiments, ATRA significantly enhanced insulin-induced IRS1 tyrosine phosphorylation solely in the presence of leptin. A selective RARα/β agonist, tamibarotene, also enhanced hepatic LEPR expression, STAT3 phosphorylation, and ameliorated insulin resistance in KK-Ay mice. We discovered an unrecognized mechanism of retinoid action for the activation of hepatic leptin signaling, which resulted in enhancing insulin sensitivity in two mouse models of insulin resistance. Moreover, we also found that retinoids attenuate hepatic iron overload and iron-induced oxidative stress, which have recently emerged as an important factor for the development and progression of insulin resistance. Our data suggest that retinoids might have potential for treating NAFLD associated with insulin resistance. PMID:22864348

  7. Iron Status and Metabolic Syndrome in Patients with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Ghamarchehreh, Mohammad Ebrahim; Jonaidi-Jafari, Nematollah; Bigdeli, Mohammad; Khedmat, Hossein; Saburi, Amin

    2016-01-01

    BACKGROUND A hypothesis has been presented about the role of serum iron, ferritin and transferrin saturation among patients with non-alcoholic fatty liver disease (NAFLD) and resistance to insulin (metabolic syndrome [MetS]), but there is much controversy. This study aimed at investigating the level of serum iron and demographic characteristics in patients with NAFLD with or without MetS. METHODS A case-control study was conducted on patients with elevated liver enzymes referring to Baqiyatallah clinic, Tehran, Iran during 2010-2011. After ruling out other causes of increased aminotransferases and approving the diagnosis of NAFLD, the patients were divided into two groups of with or without MetS. Then, the individuals’ demographic, sonographic, and laboratory characteristics were recorded. RESULTS This research included 299 patients suffering from NAFLD who were divided into MetS (n=143; 47.8%) and non-MetS (n=156; 52.2%) groups. The age, systolic and diastolic blood pressure, body mass index, waist/hip ratio, glucose tolerance test, serum insulin, C. peptide, triglyceride, and HB A1c were different between MetS and non-MetS groups (p<0.05). There was no significant difference in serum iron and ferritin levels between the two groups, however, a significant correlation was found between serum ferritin and alanine transaminase (p=0.005) and also aspartate aminotransferase (p=0.032). CONCLUSION Our findings did not show a significant relationship between iron, in free or storage form, and the presence of MetS among patients with NAFLD, but serum ferritin can correlate with hepatocytes injuries indicated by raised aminotransferases. Nevertheless, to clarify this relationship further molecular, genomic, and histopathological studies are required. PMID:26933479

  8. Nonalcoholic Fatty Liver Disease Relationship with Metabolic Syndrome in Class III Obesity Individuals

    PubMed Central

    Cordeiro, A.; Pereira, S. E.; Saboya, C. J.; Ramalho, A.

    2015-01-01

    Introduction. Obesity is represented mainly by abdominal obesity and insulin resistance (IR), both present in most individuals diagnosed with metabolic syndrome (MS). IR is the key risk factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Objective. To relate NAFLD to MS in class III obese individuals. Methodology. A descriptive cross-sectional study with class III obese individuals, aged ≥ 20–60 years. Blood pressure measurement, weight, height, body mass index (BMI), waist circumference (WC) and blood glucose, insulin, high-density lipoprotein cholesterol (HDL-c), and triglycerides data were obtained. HOMA-IR (homeostatic model assessment insulin resistance) calculation was carried out with a cutoff value of 2.71 for IR evaluation. The diagnosis of NAFLD was performed by liver biopsy and the diagnosis of MS was performed in accordance with the National Cholesterol Education Program/Adult Treatment Panel III (NCEPATP III). Results. Of the 50 individuals evaluated, 86% were women and BMI means were 45.4 ± 3.6 Kg/m2. The overall individuals had NAFLD, 70% steatosis, and 30% steatohepatitis. The diagnosis of MS occurred in 56% but showed no significant association with NAFLD (P = 0.254). Triglycerides (178 ± 65.5 mg/dL) and insulin (28.2 ± 22.6 mcU/mL) mean values were significantly higher in steatohepatitis (P = 0.002 and P = 0.042, resp.) compared to individuals with steatosis. IR was confirmed in 76% and showed a relationship with NAFLD severity. Conclusion. NAFLD was not related to MS; however, MS components, evaluated in isolation, as well as IR, were related to the presence and severity of NAFLD. PMID:26120587

