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Sample records for lactation promotes nonalcoholic

  1. Monitoring food and non-alcoholic beverage promotions to children.

    PubMed

    Kelly, B; King, L; Baur, L; Rayner, M; Lobstein, T; Monteiro, C; Macmullan, J; Mohan, S; Barquera, S; Friel, S; Hawkes, C; Kumanyika, S; L'Abbé, M; Lee, A; Ma, J; Neal, B; Sacks, G; Sanders, D; Snowdon, W; Swinburn, B; Vandevijvere, S; Walker, C

    2013-10-01

    Food and non-alcoholic beverage marketing is recognized as an important factor influencing food choices related to non-communicable diseases. The monitoring of populations' exposure to food and non-alcoholic beverage promotions, and the content of these promotions, is necessary to generate evidence to understand the extent of the problem, and to determine appropriate and effective policy responses. A review of studies measuring the nature and extent of exposure to food promotions was conducted to identify approaches to monitoring food promotions via dominant media platforms. A step-wise approach, comprising 'minimal', 'expanded' and 'optimal' monitoring activities, was designed. This approach can be used to assess the frequency and level of exposure of population groups (especially children) to food promotions, the persuasive power of techniques used in promotional communications (power of promotions) and the nutritional composition of promoted food products. Detailed procedures for data sampling, data collection and data analysis for a range of media types are presented, as well as quantifiable measurement indicators for assessing exposure to and power of food and non-alcoholic beverage promotions. The proposed framework supports the development of a consistent system for monitoring food and non-alcoholic beverage promotions for comparison between countries and over time. PMID:24074211

  2. Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine initiated early hepatocarcinogenesis in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It has been suggested that patients with nonalcoholic steatohepatitis (NASH) are at a high risk for liver cancer. However, it is unknown whether high-fat diet induced NASH promotes hepatocarcinogenesis. In the present study, Sprague-Dawley rats were injected with a low dose of hepatic carcinogen die...

  3. Nonalcoholic Steatohepatitis Induced by a High-Fat Diet Promotes Diethylnitrosamine Initiated Early Hepatocarcinogenesis in Rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It has been suggested that patients with nonalcoholic steatohepatitis (NASH) have a high risk for liver cancer. However, it is unknown whether high-fat diet induced NASH promotes chemical carcinogen-initiated hepatocarcinogenesis. In the present study, Sprague-Dawley rats were injected with a low d...

  4. 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

  5. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2.

    PubMed

    Miura, Kouichi; Yang, Ling; van Rooijen, Nico; Ohnishi, Hirohide; Seki, Ekihiro

    2012-06-01

    Inflammatory cell infiltration in the liver is a hallmark of nonalcoholic steatohepatitis (NASH). The chemokine-chemokine receptor interaction induces inflammatory cell recruitment. CC-chemokine receptor (CCR)2 is expressed on hepatic macrophages and hepatic stellate cells. This study aims to investigate the therapeutic potential of CCR2 to NASH. Twenty-two weeks on a choline-deficient amino acid-defined (CDAA) diet induced steatosis, inflammatory cell infiltration, and liver fibrosis with increased CCR2 and monocyte chemoattractant protein (MCP)-1 expression in the wild-type livers. The infiltrated macrophages expressed CD68, CCR2, and a marker of bone marrow-derived monocytes, Ly6C. CCR2(-/-) mice had less steatosis, inflammatory cell infiltration, and fibrosis, and hepatic macrophages expressing CD68 and Ly6C were decreased. Toll-like receptor (TLR)4(-/-), TLR9(-/-), and MyD88(-/-) mice had reduced hepatic macrophage infiltration with decreased MCP-1 and CCR2 expression because TLR signaling is a potent inducer of MCP-1. To assess the role of Kupffer cells at the onset of NASH, Kupffer cells were depleted by liposomal clodronate. The Kupffer cell depletion ameliorated steatohepatitis with a decrease in the MCP-1 expression and recruitment of Ly6C-expressing macrophages at the onset of NASH. Finally, to test the therapeutic potential of targeting CCR2, a CCR2 inhibitor was administered to mice on a CDAA diet. The pharmaceutical inhibition of CCR2 prevented infiltration of the Ly6C-positive macrophages, resulting in an inhibition of liver inflammation and fibrosis. We concluded that CCR2 and Kupffer cells contribute to the progression of NASH by recruiting bone marrow-derived monocytes. PMID:22442158

  6. 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

  7. Lactation

    PubMed Central

    1989-01-01

    Lactation is the most energy-efficient way to provide for the dietary needs of young mammals, their mother's milk being actively protective, immunomodulatory, and ideal for their needs. Intrauterine mammary gland development in the human female is already apparent by the end of the sixth week of gestation. During puberty and adolescence secretions of the anterior pituitary stimulate the maturation of the graafian follicles in the ovaries and stimulate the secretion of follicular estrogens, which stimulate development of the mammary ducts. Pregnancy has the most dramatic effect on the breast, but development of the glandular breast tissue and deposition of fat and connective tissue continue under the influence of cyclic sex-hormone stimulation. Many changes occur in the nipple and breast during pregnancy and at delivery as a prelude to lactation. Preparation of the breasts is so effective that lactation could commence even if pregnancy were discontinued at 16 weeks. Following birth, placental inhibition of milk synthesis is removed, and a woman's progesterone blood levels decline rapidly. The breasts fill with milk, which is a high-density, low-volume feed called colostrum until about 30 hours after birth. Because it is not the level of maternal hormones, but the efficiency of infant suckling and/or milk removal that governs the volume of milk produced in each breast, mothers who permit their infants to feed ad libitum commonly observe that they have large volumes of milk 24-48 hours after birth. The two maternal reflexes involved in lactation are the milk-production and milk-ejection reflex. A number of complementary reflexes are involved when the infant feeds: the rooting reflex (which programmes the infant to search for the nipple), the sucking reflex (rhythmic jaw action creating negative pressure and a peristaltic action of the tongue), and the swallowing reflex. The infant's instinctive actions need to be consolidated into learned behaviour in the postpartum

  8. 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

  9. Galactose promotes fat mobilization in obese lactating and non-lactating women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Galactose consumption results in a lower rise in plasma glucose and insulin concentrations when compared to glucose. The lower insulin might promote lipolysis during meal absorption. An isocaloric galactose drink, when compared to glucose, will sustain fat mobilization during meal consumption while...

  10. Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis-promoted hepatocarcinogenesis in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Epidemiological and experimental studies provide supportive evidence that lycopene (LY), a major carotenoid from tomatoes and tomato products, may act as a chemopreventive agent against certain types of cancers. We recently showed that high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) ...

  11. Galactose promotes fat mobilization in obese lactating and nonlactating women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Galactose consumption as the only carbohydrate source, results in little increase in plasma glucose and insulin concentrations when compared with fasting. Lower insulin might promote endogenous lipolysis during meal absorption, which may facilitate fat loss. The objective was to test the hypothesis ...

  12. Hypocretinergic system in the medial preoptic area promotes maternal behavior in lactating rats.

    PubMed

    Rivas, Mayda; Torterolo, Pablo; Ferreira, Annabel; Benedetto, Luciana

    2016-07-01

    Hypocretin-1 and 2 (HCRT-1 and HCRT-2, respectively) are neuropeptides synthesized by neurons located in the postero-lateral hypothalamus, whose projections are widely distributed throughout the brain. The hypocretinergic (HCRTergic) system has been associated with the generation and maintenance of wakefulness, as well as with the promotion of motivated behaviors. In lactating rats, intra-cerebroventricular HCRT-1 administration stimulates maternal behavior, whilst lactation per se increases the expression of HCRT type 1 receptor (HCRT-R1). Due to the fact that HCRTergic receptors are expressed in the medial preoptic area (mPOA), a region critically involved in maternal behavior, we hypothesize that HCRT-1 promotes maternal behavior acting on this region. In order to evaluate this hypothesis, we assessed the maternal behavior of lactating rats following microinjections of HCRT-1 (10 or 100μM) and the selective HCRT-R1 antagonist SB-334867 (250μM) into the mPOA, during the first and second postpartum weeks. While intra-mPOA microinjections of HCRT-1 (100μM) increased corporal pup licking during the second postpartum week, the blockade of HCRT-R1 significantly decreased active components of maternal behavior, such as retrievals, corporal and ano-genital lickings, and increased the time spent in nursing postures in both postpartum periods. We conclude that HCRTergic system in the mPOA may stimulate maternal behavior, suggesting that endogenous HCRT-1 is necessary for the natural display of this behavior. PMID:27083313

  13. Fine Tuning of the Lactate and Diacetyl Production through Promoter Engineering in Lactococcus lactis

    PubMed Central

    Guo, Tingting; Kong, Jian; Zhang, Li; Zhang, Chenchen; Hu, Shumin

    2012-01-01

    Lactococcus lactis is a well-studied bacterium widely used in dairy fermentation and capable of producing metabolites with organoleptic and nutritional characteristics. For fine tuning of the distribution of glycolytic flux at the pyruvate branch from lactate to diacetyl and balancing the production of the two metabolites under aerobic conditions, a constitutive promoter library was constructed by randomizing the promoter sequence of the H2O-forming NADH oxidase gene in L. lactis. The library consisted of 30 promoters covering a wide range of activities from 7,000 to 380,000 relative fluorescence units using a green fluorescent protein as reporter. Eleven typical promoters of the library were selected for the constitutive expression of the H2O-forming NADH oxidase gene in L. lactis, and the NADH oxidase activity increased from 9.43 to 58.17-fold of the wild-type strain in small steps of activity change under aerobic conditions. Meanwhile, the lactate yield decreased from 21.15±0.08 mM to 9.94±0.07 mM, and the corresponding diacetyl production increased from 1.07±0.03 mM to 4.16±0.06 mM with the intracellular NADH/NAD+ ratios varying from 0.711±0.005 to 0.383±0.003. The results indicated that the reduced pyruvate to lactate flux was rerouted to the diacetyl with an almost linear flux variation via altered NADH/NAD+ ratios. Therefore, we provided a novel strategy to precisely control the pyruvate distribution for fine tuning of the lactate and diacetyl production through promoter engineering in L. lactis. Interestingly, the increased H2O-forming NADH oxidase activity led to 76.95% lower H2O2 concentration in the recombinant strain than that of the wild-type strain after 24 h of aerated cultivation. The viable cells were significantly elevated by four orders of magnitude within 28 days of storage at 4°C, suggesting that the increased enzyme activity could eliminate H2O2 accumulation and prolong cell survival. PMID:22558426

  14. 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

  15. 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

  16. Adipose tissue-derived stem cells promote the reversion of non-alcoholic fatty liver disease: An in vivo study.

    PubMed

    Liao, Naishun; Pan, Fan; Wang, Yingchao; Zheng, Youshi; Xu, Bo; Chen, Wenwei; Gao, Yunzhen; Cai, Zhixiong; Liu, Xiaolong; Liu, Jingfeng