  9. Association between caffeine consumption and nonalcoholic fatty liver disease: a systemic review and meta-analysis

    PubMed Central

    Shen, Huafeng; Rodriguez, Andrea C.; Shiani, Ashok; Lipka, Seth; Shahzad, Ghulamullah; Kumar, Ambuj; Mustacchia, Paul

    2016-01-01

    Objectives: Caffeine consumption is reported to be associated with reduced hepatic fibrosis in patients with chronic liver diseases. We performed a systematic review and meta-analysis to assess the association between caffeine consumption and prevalence or hepatic fibrosis of nonalcoholic fatty liver disease (NAFLD) in observational studies. Methods: We searched the literature of all languages from PubMed, EMBASE, and the Cochrane library from 1 January 1980 through 10 January 2015. Total caffeine consumption was defined as the daily intake of caffeine (mg/day) from all caffeine-containing products. Combined and subgroup analyses stratified by study designs, study locations, and type of caffeine intake were performed. Results: Four cross-sectional and two case control studies with a total of 20,064 subjects were included in the meta-analysis. Among these, three studies with 18,990 subjects were included in the analysis for prevalence of NAFLD while the other three studies with 1074 subjects were for hepatic fibrosis. Total caffeine consumption (mg/day) was not significantly associated with either the prevalence [pooled mean difference (MD) 2.36; 95% confidence interval (CI) −35.92 to 40.64] or hepatic fibrosis (higher versus lower stages; pooled MD −39.95; 95% CI −132.72 to 52.82) of NAFLD. Subgroup analyses stratified by study designs and locations were also not significant. However, after stratifying by type of caffeine intake, regular coffee caffeine intake (mg/day) was significantly associated with reduced hepatic fibrosis of NAFLD (pooled MD −91.35; 95% CI −139.42 to −43.27; n = 2 studies). Conclusion: Although total caffeine intake is not associated with the prevalence or hepatic fibrosis of NAFLD, regular coffee caffeine consumption may significantly reduce hepatic fibrosis in patients with NAFLD. PMID:26770272

  10. Association Between Pulmonary Function and Nonalcoholic Fatty Liver Disease in the NHANES III Study

    PubMed Central

    Peng, Tao-Chun; Kao, Tung-Wei; Wu, Li-Wei; Chen, Ying-Jen; Chang, Yaw-Wen; Wang, Chung-Ching; Tsao, Yu-Tzu; Chen, Wei-Liang

    2015-01-01

    Abstract Emerging evidence indicates that nonalcoholic fatty liver disease (NAFLD) is associated with a wide variety of extrahepatic complications. However, the potential association between impaired pulmonary function and NAFLD has been less investigated. This study examined the relationship between pulmonary function and hepatic steatosis in 9976 adults participating in a cross-sectional analysis of the Third National Health and Nutrition Examination Survey (NHANES III). NAFLD was defined as hepatic steatosis presented on ultrasound examinations in the absence of other known liver diseases. The associations between predicted forced expiratory volume in 1 second (FEV1)% or predicted forced vital capacity (FVC)% and NAFLD were examined using multivariable linear regression while controlling for confounders. The association between obstructive or restrictive spirometry patterns and NAFLD was also evaluated using multivariable logistic regression analysis. After adjustment for multiple covariates, predicted FEV1% and FVC% were significantly and inversely associated with the degree of hepatic steatosis (P for trend <0.001 for both). The restrictive lung pattern was significantly related to participants with moderate and severe hepatic steatosis as compared with those without steatosis (OR 1.65, 95% CI 1.14–2.39 and OR 1.85, 95% CI 1.13–2.82), whereas the obstructive lung pattern was not associated with the presence of hepatic steatosis. Individuals with a greater degree of hepatic steatosis were at greater risk for poor pulmonary function, especially in restrictive pattern. These novel findings demonstrate that impaired pulmonary function is also an extrahepatic complication of NAFLD. PMID:26020401

  11. Water Soluble Vitamin E Administration in Wistar Rats with Non-alcoholic Fatty Liver Disease

    PubMed Central

    Tzanetakou, Irene P; Doulamis, Ilias P; Korou, Laskarina-Maria; Agrogiannis, George; Vlachos, Ioannis S; Pantopoulou, Alkisti; Mikhailidis, Dimitri P; Patsouris, Efstratios; Vlachos, Ioannis; Perrea, Despina N

    2012-01-01

    Objective: A diet rich in fat is associated with hepatic fat deposition [steatosis; non-alcoholic fatty liver disease (NAFLD)]. The exact cause of NAFLD however, is still unknown. The aim of this study was to assess the effect of a water-soluble formulation of vitamin E on a dietary-induced-NAFLD animal model. Methods: Adult male Wistar rats (n=20) were allocated to 2 groups: Controls (Group A, n=6), which received a standard chow diet for 24 weeks and a High Cholesterol group (HC: n=14), which received a standard chow diet enriched with cholesterol for the first 14 weeks of the experiment (t1). At t1, the HC group was divided into: Group HC(B), which received a high-saturated-fat/high-cholesterol (HSF/HCH) diet and Group HC(C), which followed the same HSF/HCH diet but was also administered water soluble vitamin E (10 IU/kg body weight/day), for 10 more weeks. Results: At the end of the study, group HC(C) exhibited significantly lower mean total cholesterol (T-CHOL) than group HC(B) (p<0.001). No significant differences were observed between HC(C) and Control groups in blood glucose and serum lipid concentrations. Liver Function Tests did not vary between all groups at the end of the study. Animals in group HC(B) exhibited higher SGOT at the end of the study compared with the beginning of the study (p<0.05). Group HC(B) exhibited the highest scores in steatosis, and grading (according to the NAFLD scoring system) in the histopathological analysis (p≤0.001 in all cases). Conclusions: Vitamin E seems to exert a hypolipidemic and hepatoprotective role in the presence of a HSF/HCH atherogenic diet in a rat model. PMID:22930662

  12. The prevalence of metabolic risk factors among outpatients with diagnosed nonalcoholic fatty liver disease in Lithuania

    PubMed Central

    Valantinas, Jonas; Apanaviciene, Daiva Asta; Maroziene, Ligita; Sveikata, Audrius

    2012-01-01

    Summary Background Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease; there is growing evidence that it is a hepatic manifestation of a metabolic syndrome. This study aimed to assess the prevalence of metabolic risk factors among patients with NAFLD. Material/Methods Outpatients with NAFLD were recruited into the study. Family physicians recorded patients’ demographic and anthropometric data, leisure-time physical activity, concomitant diseases, and pharmacological treatment for NAFLD into standardized Case Report Forms. Results In total, data on 798 patients were analyzed. Most patients were women and they were older than the men (mean age, 60.2±9.6 vs. 54.5±11.4 years; p<0.05). Metabolic risk factors (obesity, arterial hypertension, dyslipidemia) were highly prevalent in the study patients, and these factors were more prevalent among women. There were no differences in the mean Body Mass Index (BMI), in the proportion of men or women with BMI >30 kg/m2 or central obesity in the 2 age groups (≤60 years and >60 years). Hypertension and diabetes were more prevalent among older men and women. Dyslipidemia was more common among older women. The level of leisure-time physical activity was lower in women and in older patients. The most frequently prescribed pharmacological agents were cytoprotective agents, lipid-lowering drugs, and antioxidants. Conclusions Metabolic risk factors were highly prevalent among patients with NAFLD. Obesity, hypertension, and dyslipidemia were more prevalent among women. The differences in the prevalence of hypertension seemed to be influenced by older age of women. PMID:22534719