    2016-05-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver injury and seriously affects human health. In the present study, we aimed to investigate whether adipose tissue-derived stem cell (ADSC) transplantation in combination with dietary modification was capable of reversing the progression of NAFLD. After establishing a rat model of NAFLD by feeding them a high-fat diet (HFD), ADSCs were transplanted via the portal vein into rats with HFD-induced NAFLD, and simultaneously fed a modified diet. Thereafter, gross liver morphology, the hepatosomatic (HSI) index and indicators of liver function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were evaluated. Subsequently, the serum levels of total cholesterol (TC), triglycerides (TGs) and fatty acids (FAs) were also assayed. Furthermore, H&E and oil red O staining were used to confirm the pathological effects of NAFLD in the rat livers. Although dietary modification alone caused liver function to recover, ADSC transplantation in combination with dietary modification further decreased the HSI index, the serum levels of ALT, TBIL, TC, TGs, FAs, reduced lipid accumulation to normal levels, and reversed the hepatic pathological changes in the rat livers. Taken together, these findings suggest that ADSC transplantation assists in the reversion of NAFLD by improving liver function and promoting lipid metabolism, thereby exerting hepatoprotective effects. Thus, we suggest that ADSC transplantation is a promising, potential therapeutic strategy for NAFLD treatment. PMID:26986083

  17. Targeting a Rate-Promoting Vibration with an Allosteric Mediator in Lactate Dehydrogenase.

    PubMed

    Dzierlenga, Michael W; Schwartz, Steven D

    2016-07-01

    We present a new type of allosteric modulation in which a molecule bound outside the active site modifies the chemistry of an enzymatic reaction through rapid protein dynamics. As a test case for this type of allostery, we chose an enzyme with a well-characterized rate-promoting vibration, lactate dehydrogenase; identified a suitable small molecule for binding; and used transition path sampling to obtain ensembles of reactive trajectories. We found that the small molecule significantly affected the reaction by changing the position of the transition state and, through applying committor distribution analysis, showed that it removed the protein component from the reaction coordinate. The ability of a small-molecule to disrupt enzymatic reactions through alteration of subpicosecond protein motion opens the door for new experimental studies on protein motion coupled to enzymatic reactions and possibly the design of drugs to target these enzymes. PMID:27327209

  18. From efficacy to effectiveness: selecting indicators for a community-based lactational amenorrhoea method promotion programme.

    PubMed

    Bender, D E; Dusch, E; McCann, M F

    1998-04-01

    This paper reviews the results of clinical trials and community studies of lactational amenorrhoea and its role as a contraceptive method (LAM). Indicators which are used in efficacy trials and effectiveness interventions are compared and sets of indicators of effectiveness appropriate to community-based LAM programmes are recommended. A five-tiered ecological framework is used to facilitate selection of indicators which range from individual to policy level outcomes. The indicator framework is intended as a tool for health practitioners in family planning and maternal and child health service delivery settings who are interested in designing programmatic interventions for the promotion of LAM, particularly among less well-educated women of lower socioeconomic communities. PMID:9746825

  19. Lactate promotes PGE2 synthesis and gluconeogenesis in monocytes to benefit the growth of inflammation-associated colorectal tumor

    PubMed Central

    Wei, Libin; Zhou, Yuxin; Yao, Jing; Qiao, Chen; Ni, Ting; Guo, Ruichen; Guo, Qinglong; Lu, Na

    2015-01-01

    Reprogramming energy metabolism, such as enhanced glycolysis, is an Achilles' heel in cancer treatment. Most studies have been performed on isolated cancer cells. Here, we studied the energy-transfer mechanism in inflammatory tumor microenvironment. We found that human THP-1 monocytes took up lactate secreted from tumor cells through monocarboxylate transporter 1. In THP-1 monocytes, the oxidation product of lactate, pyruvate competed with the substrate of proline hydroxylase and inhibited its activity, resulting in the stabilization of HIF-1α under normoxia. Mechanistically, activated hypoxia-inducible factor 1-α in THP-1 monocytes promoted the transcriptions of prostaglandin-endoperoxide synthase 2 and phosphoenolpyruvate carboxykinase, which were the key enzyme of prostaglandin E2 synthesis and gluconeogenesis, respectively, and promote the growth of human colon cancer HCT116 cells. Interestingly, lactate could not accelerate the growth of colon cancer directly in vivo. Instead, the human monocytic cells affected by lactate would play critical roles to ‘feed’ the colon cancer cells. Thus, recycling of lactate for glucose regeneration was reported in cancer metabolism. The anabolic metabolism of monocytes in inflammatory tumor microenvironment may be a critical event during tumor development, allowing accelerated tumor growth. PMID:25938544

  20. The Comparative Effects of Sports Massage, Active Recovery, and Rest in Promoting Blood Lactate Clearance After Supramaximal Leg Exercise

    PubMed Central

    Martin, Nancy A.; Zoeller, Robert F.; Robertson, Robert J.; Lephart, Scott M.

    1998-01-01

    Objective: To determine the comparative effect of sports massage, active recovery, and rest on promoting blood lactate clearance after maximal anaerobic (supramaximal) leg exercise. Design and Setting: A counterbalanced experimental design with repeated measures was used. The repeated measures were the three treatment conditions. The order of the conditions was determined by random assignment to a counterbalanced test sequence. All data were collected in the Human Energy Research Laboratory at the University of Pittsburgh. Subjects: Ten male competitive cyclists volunteered for this investigation. Measurements: Serial venous blood samples were drawn and analyzed for blood lactate concentration for each test condition. Results: There were significant main effects for both absolute and relative values of blood lactate concentration between the three treatment groups and across time within groups. Conclusions: After supramaximal leg exercise, active recovery produced significant decreases in both absolute and relative measures of blood lactate concentration when compared with the sports massage and rest conditions. No significant difference was found between sports massage and rest for either absolute or relative changes in blood lactate concentration. PMID:16558481

  1. The demands of lactation promote differential regulation of lipid stores in fasting elephant seals.

    PubMed

    Fowler, Melinda A; Debier, Cathy; Champagne, Cory D; Crocker, Daniel E; Costa, Daniel P

    2016-01-01

    Fasting animals must ration stored reserves appropriately for metabolic demands. Animals that experience fasting concomitant with other metabolically demanding activities are presented with conflicting demands of energy conservation and expenditure. Our objective was to understand how fasting northern elephant seals regulate the mobilization of lipid reserves and subsequently milk lipid content during lactation. We sampled 36 females early and 39 at the end of lactation. To determine the separate influences of lactation from fasting, we also sampled fasting but non-lactating females early and late (8 and 6 seals, respectively) in their molting fasting period. Mass and adiposity were measured, as well as circulating non-esterified fatty acid (NEFA), triacylglycerol (TAG), cortisol, insulin and growth hormone levels. Milk was collected from lactating females. Milk lipid content increased from 31% in early to 51% in late lactation. In lactating females plasma NEFA was positively related to cortisol and negatively related to insulin, but in molting seals, only variation in cortisol was related to NEFA. Milk lipid content varied with mass, adiposity, NEFA, TAG, cortisol and insulin. Surprisingly, growth hormone concentration was not related to lipid metabolites or milk lipid. Suppression of insulin release appears to be the differential regulator of lipolysis in lactating versus molting seals, facilitating mobilization of stored lipids and maintenance of high NEFA concentrations for milk synthesis. Milk lipid was strongly impacted by the supply of substrate to the mammary gland, indicating regulation at the level of mobilization of lipid reserves. PMID:26407500

  2. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems.

    PubMed

    Thevenet, Jonathan; De Marchi, Umberto; Domingo, Jaime Santo; Christinat, Nicolas; Bultot, Laurent; Lefebvre, Gregory; Sakamoto, Kei; Descombes, Patrick; Masoodi, Mojgan; Wiederkehr, Andreas

    2016-05-01

    Medium-chain triglycerides have been used as part of a ketogenic diet effective in reducing epileptic episodes. The health benefits of the derived medium-chain fatty acids (MCFAs) are thought to result from the stimulation of liver ketogenesis providing fuel for the brain. We tested whether MCFAs have direct effects on energy metabolism in induced pluripotent stem cell-derived human astrocytes and neurons. Using single-cell imaging, we observed an acute pronounced reduction of the mitochondrial electrical potential and a concomitant drop of the NAD(P)H signal in astrocytes, but not in neurons. Despite the observed effects on mitochondrial function, MCFAs did not lower intracellular ATP levels or activate the energy sensor AMP-activated protein kinase. ATP concentrations in astrocytes were unaltered, even when blocking the respiratory chain, suggesting compensation through accelerated glycolysis. The MCFA decanoic acid (300 μM) promoted glycolysis and augmented lactate formation by 49.6%. The shorter fatty acid octanoic acid (300 μM) did not affect glycolysis but increased the rates of astrocyte ketogenesis 2.17-fold compared with that of control cells. MCFAs may have brain health benefits through the modulation of astrocyte metabolism leading to activation of shuttle systems that provide fuel to neighboring neurons in the form of lactate and ketone bodies.-Thevenet, J., De Marchi, U., Santo Domingo, J., Christinat, N., Bultot, L., Lefebvre, G., Sakamoto, K., Descombes, P., Masoodi, M., Wiederkehr, A. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems. PMID:26839375

  3. The complement component C5 promotes liver steatosis and inflammation in murine non-alcoholic liver disease model.

    PubMed

    Bavia, Lorena; Cogliati, Bruno; Dettoni, Juliano Bertollo; Ferreira Alves, Venancio Avancini; Isaac, Lourdes

    2016-09-01

    Non-Alcoholic Fatty Liver Disease (NALD) is considering a hepatic manifestation of metabolic syndrome. Although the pathogenesis of NALD is not completely understood, insulin resistance and inflammatory cytokines are implicated. Considering that component C5 is a central mediator of inflammation, we investigated the role of C5 in the establishment of NALD. Eight to ten-week old B6 C5(+) and A/J C5(-) male mice were fed a high fat diet containing glucose (HFDG) for 6 and 10 weeks. We observed that B6 C5(+) mice HFDG-fed for 10 weeks developed hepatomegaly, triglycerides (TG) accumulation, steatosis and enhanced liver TNF-α, IL-6, IL-12p70 and IL-17 levels when compared to A/J C5(-) mice. Next, B6 C5(+) mice were compared with congenic B6 C5(-) mice. Again, B6 C5(+) HFDG-fed mice developed more steatosis, liver centro-lobular inflammation and presented higher levels of liver IL-1β, IL-12p70, IL-17 and TFG-β than B6 C5(-) mice under the same conditions. B6 C5(+) mice HFDG-fed also presented lower concentrations of serum albumin, serum cholesterol, blood leukocytes and liver NO production when compared with B6 C5(-) mice. We concluded that murine C5 contributes effectively to liver steatosis and inflammation in NALD pathogenesis. In addition, C5 is also important to control serum cholesterol and albumin levels in the C57BL/6 genetic background. PMID:27477770