  13. Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population

    PubMed Central

    2012-01-01

    Background A reliable and inexpensive noninvasive marker of hepatic fibrosis is required in patients with nonalcoholic fatty liver disease (NAFLD). FIB4 index (based on age, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels, and platelet counts) is expected to be useful for evaluating hepatic fibrosis. We validated the performance of FIB4 index in a Japanese cohort with NAFLD. Methods The areas under the receiver operating characteristic curves (AUROC) for FIB4 and six other markers were compared, based on data from 576 biopsy-proven NAFLD patients. Advanced fibrosis was defined as stage 3-4 fibrosis. FIB4 index was assessed as: age (yr) × AST (IU/L)/(platelet count (109/L) × √ALT (IU/L)) Results Advanced fibrosis was found in 64 (11%) patients. The AUROC for FIB4 index was superior to those for the other scoring systems for differentiating between advanced and mild fibrosis. Only 6 of 308 patients with a FIB4 index below the proposed low cut-off point (< 1.45) were under-staged, giving a high negative predictive value of 98%. Twenty-eight of 59 patients with a FIB4 index above the high cut-off point (> 3.25) were over-staged, giving a low positive predictive value of 53%. Using these cutoffs, 91% of the 395 patients with FIB-4 values outside 1.45-3.25 would be correctly classified. Implementation of the FIB4 index in the Japanese population would avoid 58% of liver biopsies. Conclusion The FIB4 index was superior to other tested noninvasive markers of fibrosis in Japanese patients with NAFLD, with a high negative predictive value for excluding advanced fibrosis. The small number of cases of advanced fibrosis in this cohort meant that this study had limited power for validating the high cut-off point. PMID:22221544

  14. Association between sleep condition and arterial stiffness in Chinese adult with nonalcoholic fatty liver disease.

    PubMed

    Cao, Xia; Zhou, Jiansong; Yuan, Hong; Chen, Zhiheng

    2016-07-01

    Nonalcoholic fatty liver (NAFLD) usually has worse cardiovascular risk factors. Given the potential association between deterioration of sleep and arterial stiffness, we aim to investigate the association between deterioration of sleep and arterial stiffness in a middle-aged Chinese population with NAFLD. In this cross-sectional study, 15,372 Chinese aged 40-60 years who participated in periodic health checkups in central south China, were included. Self-reported sleep duration and sleep quality, anthropometric, biochemical, and liver ultrasound scan were analyzed and brachial-ankle pulse wave velocity (baPWV) was used as the indicator of arterial stiffness. Poor sleep quality was found to be associated with increased arterial stiffness, with odds ratios and 95 % confidence intervals (CIs) of 2.28 (95 % CI, 1.53-3.38) compared with good sleep quality. Using sleep duration ≥ 8 h as the reference, there was no significant association between sleep duration of ≤ 6 or 6-8 h and arterial stiffness after multivariable-adjusted. In additional analyses, further investigation of the association of different combinations of sleep duration and quality in relation to arterial stiffness indicated participants with poor sleep quality and sleep duration ≤ 6 h were more likely to have arterial stiffness than those with good quality sleep who sleep for ≥ 8 h (OR 2.59, 95 % CI 1.58-4.24). The present study indicates that short sleep duration, poor sleep quality in individuals with NAFLD correlate with increased arterial stiffness. PMID:27034174

  15. Obesity dependent metabolic signatures associated with nonalcoholic fatty liver disease progression

    PubMed Central

    Barr, J.; Caballería, J.; Martínez-Arranz, I.; Domínguez-Díez, A.; Alonso, C.; Muntané, J.; Pérez-Cormenzana, M.; García-Monzón, C.; Mayo, R.; Martín-Duce, A.; Romero-Gómez, M.; Iacono, O. Lo; Tordjman, J.; Andrade, R.J.; Pérez-Carreras, M.; Le Marchand-Brustel, Y.; Tran, A.; Fernández-Escalante, C.; Arévalo, E.; García–Unzueta, M.; Clement, K.; Crespo, J.; Gual, P.; Gómez-Fleitas, M.; Martínez-Chantar, M.L.; Castro, A.; Lu, S.C.; Vázquez-Chantada, M.; Mato, J.M.

    2012-01-01

    Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual’s level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values = 0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention. PMID:22364559

  16. The Impact of Nonalcoholic Fatty Liver Disease on Renal Function in Children with Overweight/Obesity.

    PubMed

    Pacifico, Lucia; Bonci, Enea; Andreoli, Gian Marco; Di Martino, Michele; Gallozzi, Alessia; De Luca, Ester; Chiesa, Claudio

    2016-01-01

    The association between nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease has attracted interest and attention over recent years. However, no data are available in children. We determined whether children with NAFLD show signs of renal functional alterations, as determined by estimated glomerular filtration rate (eGFR) and urinary albumin excretion. We studied 596 children with overweight/obesity, 268 with NAFLD (hepatic fat fraction ≥5% on magnetic resonance imaging) and 328 without NAFLD, and 130 healthy normal-weight controls. Decreased GFR was defined as eGFR < 90 mL/min/1.73 m². Abnormal albuminuria was defined as urinary excretion of ≥30 mg/24 h of albumin. A greater prevalence of eGFR < 90 mL/min/1.73 m² was observed in patients with NAFLD compared to those without liver involvement and healthy subjects (17.5% vs. 6.7% vs. 0.77%; p < 0.0001). The proportion of children with abnormal albuminuria was also higher in the NAFLD group compared to those without NAFLD, and controls (9.3% vs. 4.0% vs. 0; p < 0.0001). Multivariate logistic regression analysis revealed that NAFLD was associated with decreased eGFR and/or microalbuminuria (odds ratio, 2.54 (confidence interval, 1.16-5.57); p < 0.05) independently of anthropometric and clinical variables. Children with NAFLD are at risk for early renal dysfunction. Recognition of this abnormality in the young may help to prevent the ongoing development of the disease. PMID:27472326

  17. The Impact of Nonalcoholic Fatty Liver Disease on Renal Function in Children with Overweight/Obesity

    PubMed Central

    Pacifico, Lucia; Bonci, Enea; Andreoli, Gian Marco; Di Martino, Michele; Gallozzi, Alessia; De Luca, Ester; Chiesa, Claudio

    2016-01-01

    The association between nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease has attracted interest and attention over recent years. However, no data are available in children. We determined whether children with NAFLD show signs of renal functional alterations, as determined by estimated glomerular filtration rate (eGFR) and urinary albumin excretion. We studied 596 children with overweight/obesity, 268 with NAFLD (hepatic fat fraction ≥5% on magnetic resonance imaging) and 328 without NAFLD, and 130 healthy normal-weight controls. Decreased GFR was defined as eGFR < 90 mL/min/1.73 m2. Abnormal albuminuria was defined as urinary excretion of ≥30 mg/24 h of albumin. A greater prevalence of eGFR < 90 mL/min/1.73 m2 was observed in patients with NAFLD compared to those without liver involvement and healthy subjects (17.5% vs. 6.7% vs. 0.77%; p < 0.0001). The proportion of children with abnormal albuminuria was also higher in the NAFLD group compared to those without NAFLD, and controls (9.3% vs. 4.0% vs. 0; p < 0.0001). Multivariate logistic regression analysis revealed that NAFLD was associated with decreased eGFR and/or microalbuminuria (odds ratio, 2.54 (confidence interval, 1.16–5.57); p < 0.05) independently of anthropometric and clinical variables. Children with NAFLD are at risk for early renal dysfunction. Recognition of this abnormality in the young may help to prevent the ongoing development of the disease. PMID:27472326

  18. Effectiveness of exercise in hepatic fat mobilization in non-alcoholic fatty liver disease: Systematic review

    PubMed Central

    Golabi, Pegah; Locklear, Cameron T; Austin, Patrick; Afdhal, Sophie; Byrns, Melinda; Gerber, Lynn; Younossi, Zobair M