  4. Lactate promotes glioma migration by TGF-β2–dependent regulation of matrix metalloproteinase-2

    PubMed Central

    Baumann, Fusun; Leukel, Petra; Doerfelt, Anett; Beier, Christoph P.; Dettmer, Katja; Oefner, Peter J.; Kastenberger, Michael; Kreutz, Marina; Nickl-Jockschat, Thomas; Bogdahn, Ulrich; Bosserhoff, Anja-Katrin; Hau, Peter

    2009-01-01

    Lactate dehydrogenase type A (LDH-A) is a key metabolic enzyme catalyzing pyruvate into lactate and is excessively expressed by tumor cells. Transforming growth factor-β2 (TGF-β2) is a key regulator of invasion in high-grade gliomas, partially by inducing a mesenchymal phenotype and by remodeling the extracellular matrix. In this study, we tested the hypothesis that lactate metabolism regulates TGF-β2–mediated migration of glioma cells. Small interfering RNA directed against LDH-A (siLDH-A) suppresses, and lactate induces, TGF-β2 expression, suggesting that lactate metabolism is strongly associated with TGF-β2 in glioma cells. Here we demonstrate that TGF-β2 enhances expression, secretion, and activation of matrix metalloproteinase-2 (MMP-2) and induces the cell surface expression of integrin αvβ3 receptors. In spheroid and Boyden chamber migration assays, inhibition of MMP-2 activity using a specific MMP-2 inhibitor and blocking of integrin αvβ3 abrogated glioma cell migration stimulated by TGF-β2. Furthermore, siLDH-A inhibited MMP2 activity, leading to inhibition of glioma migration. Taken together, we define an LDH-A–induced and TGF-β2–coordinated regulatory cascade of transcriptional regulation of MMP-2 and integrin αvβ3. This novel interaction between lactate metabolism and TGF-β2 might constitute a crucial mechanism for glioma migration. PMID:19033423

  5. Sodium selenite supplementation during pregnancy and lactation promotes anxiolysis and improves mnemonic performance in wistar rats' offspring.

    PubMed

    Laureano-Melo, Roberto; Império, Güínever Eustáquio do; da Silva-Almeida, Claudio; Kluck, George Eduardo Gabriel; Cruz Seara, Fernando de Azevedo; da Rocha, Fábio Fagundes; da Silveira, Anderson Luiz Bezerra; Reis, Luís Carlos; Ortiga-Carvalho, Tania Maria; da Silva Côrtes, Wellington

    2015-11-01

    Selenium is a micronutrient which is part of selenoprotein molecules and participates in a vast number of physiological roles and, among them,we have fetal and neonatal development. Therefore, the aimof this studywas to evaluate possible behavioral changes in offspring of female rats supplemented during pregnancy and lactation with sodium selenite. To address that, we treated two groups of female rats by saline or sodium selenite at a dose of 1mg/kg through oral route and performed neurochemical and behavioral tests. In the offspring, the thyroid profile and hippocampal neurochemistrywere evaluated. Behavioral testswere performed in pups both during childhood and adulthood. We found out that selenium (Se) supplementation increased serum levels of triiodothyronine (25%, p b 0.001) and thyroxine (18%, p b 0.05) and promoted a tryptophan hydroxylase 2 (TPH 2) expression decrease (17%, p b 0.01) and tyrosine hydroxylase (TH) expression increase (202%, p b 0.01) in the hippocampus. The cholinesterase activity was decreased (28%, p b 0.01) in Se supplemented rats, suggesting a neurochemical modulation in the hippocampal activity. During childhood, the Sesupplemented offspring had a reduction in anxiety-like behavior both in elevated plus maze test and in light–dark box test. In adulthood, Se-treated pups had an increase in the locomotor activity (36%, p b 0.05) and in rearing episodes (77%, p b 0.001) in the open field test, while in the elevated plus maze test they also exhibited an increase in the time spent in the open arms (243%, p b 0.01). For the object recognition test, Se-treated offspring showed increase in the absolute (230.16%, p b 0.05) and relative index discrimination (234%, p b 0.05). These results demonstrate that maternal supplementation by sodium selenite promoted psychobiological changes both during childhood and adulthood. Therefore, the behavioral profile observed possibly can be explained by neurochemical changes induced by thyroid hormones during

  6. 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 ...

  7. Nonalcoholic Wernicke's encephalopathy.

    PubMed

    Welsh, Amanda; Rogers, Peter; Clift, Fraser

    2016-07-01

    Wernicke's encephalopathy (WE) is a serious neurologic condition resulting from thiamine deficiency. The majority of cases involve alcoholism; however, nonalcohol-associated WE does occur and is under-recognized. We discuss a case of a 22-year-old man with a history of Crohn's disease who presented to our emergency department with multiple neurologic complaints related to WE. PMID:25985980

  8. Microbiota and nonalcoholic steatohepatitis.

    PubMed

    Imajo, Kento; Yoneda, Masato; Ogawa, Yuji; Wada, Koichiro; Nakajima, Atsushi

    2014-01-01

    The recent rise in obesity-related diseases, such as nonalcoholic fatty liver disease and its strong association with microbiota, has elicited interest in the underlying mechanisms of these pathologies. Experimental models have highlighted several mechanisms connecting microbiota to the development of liver dysfunction in nonalcoholic steatohepatitis (NASH) such as increased energy harvesting from the diet, small intestine bacterial overgrowth, modulation of the intestinal barrier by glucagon-like peptide-2 secretions, activation of innate immunity through the lipopolysaccharide-CD14 axis caused by obesity-induced leptin, periodontitis, and sterile inflammation. The manipulation of microbiota through probiotics, prebiotics, antibiotics, and periodontitis treatment yields encouraging results for the treatment of obesity, diabetes, and NASH, but data in humans is scarce. PMID:24337650

  9. Synbiotics suppress the release of lactate dehydrogenase, promote non-specific immunity and integrity of jejunum mucosa in piglets.

    PubMed

    Andrejčáková, Zuzana; Sopková, Drahomíra; Vlčková, Radoslava; Kulichová, Lucia; Gancarčíková, Soňa; Almášiová, Viera; Holovská, Katarína; Petrilla, Vladimír; Krešáková, Lenka

    2016-09-01

    The aim of our experiment was to study how synbiotics are able to deal with the problems of post-weaning piglets. Lactobacillus plantarum - Biocenol(TM) LP96 (CCM 7512), Lactobacillus fermentum - Biocenol(TM) LF99 (CCM 7514) and flaxseed (rich in n-3 polyunsaturated fatty acids) were administered to 36 conventional piglets from a problematic breed with confirmed presence of enterotoxigenic Escherichia coli and Coronavirus. The experimental piglets were supplied with probiotic cheeses and crushed flax-seed in the period starting 10 days before weaning and lasting up to 14 days post-weaning. Piglets in the control group were supplied only control cheese. The impact of such additives on the release of lactate dehydrogenase (LDH; spectroscopic and electrophoretic assay), alteration of immunity (index of metabolic activity), jejunum histology (light microscopy), and health of conventional piglets from a problematic breed (monitoring of hematology, consistency and moisture of feces and body temperature) were examined. We found significant decrease in LDH leakage in the blood serum and tissue extracts, indicating better cell membrane integrity in the individual organs of animals. Probiotics and flaxseed applied together seem to be a good source of nutrients to improve the immune status and the integrity of jejunum mucosa during infection. © 2015 Japanese Society of Animal Science. PMID:27581561

  10. In utero and lactational exposure to blueberry via maternal diet promotes mammary epithelial differentiation in prepubescent female rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Early developmental events influence the fine tuning of later susceptibility to adult diseases. Diet is a determinant of breast cancer risk, and our previous studies showed that diet-mediated changes in transcriptional programs promote early mammary gland differentiation. While consumption of fruits...

  11. 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

  12. Pathogenesis of Nonalcoholic Steatohepatitis.

    PubMed

    Machado, Mariana Verdelho; Diehl, Anna Mae

    2016-06-01

    Nonalcoholic steatohepatitis (NASH) is a necro-inflammatory response that ensues when hepatocytes are injured by lipids (lipotoxicity). NASH is a potential outcome of nonalcoholic fatty liver (NAFL), a condition that occurs when lipids accumulate in hepatocytes. NASH may be reversible, but it can also result in cirrhosis and primary liver cancer. We are beginning to learn about the mechanisms of progression of NAFL and NASH. NAFL does not inevitably lead to NASH because NAFL is a heterogeneous condition. This heterogeneity exists because different types of lipids with different cytotoxic potential accumulate in the NAFL, and individuals with NAFL differ in their ability to defend against lipotoxicity. There are no tests that reliably predict which patients with NAFL will develop lipotoxicity. However, NASH encompasses the spectrum of wound-healing responses induced by lipotoxic hepatocytes. Differences in these wound-healing responses among individuals determine whether lipotoxic livers regenerate, leading to stabilization or resolution of NASH, or develop progressive scarring, cirrhosis, and possibly liver cancer. We review concepts that are central to the pathogenesis of NASH. PMID:26928243

  13. Policy considerations for the introduction and promotion of the lactational amenorrhea method: advantages and disadvantages of LAM.

    PubMed

    Kennedy, K I; Kotelchuck, M

    1998-09-01

    Some attributes of LAM are unquestionably positive, such as the fact that it is effective. Clinical trials of LAM have upheld the Bellagio Consensus that the chance of pregnancy is less than 2% in the first 6 months postpartum in amenorrheic women who are fully or nearly fully breastfeeding. Secondary data analyses in numerous settings have drawn the same conclusion. Whether as a strategy or a method, used correctly or even if used imperfectly, LAM is a reliable way to avoid pregnancy. To the extent that LAM represents an additional contraceptive option, this is also clearly positive since a broad array of contraceptive options maximizes the likelihood of finding a good fit between user and method, and increases contraceptive use. Other characteristics of LAM represent potentially positive impacts. If LAM is shown to be an effective conduit to other modern methods, the implications are profoundly positive. If LAM is cost effective, for households and/or for programs, this will also make the method extraordinarily attractive. Conversely, some aspects of LAM are negative, such as the fact that it affords no protection against STDs, it requires counseling from a well-informed provider, and intensive breastfeeding can make heavy demands on the woman's time. Many of the remaining attributes of LAM may not be important to a policy decision about LAM promotion. For example, whether LAM is actualized as a strategy or a method may not be important to a decision to promote LAM, although it has a huge impact on how services are delivered. Some factors may be profound on a local or individual level. For example, one simple factor, such as the absence of full/nearly full breastfeeding, can rule out the method as an option, while another, such as the fact that it provides the needed waiting period during vasectomy counseling, can make LAM the method of choice. Although LAM seems unlikely to have widespread popularity in societies like the United States, within such settings are

  14. 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

  15. 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 ...