    2016-01-01

    AIM: To investigate the efficacy of exercise interventions on hepatic fat mobilization in non-alcoholic fatty liver disease (NAFLD) patients. METHODS: Ovid-Medline, PubMed, EMBASE and Cochrane database were searched for randomized trials and prospective cohort studies in adults aged ≥ 18 which investigated the effects of at least 8 wk of exercise only or combination with diet on NAFLD from 2010 to 2016. The search terms used to identify articles, in which exercise was clearly described by type, duration, intensity and frequency were: “NASH”, “NAFLD”, “non-alcoholic steatohepatitis”, “non-alcoholic fatty liver disease”, “fat”, “steatosis”, “diet”, “exercise”, “MR spectroscopy” and “liver biopsy”. NAFLD diagnosis, as well as the outcome measures, was confirmed by either hydrogen-magnetic resonance spectroscopy (H-MRS) or biopsy. Trials that included dietary interventions along with exercise were accepted if they met all criteria. RESULTS: Eight studies met selection criteria (6 with exercise only, 2 with diet and exercise with a total of 433 adult participants). Training interventions ranged between 8 and 48 wk in duration with a prescribed exercise frequency of 3 to 7 d per week, at intensities between 45% and 75% of VO2 peak. The most commonly used imaging modality was H-MRS and one study utilized biopsy. The effect of intervention on fat mobilization was 30.2% in the exercise only group and 49.8% in diet and exercise group. There was no difference between aerobic and resistance exercise intervention, although only one study compared the two interventions. The beneficial effects of exercise on intrahepatic triglyceride (IHTG) were seen even in the absence of significant weight loss. Although combining an exercise program with dietary interventions augmented the reduction in IHTG, as well as improved measures of glucose control and/or insulin sensitivity, exercise only significantly decreased hepatic lipid contents

  19. Plasmatic higher levels of homocysteine in Non-alcoholic fatty liver disease (NAFLD)

    PubMed Central

    2013-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, which includes a spectrum of hepatic pathology such as simple steatosis, steatohepatitis, fibrosis and cirrhosis. The increased serum levels of homocysteine (Hcy) may be associated with hepatic fat accumulation. Genetic mutations in the folate route may only mildly impair Hcy metabolism. The aim of this study was to investigate the relation between liver steatosis with plasma homocysteine level and MTHFR C677T and A1298C polymorphisms in Brazilian patients with NAFLD. Methods Thirty-five patients diagnosed with NAFLD by liver biopsy and forty-five healthy controls neither age nor sex matched were genotyped for C677T and A1298C MTHFR polymorphisms using PCR-RFLP and PCR-ASA, respectively, and Hcy was determined by HPLC. All patients were negative for markers of Wilson’s, hemochromatosis and autoimmune diseases. Their daily alcohol intake was less than 100 g/week. A set of metabolic and serum lipid markers were also measured at the time of liver biopsies. Results The plasma Hcy level was higher in NAFLD patients compared to the control group (p = 0.0341). No statistical difference for genotypes 677C/T (p = 0.110) and 1298A/C (p = 0.343) in patients with NAFLD and control subjects was observed. The genotypes distribution was in Hardy-Weinberg equilibrium (677C/T p = 0.694 and 1298 A/C p = 0.188). The group of patients and controls showed a statistically significant difference (p < 0.001) for BMI and HOMA_IR, similarly to HDL cholesterol levels (p < 0,006), AST, ALT, γGT, AP and triglycerides levels (p < 0.001). A negative correlation was observed between levels of vitamin B12 and Hcy concentration (p = 0.005). Conclusion Our results indicate that plasma Hcy was higher in NAFLD than controls. The MTHFR C677T and A1298C polymorphisms did not differ significantly between groups, despite the 677TT homozygous frequency was higher in patients (17

  20. Ameliorative effects of lutein on non-alcoholic fatty liver disease in rats

    PubMed Central

    Qiu, Xiang; Gao, Dan-Hong; Xiang, Xiao; Xiong, Yu-Fang; Zhu, Teng-Shi; Liu, Lie-Gang; Sun, Xiu-Fa; Hao, Li-Ping

    2015-01-01

    AIM: To investigate the therapeutic effects of lutein against non-alcoholic fatty liver disease (NAFLD) and the related underlying mechanism. METHODS: After 9 d of acclimation to a constant temperature-controlled room (20 °C-22 °C) under 12 h light/dark cycles, male Sprague-Darley rats were randomly divided into two groups and fed a standard commercial diet (n = 8) or a high-fat diet (HFD) (n = 32) for 10 d. Animals receiving HFD were then randomly divided into 4 groups and administered with 0, 12.5, 25, or 50 mg/kg (body weight) per day of lutein for the next 45 d. At the end of the experiment, the perinephric and abdominal adipose tissues of the rats were isolated and weighed. Additionally, serum and liver lipid metabolic condition parameters were measured, and liver function and insulin resistance state indexes were assessed. Liver samples were collected and stained with hematoxylin eosin and Oil Red O, and the expression of the key factors related to insulin signaling and lipid metabolism in the liver were detected using Western blot and real-time polymerase chain reaction analyses. RESULTS: Our data showed that after being fed a high-fat diet for 10 d, the rats showed a significant gain in body weight, energy efficiency, and serum total cholesterol (TC) and triglyceride (TG) levels. Lutein supplementation induced fat loss in rats fed a high-fat diet, without influencing body weight or energy efficiency, and decreased serum TC and hepatic TC and TG levels. Moreover, lutein supplementation decreased hepatic levels of lipid accumulation and glutamic pyruvic transaminase content, and also improved insulin sensitivity. Lutein administration also increased the expression of key factors in hepatic insulin signaling, such as insulin receptor substrate-2, phosphatidylinositol 3-kinase, and glucose transporter-2 at the gene and protein levels. Furthermore, high-dose lutein increased the expression of peroxisome proliferators activated receptor-α and sirtuin 1

  1. Long-Term Treatment with n-3 Polyunsaturated Fatty Acids as a Monotherapy in Children with Nonalcoholic Fatty Liver Disease

    PubMed Central

    Boyraz, Mehmet; Pirgon, Özgür; Dündar, Bumin; Çekmez, Ferhat; Hatipoğlu, Nihal

    2015-01-01

    Objective: To investigate the efficacy and safety of n-3 polyunsaturated fatty acids (PUFA) treatment in obese children with nonalcoholic fatty liver disease (NAFLD). Methods: One hundred and eight obese (body mass index (BMI) >95th percentile for age and sex) adolescents with NAFLD were included in the study. Mean age of the subjects was 13.8±3.9 years (9-17 yrs). The diagnosis of NAFLD was based on the presence of liver steatosis with high transaminases. The subjects were randomly divided into two groups. Group 1 (PUFA group, n=52) received a 1000 mg dose of PUFA once daily for 12 months and lifestyle intervention. Group 2 (placebo group, n=56) received a recommended diet plus placebo and lifestyle intervention for 12 months. Insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) from fasting samples. Results: BMI, fasting insulin levels and HOMA-IR values in both groups decreased significantly at the end of the study. In group 1, 67.8% of the patients had a decrease from baseline in the prevalence of steatosis (p<0.001). Frequency of elevated alanine aminotransferase (ALT) levels (39.2% to 14.2%; p<0.01) and elevated aspartate aminotransferase (AST) levels (25% to 17.8%; p=0.01) decreased significantly in the PUFA group. Following a 12-month diet plus placebo and lifestyle intervention treatment, 40.3% (21) of the patients in the placebo group also showed a decrease in frequency of steatosis (p=0.04) and slight decreases in frequency of elevated ALT levels (38.4% to 28.8%; p=0.01) and AST levels (30.7% to 28.8%; p>0.05). Conclusion: Our results indicated that n-3 PUFA treatment is safe and efficacious in obese children with NAFLD and can improve ultrasonographic findings and the elevated transaminase levels. PMID:26316434

  2. The effect of magnesium supplementation and weight loss on liver enzymes in patients with nonalcoholic fatty liver disease

    PubMed Central

    Karandish, Majid; Tamimi, Mahtab; Shayesteh, Ali Akbar; Haghighizadeh, Mohammad Hosein; Jalali, Mohammad Taha