  16. 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

  17. Chitosan promotes immune responses, ameliorates glutamic oxaloacetic transaminase and glutamic pyruvic transaminase, but enhances lactate dehydrogenase levels in normal mice in vivo

    PubMed Central

    YEH, MING-YANG; SHIH, YUNG-LUEN; CHUNG, HSUEH-YU; CHOU, JASON; LU, HSU-FENG; LIU, CHIA-HUI; LIU, JIA-YOU; HUANG, WEN-WEN; PENG, SHU-FEN; WU, LUNG-YUAN; CHUNG, JING-GUNG

    2016-01-01

    Chitosan, a naturally derived polymer, has been shown to possess antimicrobial and anti-inflammatory properties; however, little is known about the effect of chitosan on the immune responses and glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and lactate dehydrogenase (LDH) activities in normal mice. The aim of the present study was to investigate whether chitosan has an effect on the immune responses and GOT, GPT and LDH activities in mice in vivo. BALB/c mice were divided into four groups. The negative control group was treated with a normal diet; the positive control group was treated with a normal diet plus orally administered acetic acid and two treatment groups were treated with a normal diet plus orally administered chitosan in acetic acid at doses of 5 and 20 mg/kg, respectively, every other day for 24 days. Mice were weighed during the treatment, and following the treatment, blood was collected, and liver and spleen samples were isolated and weighted. The blood samples were used for measurement of white blood cell markers, and the spleen samples were used for analysis of phagocytosis, natural killer (NK) cell activity and cell proliferation using flow cytometry. The results indicated that chitosan did not markedly affect the body, liver and spleen weights at either dose. Chitosan increased the percentages of CD3 (T-cell marker), CD19 (B-cell marker), CD11b (monocytes) and Mac-3 (macrophages) when compared with the control group. However, chitosan did not affect the phagocytic activity of macrophages in peripheral blood mononuclear cells, although it decreased it in the peritoneal cavity. Treatment with 20 mg/kg chitosan led to a reduction in the cytotoxic activity of NK cells at an effector to target ratio of 25:1. Chitosan did not significantly promote B-cell proliferation in lipopolysaccharide-pretreated cells, but significantly decreased T-cell proliferation in concanavalin A-pretreated cells, and decreased the activity of

  18. Lactation Consultant

    MedlinePlus

    ... about infant and child feeding; utilize a pragmatic problem-solving approach, sensitive to the learner’s culture, questions and concerns; provide anticipatory guidance to promote optimal breastfeeding practices ... or complications; provide positive feedback and emotional support ...

  19. 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

  20. Perspectives on Treatment for Nonalcoholic Steatohepatitis.

    PubMed

    Lassailly, Guillaume; Caiazzo, Robert; Pattou, François; Mathurin, Philippe

    2016-06-01

    It is important to provide treatment to patients with nonalcoholic steatohepatitis (NASH) because one third of patients with the metabolic syndrome die of liver disease. Basic research studies have elucidated mechanisms of NASH pathogenesis, which could lead to therapeutic targets. Health agencies have confirmed strategies for the optimal management of NASH and approved new drugs and treatments, which urgently are needed. The US Food and Drug Administration recently endorsed end points for NASH therapy. The reversal of NASH with no evidence of progression to advanced fibrosis has been defined as the end point for phase 2b and phase 3 trials in patients with NASH and early stage fibrosis. Although a decrease in the nonalcoholic fatty liver disease activity score could serve as an end point in clinical trials, it is not clear whether patients with lower scores have a lower risk of progression to advanced fibrosis. End points for clinical trials of patients with NASH cirrhosis currently are based on model for end-stage liver disease and Child-Pugh-Turcotte scores, as well as the hepatic venous pressure gradient. Different strategies are being explored to reduce liver diseases that are linked to a sedentary lifestyle, overeating, and genetic factors. In association with insulin resistance and deregulation of the lipid metabolism (accumulation of lipotoxins that promote hepatic lipogenesis, adipose tissue lipolysis, and impaired β-oxidation), these factors could increase the risk of liver steatosis with necroinflammatory lesions and fibrosis. We review the pathogenic mechanisms of NASH and therapeutic options, as well as strategies that are being developed for the treatment of injury to the liver and other organs. PMID:26971824

  1. Lactation and reproduction*

    PubMed Central

    Thomson, A. M.; Hytten, F. E.; Black, A. E.

    1975-01-01

    The authors review the literature on the effect of lactation on fertility in the absence of contraception and on the effects of contraceptive measures on lactation. They examine data from several countries on the intervals between births and on the return of menstruation and ovulation after childbirth, comparing lactating with nonlactating women. They conclude that lactation is an inefficient contraceptive for the individual, but that in populations sustained lactation is associated with reduced fertility. Possible physiological mechanisms causing lactation amenorrhoea are discussed. Though much of the literature on the effect of contraceptives on lactation is inadequate, there is general agreement that the estrogen component of hormonal preparations has an adverse effect on lactation, but that progestins alone do not. Many questions remain. Is this effect seen in established lactation, or only in the puerperal period? Is it a direct pharmacological effect, or are pill-users the mothers least motivated to maintain breast-feeding? Does a close relationship exist between hormones given and lactation performance? The authors comment on some of the technical deficiencies of previous studies in this field and discuss practical possibilities of, and limitations to, obtaining adequate scientific information in the future. PMID:1084804

  2. Hepatocellular carcinoma and non-alcoholic steatohepatitis: The state of play

    PubMed Central

    Charrez, Bérénice; Qiao, Liang; Hebbard, Lionel

    2016-01-01

    Hepatocellular carcinoma (HCC) is now the fifth cancer of greatest frequency and the second leading cause of cancer related deaths worldwide. Chief amongst the risks of HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The latter can promote non-alcoholic fatty liver disease (NAFLD), that can lead to the inflammatory form non-alcoholic steatohepatitis (NASH), and can in turn promote HCC. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give a summary of the recent findings that describe and associate NAFLD and NASH with the subsequent HCC progression. We will focus our discussion on clinical and genomic associations that describe new risks for NAFLD and NASH promoted HCC. In addition, we will consider novel murine models that clarify some of the mechanisms that drive NASH HCC formation. PMID:26937137

  3. Promotion

    PubMed Central

    Alam, Hasan B.

    2013-01-01

    This article gives an overview of the promotion process in an academic medical center. A description of different promotional tracks, tenure and endowed chairs, and the process of submitting an application is provided. Finally, some practical advice about developing skills and attributes that can help with academic growth and promotion is dispensed. PMID:24436683

  4. Red cell distribution width and nonalcoholic steatohepatitis

    PubMed Central

    Gulcan Kurt, Yasemin; Cayci, Tuncer; Aydin, Fevzi Nuri; Agilli, Mehmet

    2014-01-01

    Red cell distribution width is a measure of deviation of the volume of red blood cells. It is a marker of anisocytosis and often used to evaluate the possible causes of anemia. Elevated red cell distribution width levels are also associated with acute and chronic inflammatory responses. In nonalcoholic steatohepatitis, inflammation is accompanied with steatosis. For assuming red cell distribution width as a marker of nonalcoholic steatohepatitis, intervening factors such as levels of inflammatory markers should also be evaluated. PMID:25473202

  5. Physiology of lactation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The breast changes in size, shape, and function during puberty, pregnancy, and lactation. The physiology of lactation is reviewed here. The breast is composed of fat and connective tissue that supports a tubuloalveolar structure. During development, anatomic changes involving new lobule formation an...

  6. Acidophil bodies in nonalcoholic steatohepatitis.

    PubMed

    Yeh, Matthew M; Belt, Patricia; Brunt, Elizabeth M; Kowdley, Kris V; Wilson, Laura A; Ferrell, Linda

    2016-06-01

    The significance of the quantity of acidophil bodies (AB) in nonalcoholic steatohepatitis (NASH) is not certain. We quantified AB in liver biopsies and examined the association with the diagnosis of NASH and other histologic features. We reviewed 157 liver biopsies from the NASH Clinical Research Network Database collected in 2006. One hundred twenty-seven biopsies were from adult patients. Diagnoses were 94 definite NASH, 40 borderline NASH, and 23 definitely not NASH. The total length and average width of the core biopsies were measured, and the biopsy areas were calculated (mm(2)). Total AB were counted, and mean AB count per mm(2) was calculated (AB/mm(2)) to derive acidophil body index (ABI). ABI was 0.04 (±0.08) in definite NASH and 0.02 (±0.05) in borderline/definitely not NASH groups combined (P = .02) in all 157 biopsies; similar findings were present in the 127 adult-only biopsies (0.04 ± 0.05 and 0.02 ± 0.05, respectively; P = .05). In all 157 biopsies, increased ABI was associated with greater lobular inflammation (P = .01) and many ballooned hepatocytes (P = .048). There was a positive relationship between ABI and high nonalcoholic fatty liver disease activity scores, but this association was not statistically significant. There was no association between ABI and steatosis or fibrosis stage either in the entire cohorts or in the subset of adult patients. In conclusion, the density of AB is associated with lobular inflammation, ballooned hepatocytes, and the diagnosis of NASH in adult and pediatric liver biopsies, suggesting the implication of the apoptotic pathway in NASH-associated liver cell injury. PMID:26980020

  7. [Psychopharmacotherapy in pregnancy and lactation. 2: Lactation].

    PubMed

    Lanczik, M; Knoche, M; Fritze, J

    1998-01-01

    Whilst the incidence of psychiatric disorders decreases during pregnancy, the risk during the postpartum period increases significantly, often leading to the necessity of psychopharmacological intervention during the puerperium, and subsequently during lactation and breast-feeding. The necessity for lithium prophylaxis in manic-depressive women after childbirth has been identified, and it is recommended that weaning rather than omission of psychopharmacological treatment is preferable during the puerperium. PMID:9522328

  8. PATHOPHYSIOLOGY GUIDED TREATMENT OF NONALCOHOLIC STEATOHEPATITIS

    PubMed Central

    Nguyen, Tuyet A. T.; Sanyal, Arun J.

    2016-01-01

    Nonalcoholic fatty liver disease is a spectrum that ranges from benign steatosis to steatohepatitis. It has become the most common cause of chronic liver disease, and yet there continues to be a lack of effective therapeutic options. This article reviews current concepts underlying the pathophysiologic basis of nonalcoholic steatohepatitis from development of insulin resistance to the establishment of fibrosis. Then using a physiology-based approach, specific targeted therapeutics are reviewed along with their drawbacks. The evidence behind current therapies are based predominantly on small trials and as such, no recommendations can be made until larger randomized trials are conducted. PMID:22320918

  9. Lactate: Friend or Foe.

    PubMed

    Hall, Mederic M; Rajasekaran, Sathish; Thomsen, Timothy W; Peterson, Andrew R

    2016-03-01

    Lactic acid has played an important role in the traditional theory of muscle fatigue and limitation of endurance exercise performance. It has been called a waste product of anaerobic metabolism and has been believed to be responsible for the uncomfortable "burn" of intense exercise and directly responsible for the metabolic acidosis of exercise, leading to decreased muscle contractility and ultimately cessation of exercise. Although this premise has been commonly taught, it is not supported by the scientific literature and has led to a great deal of confusion among the sports medicine and exercise science communities. This review will provide the sports medicine clinician with an understanding of contemporary lactate theories, including lactate's role in energy production, its contributions to metabolic acidosis, and its function as an energy substrate for a variety of tissues. Lactate threshold concepts will also be discussed, including a practical approach to understanding prediction of performance and monitoring of training progress based on these parameters. PMID:26972271

  10. Nonalcoholic steatohepatitis and hepatocellular carcinoma: Brazilian survey

    PubMed Central

    Cotrim, Helma P.; Oliveira, Claudia P.; Coelho, Henrique Sérgio M.; Alvares-da-Silva, Mario R.; Nabuco, Leticia; Parise, Edison Roberto; Ivantes, Claúdia; Martinelli, Ana LC; Galizzi-Filho, João; Carrilho, Flair J.

    2016-01-01

    OBJECTIVE: The majority of cases of hepatocellular carcinoma have been reported in individuals with cirrhosis due to chronic viral hepatitis and alcoholism, but recently, the prevalence has become increasingly related to nonalcoholic steatohepatitis around the world. The study aimed to evaluate the clinical and histophatological characteristics of hepatocellular carcinoma in Brazilians' patients with nonalcoholic steatohepatitis at the present time. METHODS: Members of the Brazilian Society of Hepatology were invited to complete a survey regarding patients with hepatocellular carcinoma related to nonalcoholic steatohepatitis. Patients with a history of alcohol intake (>20 g/day) and other liver diseases were excluded. Hepatocellular carcinoma diagnosis was performed by liver biopsy or imaging methods according to the American Association for the Study of Liver Diseases' 2011 guidelines. RESULTS: The survey included 110 patients with a diagnosis of hepatocellular carcinoma and nonalcoholic fatty liver disease from nine hepatology units in six Brazilian states (Bahia, Minas Gerais, Rio de Janeiro, São Paulo, Paraná and Rio Grande do Sul). The mean age was 67±11 years old, and 65.5% were male. Obesity was observed in 52.7% of the cases; diabetes, in 73.6%; dyslipidemia, in 41.0%; arterial hypertension, in 60%; and metabolic syndrome, in 57.2%. Steatohepatitis without fibrosis was observed in 3.8% of cases; steatohepatitis with fibrosis (grades 1-3), in 27%; and cirrhosis, in 61.5%. Histological diagnosis of hepatocellular carcinoma was performed in 47.2% of the patients, with hepatocellular carcinoma without cirrhosis accounting for 7.7%. In total, 58 patients with cirrhosis had their diagnosis by ultrasound confirmed by computed tomography or magnetic resonance imaging. Of these, 55% had 1 nodule; 17%, 2 nodules; and 28%, ≥3 nodules. CONCLUSIONS: Nonalcoholic steatohepatitis is a relevant risk factor associated with hepatocellular carcinoma in patients with and

  11. Laboratory Prototype of Bioreactor for Oxidation of Toxic D-Lactate Using Yeast Cells Overproducing D-Lactate Cytochrome c Oxidoreductase

    PubMed Central

    Karkovska, Maria

    2016-01-01

    D-lactate is a natural component of many fermented foods like yogurts, sour milk, cheeses, and pickles vegetable products. D-lactate in high concentrations is toxic for children and people with short bowel syndrome and provokes encephalopathy. These facts convincingly demonstrate a need for effective tools for the D-lactate removal from some food products. The main idea of investigation is focused on application of recombinant thermotolerant methylotrophic yeast Hansenula polymorpha “tr6,” overproducing D-lactate: cytochrome c oxidoreductase (EC 1.1.2.4, D-lactate cytochrome c oxidoreductase, D-lactate dehydrogenase (cytochrome), DLDH). In addition to 6-fold overexpression of DLDH under a strong constitutive promoter (prAOX), the strain of H. polymorpha “tr6” (gcr1 catX/Δcyb2, prAOX_DLDH) is characterized by impairment in glucose repression of AOX promoter, devoid of catalase and L-lactate-cytochrome c oxidoreductase activities. Overexpression of DLDH coupling with the deletion of L-lactate-cytochrome c oxidoreductase activity opens possibility for usage of the strain as a base for construction of bioreactor for removing D-lactate from fermented products due to oxidation to nontoxic pyruvate. A laboratory prototype of column-type bioreactor for removing a toxic D-lactate from model solution based on permeabilized cells of the H. polymorpha “tr6” and alginate gel was constructed and efficiency of this process was tested. PMID:27446952

  12. Laboratory Prototype of Bioreactor for Oxidation of Toxic D-Lactate Using Yeast Cells Overproducing D-Lactate Cytochrome c Oxidoreductase.

    PubMed

    Karkovska, Maria; Smutok, Oleh; Gonchar, Mykhailo

    2016-01-01

    D-lactate is a natural component of many fermented foods like yogurts, sour milk, cheeses, and pickles vegetable products. D-lactate in high concentrations is toxic for children and people with short bowel syndrome and provokes encephalopathy. These facts convincingly demonstrate a need for effective tools for the D-lactate removal from some food products. The main idea of investigation is focused on application of recombinant thermotolerant methylotrophic yeast Hansenula polymorpha "tr6," overproducing D-lactate: cytochrome c oxidoreductase (EC 1.1.2.4, D-lactate cytochrome c oxidoreductase, D-lactate dehydrogenase (cytochrome), DLDH). In addition to 6-fold overexpression of DLDH under a strong constitutive promoter (prAOX), the strain of H. polymorpha "tr6" (gcr1 catX/Δcyb2, prAOX_DLDH) is characterized by impairment in glucose repression of AOX promoter, devoid of catalase and L-lactate-cytochrome c oxidoreductase activities. Overexpression of DLDH coupling with the deletion of L-lactate-cytochrome c oxidoreductase activity opens possibility for usage of the strain as a base for construction of bioreactor for removing D-lactate from fermented products due to oxidation to nontoxic pyruvate. A laboratory prototype of column-type bioreactor for removing a toxic D-lactate from model solution based on permeabilized cells of the H. polymorpha "tr6" and alginate gel was constructed and efficiency of this process was tested. PMID:27446952

  13. Mixed glucose and lactate uptake by Corynebacterium glutamicum through metabolic engineering.

    PubMed

    Neuner, Andreas; Heinzle, Elmar

    2011-03-01

    The Corynebacterium glutamicum ATCC 13032 lysC(fbr) strain was engineered to grow fast on racemic mixtures of lactate and to secrete lysine during growth on lactate as well as on mixtures of lactate and glucose. The wild-type C. glutamicum only grows well on L-lactate. Overexpression of D-lactate dehydrogenase (dld) achieved by exchanging the native promoter of the dld gene for the stronger promoter of the sod gene encoding superoxide dismutase in C. glutamicum resulted in a duplication of biomass yield and faster growth without any secretion of lysine. Elementary mode analysis was applied to identify potential targets for lysine production from lactate as well as from mixtures of lactate and glucose. Two targets for overexpression were pyruvate carboxylase and malic enzyme. The overexpression of these genes using again the sod promoter resulted in growth-associated production of lysine with lactate as sole carbon source with a carbon yield of 9% and a yield of 15% during growth on a lactate-glucose mixture. Both substrates were taken up simultaneously with a slight preference for lactate. As surmised from the elementary mode analysis, deletion of glucose-6-phosphate isomerase resulted in a decreased production of lysine on the mixed substrate. Elementary mode analysis together with suitable objective functions has been found a very useful tool guiding the design of strains producing lysine on mixed substrates. PMID:21370474

  14. Alcohol's effect on lactation.

    PubMed

    Mennella, J

    2001-01-01

    Although pregnant women are discouraged from drinking alcohol because of alcohol's detrimental effect on fetal development, the lore of many cultures encourages lactating women to drink alcohol to optimize breast milk production and infant nutrition. In contrast to this folklore, however, studies demonstrate that maternal alcohol consumption may slightly reduce milk production. Furthermore, some of the alcohol consumed by a lactating woman is transferred to her milk and thus consumed by the infant. This alcohol consumption may adversely affect the infant's sleep and gross motor development and influence early learning about alcohol. Based on this science, it would seem that the recommendation for a nursing mother to drink a glass of beer or wine shortly before nursing may actually be counterproductive. PMID:11810962

  15. The Immune Landscape in Nonalcoholic Steatohepatitis

    PubMed Central

    Narayanan, Sowmya; Surette, Fionna A.

    2016-01-01

    The liver lies at the intersection of multiple metabolic pathways and consequently plays a central role in lipid metabolism. Pathological disturbances in hepatic lipid metabolism are characteristic of chronic metabolic diseases, such as obesity-mediated insulin resistance, which can result in nonalcoholic fatty liver disease (NAFLD). Tissue damage induced in NAFLD activates and recruits liver-resident and non-resident immune cells, resulting in nonalcoholic steatohepatitis (NASH). Importantly, NASH is associated with an increased risk of significant clinical sequelae such as cirrhosis, cardiovascular diseases, and malignancies. In this review, we describe the immunopathogenesis of NASH by defining the known functions of immune cells in the progression and resolution of disease. PMID:27340383

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. Hyperthyroidism Improves the Pathological Condition of Nonalcoholic Steatohepatitis: A Case of Nonalcoholic Steatohepatitis with Graves' Disease.

    PubMed

    Miyake, Teruki; Matsuura, Bunzo; Furukawa, Shinya; Todo, Yasuhiko; Yamamoto, Shin; Yoshida, Osamu; Imai, Yusuke; Watanabe, Takao; Yamamoto, Yasunori; Hirooka, Masashi; Tokumoto, Yoshio; Kumagi, Teru; Abe, Masanori; Seike, Hirotaka; Miyauchi, Shozo; Hiasa, Yoichi

    2016-01-01

    3,5,3'-triiodo-L-thyronine regulates the glucose metabolism, lipid metabolism, and hepatic steatosis. Several groups have shown the relationships between hypothyroidism and nonalcoholic fatty liver and hypothyroidism and nonalcoholic steatohepatitis (NASH). However, the effect of hyperthyroidism on NASH has not yet been investigated. We herein report effects of thyroid hormone on the pathological condition of NASH in a patient with NASH complicated by Graves' disease. In our case, the liver enzyme level improved with the increasing thyroid hormone level; however, the liver enzyme level was aggravated with the improving thyroid hormone level. Therefore, hyperthyroidism may improve the pathological condition of NASH. PMID:27477408

  3. Prevalence of Nonalcoholic Steatohepatitis Among Patients with Resectable Intrahepatic Cholangiocarcinoma

    PubMed Central

    Reddy, Srinevas K.; Hyder, Omar; Marsh, J. Wallis; Sotiropoulos, Georgios C.; Paul, Andreas; Alexandrescu, Sorin; Marques, Hugo; Pulitano, Carlo; Barroso, Eduardo; Aldrighetti, Luca; Geller, David A.; Sempoux, Christine; Herlea, Vlad; Popescu, Irinel; Anders, Robert; Rubbia-Brandt, Laura; Gigot, Jean-Francois; Mentha, Giles; Pawlik, Timothy M.