    2013-01-01

    Background: There have been few studies to examine the effect of magnesium (Mg) supplementation on liver enzymes. The aim of this study was to evaluate the effect of Mg supplementation and weight loss on liver enzymes, lipid profile, and fasting blood sugar in patients with nonalcoholic fatty liver disease (NAFLD). Materials and Methods: This study was a double-blind, placebo-controlled, randomized clinical trial. Ultrasonography was used to diagnose fatty liver in patients with alanine aminotransferase (ALT) ≥ 40 U/L and without other hepatic diseases. A total of 68 participants (18-59 years) with NAFLD were randomly divided into two groups to receive either Mg supplement (350 mg elemental Mg per day) or placebo for 90 days. At baseline and at the end of the intervention serum ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), total cholesterol (TCHO), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), blood sugar and serum insulin, and Mg levels were measured in fasting state. Low-density lipoprotein cholesterol (LDL-C) and insulin resistance (IR) were calculated using Friedewald formula and homeostasis model assessment of insulin resistance (HOMA-IR), respectively. All participants received lifestyle recommendations including low calorie diet and physical activity. Results: Significant decreases within the intervention and placebo groups were observed in ALT (57.00 (25) to 41.82 ± 19.40 U/L, P = 0.000; 68.50 ± 26.96 to 40.17 ± 19.40 U/L, P = 0.000 in Mg and placebo groups, respectively). Similar significant decreases were observed in AST and fasting serum insulin within the study groups. The decrease in weight was also significant in both groups (91.05 ± 13.77 to 87.60 ± 14.37 kg and 94.59 ± 16.85 to 91.45 ± 16.39 kg in Mg and placebo groups, respectively). LDL-C and TCHO were decreased significantly in placebo group but not in the intervention group. Serum Mg was increased significantly in the intervention group. No

  3. Nonalcoholic Fatty Liver Disease: Correlation of the Liver Parenchyma Fatty Acid with Intravoxel Incoherent Motion MR Imaging–An Experimental Study in a Rat Model

    PubMed Central

    Yu, Seung-Man; Ki, Sung Hwan; Baek, Hyeon-Man

    2015-01-01

    Purpose To prospectively evaluate the changes in fatty acid concentration after administrating a 60% high-fat diet to a non-alcoholic fatty liver disease rat model and to perform a correlation analysis between fatty acid with molecular diffusion (Dtrue), perfusion-related diffusion (Dfast), and perfusion fraction (Pfraction). Material and Methods This prospective study was approved by the appropriate ethics committee. Ten male Sprague-Dawley rats were fed a 60% high-fat diet until the study was finished. Point-resolved spectroscopy sequence 1H-MRS with TR = 1,500 msec, TE = 35 msec, NEX = 64, and 8×8×8 mm3 voxel was used to acquire magnetic resonance spectroscopy (MRS) data. Diffusion-weighted imaging was performed on a two-dimensional multi-b value spin echo planar image with the following parameters: repetition time msec/echo time msec, 4500 /63; field of view, 120×120 msec2; matrix, 128×128; section thickness, 3 mm; number of repetition, 8; and multiple b value, 0, 25, 50, 75, 100, 200, 500, 1000 sec/mm2. Baseline magnetic resonance imaging and magnetic resonance spectroscopy data (control) were acquired. 1H proton MRS and diffusion-weighted imaging were obtained every 2 weeks for 8 weeks. The individual contributions of the true molecular diffusion and the incoherent motions of water molecules in the capillary network to the apparent diffusion changes were estimated using a least-square nonlinear fitting in MatLab. A Wilcoxon signed-rank test with the Kruskal-Wallis test was used to compare each week’s fatty acid mean quantification. Spearman’s correlation coefficient was used to evaluate the correlation between each fatty acid (e.g., total lipid (TL), total saturated fatty acid (TSFA), total unsaturated fatty acid (TUSFA), total unsaturated bond (TUSB), and polyunsaturated bond (PUSB)) and intravoxel incoherent motion (IVIM) mapping images (e.g., Dtrue, Dfast, and Pfraction). Results The highest mean TL value was at week 8 (0.278 ± 0.10) after the

  4. Hepatoprotective potential of zingerone against nonalcoholic fatty liver disease in rats fed with fructose-enriched diet.

    PubMed

    Muniandy Narayanan, Jeyabarathy; Jesudoss, Victor A S

    2016-04-01

    Overconsumption of fructose increases the risk of nonalcoholic fatty liver disease (NAFLD), obesity and metabolic syndrome. NAFLD is currently one of the most common etiologies of chronic liver disease worldwide. The aim of the present study is to evaluate the hepatoprotective potential of zingerone against fructose-enriched diet-induced rat model of nonalcoholic fatty liver disease. Male albino Wistar rats were used and randomly divided into four groups: group 1, control rats fed with standard pellet; group 2, rats were fed normal pellet with intragastric intubation of zingerone (100 mg/kg/day); group 3, rats were fed fructose enriched diet alone; group 4, rats were fed fructose enriched diet with intragastric intubation o