    2014-01-01

    Background and Aims The objective of this report was to determine the prevalence of underlying nonalcoholic steatohepatitis in resectable intrahepatic cholangiocarcinoma. Methods Demographics, comorbidities, clinicopathologic characteristics, surgical treatments, and outcomes from patients who underwent resection of intrahepatic cholangiocarcinoma at one of eight hepatobiliary centers between 1991 and 2011 were reviewed. Results Of 181 patients who underwent resection for intrahepatic cholangiocarcinoma, 31 (17.1 %) had underlying nonalcoholic steatohepatitis. Patients with nonalcoholic steatohepatitis were more likely obese (median body mass index, 30.0 vs. 26.0 kg/m2, p<0.001) and had higher rates of diabetes mellitus (38.7 vs. 22.0 %, p=0.05) and the metabolic syndrome (22.6 vs. 10.0 %, p=0.05) compared with those without nonalcoholic steatohepatitis. Presence and severity of hepatic steatosis, lobular inflammation, and hepatocyte ballooning were more common among nonalcoholic steatohepatitis patients (all p<0.001). Macrovascular (35.5 vs. 11.3 %, p=0.01) and any vascular (48.4 vs. 26.7 %, p=0.02) tumor invasion were more common among patients with nonalcoholic steatohepatitis. There were no differences in recurrence-free (median, 17.0 versus 19.4 months, p=0.42) or overall (median, 31.5 versus 36.3 months, p=0.97) survival after surgical resection between patients with and without nonalcoholic steatohepatitis. Conclusions Nonalcoholic steatohepatitis affects up to 20 % of patients with resectable intrahepatic cholangiocarcinoma. PMID:23355033

  4. Accelerated utilization of lactate under the effect of hypoxen after intensive exercise.

    PubMed

    Grishina, E V; Khaustova, Ya V; Pogorelova, V G; Pogorelov, A G; Kuz'mich, M K; Maevskii, E I

    2008-02-01

    Administration of substrates of energy metabolism in combination with hypoxen (sulfur-containing oligoquinone) promoted the increase in blood lactate concentration during maximum exercise, accelerated lactate utilization, and reduced the lactate/pyruvate ratio during recovery. The in vivo effects are in line with hypoxen capacity to accelerate in vitro oxidation of exogenous NADH in mitochondria by the non-rotenone-dependent pathway realized with participation of cytochrome C. PMID:19023968

  5. Hormonal contraception and lactation.

    PubMed

    Kelsey, J J

    1996-12-01

    Hormonal contraceptive measures can be used immediately postpartum if the patient so desires. Progestin-only contraceptives are preferable to estrogen-containing methods if initiated during the first six months after delivery. Progestin only contraceptives do not appear to affect milk volume, composition, or to cause deleterious effects in the infant. Ideally for women who desire a form of contraception in addition to lactation-induced amenorrhea, progestin-only methods should be started at six weeks postpartum if the woman is fully breastfeeding. Since contraception protection is provided by lactation amenorrhea, the six week delay will decrease infant exposure to exogenous hormones and decrease the incidence of irregular postpartum bleeding. Milk volume may decrease with the use of estrogen; however, no detrimental effects have been shown on infant growth or development. For women who are planning to gradually wean their infant, use of COCs may provide an easier transition to bottle-feeding. COCs should be used with caution by women who are not able to obtain supplemental milk. A decrease in milk volume can lead to earlier discontinuation of the hormonal contraceptive in an attempt to increase milk quantity. Supplementation is often needed, and then the woman ovulates again, possibly resulting in an unintended pregnancy. Many women are motivated immediately postpartum to accept contraception. For other women, lack of access to health care may provide barriers in obtaining adequate contraception later. In either case, there are adequate data to show no detriments of starting progestin-only contraceptives within days of delivery. Therefore, the best method for the patient should be employed to ensure adequate contraception while preserving optimal lactation. PMID:9025449

  6. Nonalcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis in Childhood: Endocrine-Metabolic “Mal-Programming”

    PubMed Central

    Manti, Sara; Romano, Claudio; Chirico, Valeria; Filippelli, Martina; Cuppari, Caterina; Loddo, Italia; Salpietro, Carmelo; Arrigo, Teresa

    2014-01-01

    Context: Nonalcoholic Fatty Liver Disease (NAFLD) is the major chronic liver disease in the pediatric population. NAFLD includes a broad spectrum of abnormalities (inflammation, fibrosis and cirrhosis), ranging from accumulation of fat (also known as steatosis) towards non-alcoholic steatohepatitis (NASH). The development of NAFLD in children is significantly increased. Evidence Acquisition: A literature search of electronic databases was undertaken for the major studies published from 1998 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the key words: "non-alcoholic fatty liver disease, children, non-alcoholic steatohepatitis and fatty liver". Results: NAFLD/NASH is probably promoted by “multiple parallel hits”: environmental and genetic factors, systemic immunological disorders (oxidative stress, persistent-low grade of inflammation) as well as obesity and metabolic alterations (insulin resistance and metabolic syndrome). However its exact cause still underdiagnosed and unknown. Conclusions: Pediatric NAFLD/NASH is emerging problem. Longitudinal follow-up studies, unfortunately still insufficient, are needed to better understand the natural history and outcome of NAFLD in children. This review focuses on the current knowledge regarding the epidemiology, pathogenesis, environmental, genetic and metabolic factors of disease. The review also highlights the importance of studying the underlying mechanisms of pediatric NAFLD and the need for complete and personalized approach in the management of NAFLD/NASH. PMID:24829591

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. Non-alcoholic steatohepatitis and liver transplantation.

    PubMed

    Gitto, Stefano; Vukotic, Ranka; Vitale, Giovanni; Pirillo, Martina; Villa, Erica; Andreone, Pietro

    2016-06-01

    Non-alcoholic steatohepatitis is a growing liver-related health problem. In Europe, non-alcoholic fatty liver disease is the most usual reason of chronic liver illness while steatohepatitis, its progressive form, affects 1% of Europeans and North Americans. In the United States steatohepatitis-related cirrhosis is one of the main indications for liver transplant. A targeted stratification for patients waiting for transplant and affected by this disease is mandatory especially because of their increased cardiovascular and cancer risk. The adequate treatment of NAFLD is crucial for the reduction of the disease related morbidity and mortality. In post-transplant setting, the recurrent or de novo steatosis might seriously affect the allograft short- and long-term outcome. Many conditions can represent the basis of the post-transplant steatohepatitis: obesity, hyperlipidaemia, diabetes mellitus, arterial hypertension, immunosuppressant treatment, alcoholic habit and liver graft steatosis. Today, the only consolidated therapy is represented by a deep life-style intervention since the use of drug-based alternative strategies is still limited and a very few data are available for the post-transplant period. Targeted and personalized behaviour and pharmacological interventions have to be developed for both the pre- and post-transplant phase. PMID:27038703

  16. 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

  17. 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

  18. 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

  19. 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

  20. Lactate and lactate clearance in acute cardiac care patients

    PubMed Central

    Lazzeri, Chiara; Picariello, Claudio; Dini, Carlotta Sorini; Gensini, Gian Franco; Valente, Serafina

    2012-01-01

    Hyperlactataemia is commonly used as a diagnostic and prognostic tool in intensive care settings. Recent studies documented that serial lactate measurements over time (or lactate clearance), may be clinically more reliable than lactate absolute value for risk stratification in different pathological conditions. While the negative prognostic role of hyperlactataemia in several critical ill diseases (such as sepsis and trauma) is well established, data in patients with acute cardiac conditions (i.e. acute coronary syndromes) are scarce and controversial. The present paper provides an overview of the current available evidence on the clinical role of lactic acid levels and lactate clearance in acute cardiac settings (acute coronary syndromes, cardiogenic shock, cardiac surgery), focusing on its prognostic role. PMID:24062898

  1. Migraine in pregnancy and lactation.

    PubMed

    David, Paru S; Kling, Juliana M; Starling, Amaal J

    2014-04-01

    Migraine headache is a significant health problem affecting women more than men. In women, the hormonal fluctuations seen during pregnancy and lactation can affect migraine frequency and magnitude. Understanding the evaluation of headache in pregnancy is important, especially given the increased risk of secondary headache conditions. Pregnancy and lactation can complicate treatment options for women with migraine because of the risk of certain medications to the fetus. This review includes details of the workup and then provides treatment options for migraine during pregnancy and lactation. PMID:24604057

  2. Lactate dehydrogenase-elevating virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This book chapter describes the taxonomic classification of Lactate dehydrogenase-elevating virus (LDV). Included are: host, genome, classification, morphology, physicochemical and physical properties, nucleic acid, proteins, lipids, carbohydrates, geographic range, phylogenetic properties, biologic...

  3. Lactate levels with glioblastoma multiforme.

    PubMed

    Kahlon, Arunpreet Singh; Alexander, Mariam; Kahlon, Arundeep; Wright, Jonathan

    2016-07-01

    A 37-year-old woman with known glioblastoma multiforme was admitted for treatment of new deep vein thrombosis. Anion gap and plasma lactate levels were found to be elevated. Magnetic resonance imaging of the brain showed a stable, advanced glioblastoma multiforme. All causes of lactic acidosis, including infections and medications, were ruled out. Aggressive tumors have been shown to produce lactate levels in minute quantities in their microenvironment, which helps them metastasize and evade immune response and even radiation. PMID:27365883

  4. Lactate levels with glioblastoma multiforme

    PubMed Central

    Kahlon, Arunpreet Singh; Alexander, Mariam; Kahlon, Arundeep

    2016-01-01

    A 37-year-old woman with known glioblastoma multiforme was admitted for treatment of new deep vein thrombosis. Anion gap and plasma lactate levels were found to be elevated. Magnetic resonance imaging of the brain showed a stable, advanced glioblastoma multiforme. All causes of lactic acidosis, including infections and medications, were ruled out. Aggressive tumors have been shown to produce lactate levels in minute quantities in their microenvironment, which helps them metastasize and evade immune response and even radiation. PMID:27365883

  5. Lactating Adenoma of the Breast.

    PubMed

    Barco Nebreda, Israel; Vidal, M Carmen; Fraile, Manel; Canales, Lydia; González, Clarisa; Giménez, Nuria; García-Fernández, Antonio

    2016-08-01

    Lactating adenoma is an uncommon breast palpable lesion occurring in pregnancy or lactation. Although it is a benign condition, it often requires core biopsy or even surgery to exclude malignancy. As with other solid lesions in pregnancy and lactation, lactating adenoma needs an accurate evaluation in order to ensure its benign nature. Work-up must include both imaging and histologic findings. Ultrasound evaluation remains the first step in assessing the features of the lesion. Some authors consider magnetic resonance imaging as a useful tool in cases of inconclusive evaluation after ultrasound and histologic exam in an attempt to avoid surgery. Most lactating adenomas resolve spontaneously, whereas others persist or even increase in size and must be removed. The authors present a case of a 35-year-old woman at 6 months postpartum with a lactating adenoma in her right breast. After surgical removal, breastfeeding was perfectly continued within the next 24 hours, which highlights the fact that breast surgery is most often compatible with breastfeeding. PMID:27197575

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. Sales impact of displaying alcoholic and non-alcoholic beverages in end-of-aisle locations: an observational study.

    PubMed

    Nakamura, Ryota; Pechey, Rachel; Suhrcke, Marc; Jebb, Susan A; Marteau, Theresa M

    2014-05-01

    In-store product placement is perceived to be a factor underpinning impulsive food purchasing but empirical evidence is limited. In this study we present the first in-depth estimate of the effect of end-of-aisle display on sales, focussing on alcohol. Data on store layout and product-level sales during 2010-11 were obtained for one UK grocery store, comprising detailed information on shelf space, price, price promotion and weekly sales volume in three alcohol categories (beer, wine, spirits) and three non-alcohol categories (carbonated drinks, coffee, tea). Multiple regression techniques were used to estimate the effect of end-of-aisle display on sales, controlling for price, price promotion, and the number of display locations for each product. End-of-aisle display increased sales volumes in all three alcohol categories: by 23.2% (p = 0.005) for beer, 33.6% (p < 0.001) for wine, and 46.1% (p < 0.001) for spirits, and for three non-alcohol beverage categories: by 51.7% (p < 0.001) for carbonated drinks, 73.5% (p < 0.001) for coffee, and 113.8% (p < 0.001) for tea. The effect size was equivalent to a decrease in price of between 4% and 9% per volume for alcohol categories, and a decrease in price of between 22% and 62% per volume for non-alcohol categories. End-of-aisle displays appear to have a large impact on sales of alcohol and non-alcoholic beverages. Restricting the use of aisle ends for alcohol and other less healthy products might be a promising option to encourage healthier in-store purchases, without affecting availability or cost of products. PMID:24632050

  13. 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

  14. Fructose, high fructose corn syrup, sucrose, and non-alcoholic liver disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nonalcoholic fatty liver disease (NAFLD), formerly called nonalcoholic steatohepatitis, is characterized by hepatic steatosis and abnormal triglyceride accumulation in liver cells. Its etiology, pathophysiology, and pathogenesis are still poorly understood. Some have suggested that the increased in...

  15. 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

  16. 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

  17. Lactation opposes pappalysin-1-driven pregnancy-associated breast cancer.

    PubMed

    Takabatake, Yukie; Oxvig, Claus; Nagi, Chandandeep; Adelson, Kerin; Jaffer, Shabnam; Schmidt, Hank; Keely, Patricia J; Eliceiri, Kevin W; Mandeli, John; Germain, Doris

    2016-01-01

    Pregnancy is associated with a transient increase in risk for breast cancer. However, the mechanism underlying pregnancy-associated breast cancer (PABC) is poorly understood. Here, we identify the protease pappalysin-1 (PAPP-A) as a pregnancy-dependent oncogene. Transgenic expression of PAPP-A in the mouse mammary gland during pregnancy and involution promotes the deposition of collagen. We demonstrate that collagen facilitates the proteolysis of IGFBP-4 and IGFBP-5 by PAPP-A, resulting in increased proliferative signaling during gestation and a delayed involution. However, while studying the effect of lactation, we found that although PAPP-A transgenic mice lactating for an extended period of time do not develop mammary tumors, those that lactate for a short period develop mammary tumors characterized by a tumor-associated collagen signature (TACS-3). Mechanistically, we found that the protective effect of lactation is associated with the expression of inhibitors of PAPP-A, STC1, and STC2. Collectively, these results identify PAPP-A as a pregnancy-dependent oncogene while also showing that extended lactation is protective against PAPP-A-mediated carcinogenesis. Our results offer the first mechanism that explains the link between breast cancer, pregnancy, and breastfeeding. PMID:26951623

  18. Highly efficient L-lactate production using engineered Escherichia coli with dissimilar temperature optima for L-lactate formation and cell growth

    PubMed Central

    2014-01-01

    L-Lactic acid, one of the most important chiral molecules and organic acids, is produced via pyruvate from carbohydrates in diverse microorganisms catalyzed by an NAD+-dependent L-lactate dehydrogenase. Naturally, Escherichia coli does not produce L-lactate in noticeable amounts, but can catabolize it via a dehydrogenation reaction mediated by an FMN-dependent L-lactate dehydrogenase. In aims to make the E. coli strain to produce L-lactate, three L-lactate dehydrogenase genes from different bacteria were cloned and expressed. The L-lactate producing strains, 090B1 (B0013-070, ΔldhA::diflldD::Pldh-ldhLca), 090B2 (B0013-070, ΔldhA::diflldD::Pldh-ldhStrb) and 090B3 (B0013-070, ΔldhA::diflldD::Pldh-ldhBcoa) were developed from a previously developed D-lactate over-producing strain, E. coli strain B0013-070 (ack-ptappspflBdldpoxBadhEfrdA) by: (1) deleting ldhA to block D-lactate formation, (2) deleting lldD to block the conversion of L-lactate to pyruvate, and (3) expressing an L-lactate dehydrogenase (L-LDH) to convert pyruvate to L-lactate under the control of the ldhA promoter. Fermentation tests were carried out in a shaking flask and in a 25-l bioreactor. Strains 090B1, 090B2 or 090B3 were shown to metabolize glucose to L-lactate instead of D-lactate. However, L-lactate yield and cell growth rates were significantly different among the metabolically engineered strains which can be attributed to a variation between temperature optimum for cell growth and temperature optimum for enzymatic activity of individual L-LDH. In a temperature-shifting fermentation process (cells grown at 37°C and L-lactate formed at 42°C), E. coli 090B3 was able to produce 142.2 g/l of L-lactate with no more than 1.2 g/l of by-products (mainly acetate, pyruvate and succinate) accumulated. In conclusion, the production of lactate by E. coli is limited by the competition relationship between cell growth and lactate synthesis. Enzymatic properties, especially the thermodynamics of an L

  19. Nutritional aspects of human lactation*

    PubMed Central

    Thomson, A. M.; Black, A. E.

    1975-01-01

    This paper reviews the literature on the incidence and duration of breast-feeding in various countries, the volume and composition of breast milk, the health and nutrition of breast-fed babies as judged by growth and morbidity, maternal nutritional requirements during lactation, and the effect of prolonged lactation on maternal health. It appears that lactation can be as well sustained by impoverished as by affluent mothers, and that even in communities where malnutrition is common the average growth of infants is satisfactory up to the age of about 3 months on a diet of breast milk alone. Breast milk appears to have specific anti-infective properties, but prolonged breast-feeding will not prevent infections among older infants reared in a poor environment. The authors believe that breast-feeding is the best form of nutrition for the young infant and deplore its decline in modern industrial societies. The recommendations of various FAO/WHO Expert Groups on nutritional intakes during lactation are summarized. The need for an increased daily energy intake of 4.2 MJ (1 000 kcal) is questioned, and an increase of 2.5 MJ (600 kcal) is suggested. Data on the effect of prolonged lactation on the health of the mother are scanty; body weight appears to be maintained even among poorly nourished mothers. The authors stress the need for well-planned and technically adequate studies of the material and psychological factors involved in breast feeding. PMID:816479

  20. Midtrimester abortion by ethacridine lactate.

    PubMed

    Goswami, B K; Raha, A; Gupta, A; Mukherjee, K

    1982-07-01

    This article discusses a clinical trial with the abortifacient agent ethacridine lactate as it was used for midtrimester abortion in Calcutta during the period January-July 1980. Results are then compared with intraamniotic hypertonic saline. 130 subjects were divided into 2 groups--Group 1 (60 women) were terminated with ethacridine lactate and group 2 (70 women) were terminated with saline. In cases where the patient complained of pain, analgesia was administered. In both groups, the largest concentration of women fell in the age groups 16-20 and 21-25. Similarly, single women were the largest representation in both groups although the saline group included more widows. Ethacridine lactate can be administered earlier in the 2nd trimester than saline. With it, expulsion occurred within 36 hours in 56.6% of the cases as compared with 22.9% in group 2. Both groups required the same amount of assistance with oxytocin. In group 1, there were only 3 cases (5%) of minor complications whereas in group 2, 19 cases (27.1%) developed complications. This alone strongly recommends ethacridine lactate as the preferred abortifacient. The success rate was 98%. Thus, ethacridine lactate appears to be a safe and effective agent for pregnancy termination during the 2nd trimester. PMID:7142727

  1. Lactate does not activate NF-κB in oxidative tumor cells

    PubMed Central

    Van Hée, Vincent F.; Pérez-Escuredo, Jhudit; Cacace, Andrea; Copetti, Tamara; Sonveaux, Pierre

    2015-01-01

    The lactate anion is currently emerging as an oncometabolite. Lactate, produced and exported by glycolytic and glutaminolytic cells in tumors, can be recycled as an oxidative fuel by oxidative tumors cells. Independently of hypoxia, it can also activate transcription factor hypoxia-inducible factor-1 (HIF-1) in tumor and endothelial cells, promoting angiogenesis. These protumoral activities of lactate depend on lactate uptake, a process primarily facilitated by the inward, passive lactate-proton symporter monocarboxylate transporter 1 (MCT1); the conversion of lactate and NAD+ to pyruvate, NADH and H+ by lactate dehydrogenase-1 (LDH-1); and a competition between pyruvate and α-ketoglutarate that inhibits prolylhydroxylases (PHDs). Endothelial cells do not primarily use lactate as an oxidative fuel but, rather, as a signaling agent. In addition to HIF-1, lactate can indeed activate transcription factor nuclear factor-κB (NF-κB) in these cells, through a mechanism not only depending on PHD inhibition but also on NADH alimenting NAD(P)H oxidases to generate reactive oxygen species (ROS). While NF-κB activity in endothelial cells promotes angiogenesis, NF-κB activation in tumor cells is known to stimulate tumor progression by conferring resistance to apoptosis, stemness, pro-angiogenic and metastatic capabilities. In this study, we therefore tested whether exogenous lactate could activate NF-κB in oxidative tumor cells equipped for lactate signaling. We report that, precisely because they are oxidative, HeLa and SiHa human tumor cells do not activate NF-κB in response to lactate. Indeed, while lactate-derived pyruvate is well-known to inhibit PHDs in these cells, we found that NADH aliments oxidative phosphorylation (OXPHOS) in mitochondria rather than NAD(P)H oxidases in the cytosol. These data were confirmed using oxidative human Cal27 and MCF7 tumor cells. This new information positions the malate-aspartate shuttle as a key player in the oxidative metabolism

  2. 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

  3. Antipsychotics in pregnancy and lactation

    PubMed Central

    Babu, Girish N.; Desai, Geetha; Chandra, Prabha S.

    2015-01-01

    Research on psychotropic medications during pregnancy and lactation is limited as often involves complex ethical issues. Information on safety of psychotropic drugs during these critical phases is either inconclusive or undetermined. Many women with severe mental illness have unplanned pregnancies and require antipsychotic medication during pregnancy and lactation. Multiple issues have to be considered while choosing safe treatments for pregnant and lactating women and the best approach is to individualize the treatment. Medication should be guided primarily by its safety data and by the psychiatric history of the patient. Important issues to be kept in mind include pre-pregnancy counseling for all women, including planning pregnancies; folate supplementation, discussion with patient and family regarding options, and active liaison with obstetricians, ultrasonologists and pediatricians. Whenever possible, non-pharmacological approaches should be used in addition. PMID:26330648

  4. Lactational infertility in family planning.

    PubMed

    Short, R V

    1993-04-01

    The contraceptive effect of breast-feeding is the single most important determinant of human population growth rates in traditional societies without access to modern forms of contraception; lactational amenorrhoea is Nature's contraceptive. Even today, breast-feeding still prevents more pregnancies than all modern forms of contraception in many developing countries. Afferent neural inputs from the nipple pass via the spinal cord to the hypothalamus, where they cause a local release of beta endorphin. This acts to depress GnRH secretion, thereby inhibiting pituitary gonadotrophin secretion, ovarian follicular development, ovulation and menstruation. The hypothalamic beta endorphin release also inhibits dopamine production, resulting in increased pituitary prolactin secretion. The higher the suckling frequency, the more beta endorphin that is released and hence the longer the duration of lactational amenorrhoea. Lactational amenorrhoea can be relied up to give over 98% contraceptive protection to breast-feeding women in the first 6 months postpartum, regardless of their nutritional status or the time of first supplement introduction to the baby. This is because the first postpartum menstruation usually precedes the first ovulation during these early months. Once menstruation has resumed, lactation's contraceptive effect can no longer be relied upon, even though the woman continues to breast-feed. In breast-feeding women whose amenorrhoea extends beyond 6 months, there is an increasing tendency for the first ovulation to precede the first menstruation, thereby decreasing the reliability of lactational amenorrhoea as a contraceptive. Nevertheless, many women who continue to breast-feed may still have up to 1-2 years of good contraceptive protection from prolonged lactational amenorrhoea.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8489757

  5. Catabolism of Exogenous Lactate Reveals It as a Legitimate Metabolic Substrate in Breast Cancer

    PubMed Central

    Kennedy, Kelly M.; Scarbrough, Peter M.; Ribeiro, Anthony; Richardson, Rachel; Yuan, Hong; Sonveaux, Pierre; Landon, Chelsea D.; Chi, Jen-Tsan; Pizzo, Salvatore

    2013-01-01

    Lactate accumulation in tumors has been associated with metastases and poor overall survival in cancer patients. Lactate promotes angiogenesis and metastasis, providing rationale for understanding how it is processed by cells. The concentration of lactate in tumors is a balance between the amount produced, amount carried away by vasculature and if/how it is catabolized by aerobic tumor or stromal cells. We examined lactate metabolism in human normal and breast tumor cell lines and rat breast cancer: 1. at relevant concentrations, 2. under aerobic vs. hypoxic conditions, 3. under conditions of normo vs. hypoglucosis. We also compared the avidity of tumors for lactate vs. glucose and identified key lactate catabolites to reveal how breast cancer cells process it. Lactate was non-toxic at clinically relevant concentrations. It was taken up and catabolized to alanine and glutamate by all cell lines. Kinetic uptake rates of lactate in vivo surpassed that of glucose in R3230Ac mammary carcinomas. The uptake appeared specific to aerobic tumor regions, consistent with the proposed “metabolic symbiont” model; here lactate produced by hypoxic cells is used by aerobic cells. We investigated whether treatment with alpha-cyano-4-hydroxycinnamate (CHC), a MCT1 inhibitor, would kill cells in the presence of high lactate. Both 0.1 mM and 5 mM CHC prevented lactate uptake in R3230Ac cells at lactate concentrations at ≤20 mM but not at 40 mM. 0.1 mM CHC was well-tolerated by R3230Ac and MCF7 cells, but 5 mM CHC killed both cell lines ± lactate, indicating off-target effects. This study showed that breast cancer cells tolerate and use lactate at clinically relevant concentrations in vitro (± glucose) and in vivo. We provided additional support for the metabolic symbiont model and discovered that breast cells prevailingly take up and catabolize lactate, providing rationale for future studies on manipulation of lactate catabolism pathways for therapy. PMID:24069390

  6. 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

  7. 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

  8. 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

  9. Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis

    PubMed Central

    Katayama, Akihiro; Nakatsuka, Atsuko; Eguchi, Jun; Murakami, Kazutoshi; Teshigawara, Sanae; Kanzaki, Motoko; Nunoue, Tomokazu; Hida, Kazuyuki; Wada, Nozomu; Yasunaka, Tetsuya; Ikeda, Fusao; Takaki, Akinobu; Yamamoto, Kazuhide; Kiyonari, Hiroshi; Makino, Hirofumi; Wada, Jun

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity. PMID:26581806

  10. 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

  11. 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

  12. 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

  13. Endocrine causes of nonalcoholic fatty liver disease

    PubMed Central

    Marino, Laura; Jornayvaz, François R

    2015-01-01

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

  14. Nonalcoholic Lipid Accumulation and Hepatocyte Malignant Transformation.

    PubMed

    Gu, Juanjuan; Yao, Min; Yao, Dengbing; Wang, Li; Yang, Xuli; Yao, Dengfu

    2016-06-28

    Worldwide incidence of hepatocellular carcinoma (HCC) is steadily increasing, highlighting its status as a public health concern, particularly due to its significant association with other comorbidities, such as diabetes. However, nonalcoholic fatty liver disease (NAFLD) has emerged as a primary risk factor, with its own prevalence increasing in recent years, and it has gradually caught up with the historical primary etiological factors of infection with hepatitis B virus and hepatitis C virus, exposure to aflatoxin, or alcohol liver disease. The deeply worrisome aspects of all of these high risk factors, however, are their remarkable presence within populations. Systemic and genetic mechanisms involved in the malignant transformation of liver cells, as well as useful biomarkers of early stage HCC are being investigated. However, the exact mechanisms underlying the interrelation of NAFLD and HCC remain largely unknown. In this review, some of the recent advances in our understanding of liver lipid accumulation are summarized and discussed to provide insights into the relationship between NAFLD and hepatocyte malignant transformation. PMID:27350942

  15. Nonalcoholic Lipid Accumulation and Hepatocyte Malignant Transformation

    PubMed Central

    Gu, Juanjuan; Yao, Min; Yao, Dengbing; Wang, Li; Yang, Xuli; Yao, Dengfu

    2016-01-01

    Abstract Worldwide incidence of hepatocellular carcinoma (HCC) is steadily increasing, highlighting its status as a public health concern, particularly due to its significant association with other comorbidities, such as diabetes. However, nonalcoholic fatty liver disease (NAFLD) has emerged as a primary risk factor, with its own prevalence increasing in recent years, and it has gradually caught up with the historical primary etiological factors of infection with hepatitis B virus and hepatitis C virus, exposure to aflatoxin, or alcohol liver disease. The deeply worrisome aspects of all of these high risk factors, however, are their remarkable presence within populations. Systemic and genetic mechanisms involved in the malignant transformation of liver cells, as well as useful biomarkers of early stage HCC are being investigated. However, the exact mechanisms underlying the interrelation of NAFLD and HCC remain largely unknown. In this review, some of the recent advances in our understanding of liver lipid accumulation are summarized and discussed to provide insights into the relationship between NAFLD and hepatocyte malignant transformation. PMID:27350942

  16. 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

  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. [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

  19. 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

  20. 21 CFR 582.5311 - Ferrous lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5311 Ferrous lactate. (a) Product. Ferrous lactate. (b) Conditions of use. This...

  1. 21 CFR 184.1311 - Ferrous lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... prepared by reacting calcium lactate or sodium lactate with ferrous sulfate, direct reaction of lactic acid.... (1996), pp. 154 to 155, which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1...

  2. 21 CFR 184.1311 - Ferrous lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... reacting calcium lactate or sodium lactate with ferrous sulfate, direct reaction of lactic acid with iron... to 155, which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part...

  3. Is lactation nature's contraceptive? Data from Samoa.

    PubMed

    Fitzgerald, M H

    1992-01-01

    Data from a Samoan menstruation study suggest that lactation, even intensive on-demand lactation, does not inhibit menstruation or conception. This paper explores the applied and theoretical implications of continuing to accept lactation as a universally effective fertility control mechanism. Such thinking can have disastrous implications for family planning programs, and it keeps us from challenging long-held assumptions about lactation's role in population growth in early populations. PMID:1514124

  4. Expression of Lactate Dehydrogenase in Aspergillus niger for L-Lactic Acid Production

    PubMed Central

    Dave, Khyati K.; Punekar, Narayan S.

    2015-01-01

    Different engineered organisms have been used to produce L-lactate. Poor yields of lactate at low pH and expensive downstream processing remain as bottlenecks. Aspergillus niger is a prolific citrate producer and a remarkably acid tolerant fungus. Neither a functional lactate dehydrogenase (LDH) from nor lactate production by A. niger is reported. Its genome was also investigated for the presence of a functional ldh. The endogenous A. niger citrate synthase promoter relevant to A. niger acidogenic metabolism was employed to drive constitutive expression of mouse lactate dehydrogenase (mldhA). An appraisal of different branches of the A. niger pyruvate node guided the choice of mldhA for heterologous expression. A high copy number transformant C12 strain, displaying highest LDH specific activity, was analyzed under different growth conditions. The C12 strain produced 7.7 g/l of extracellular L-lactate from 60 g/l of glucose, in non-neutralizing minimal media. Significantly, lactate and citrate accumulated under two different growth conditions. Already an established acidogenic platform, A. niger now promises to be a valuable host for lactate production. PMID:26683313

  5. 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

  6. [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

  7. 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

  8. The origin and evolution of lactation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The presence of mammary glands are the defining morphological feature of mammals, and a successful lactation is crucial to mammalian reproductive strategies. Among mammalian species, the nature of lactation and the composition of milk vary greatly. The evolution of lactation and its diversity amon...

  9. 21 CFR 582.1207 - Calcium lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Calcium lactate. 582.1207 Section 582.1207 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Additives § 582.1207 Calcium lactate. (a) Product. Calcium lactate. (b) Conditions of use. This substance...

  10. 200th anniversary of lactate research in muscle.

    PubMed

    Gladden, L Bruce

    2008-07-01

    This year, 2008, marks the bicentennial of research into lactate metabolism in muscle. Berzelius linked lactate accumulation to exercise in 1807/1808 when he noted the presence of lactate in the muscles of "hunted stags." Today, the exact mechanism of intramuscular lactate oxidation and the relationship of lactate dehydrogenase to mitochondria remain unresolved as animated debate surrounds the intracellular lactate shuttle. PMID:18580290

  11. 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

  12. Point of Care Measurement of Lactate.

    PubMed

    Di Mauro, Francesca Miranda; Schoeffler, Gretchen Lee

    2016-03-01

    Lactate is generated as a consequence of anaerobic glycolysis by all tissues of the body. Increased l-lactate, the isoform produced by most mammals, reflects increased anaerobic metabolism secondary to tissue hypoperfusion or tissue hypoxia in most clinical situations, and is called type A lactic acidosis. The utility of lactate measurement and serial lactate monitoring in veterinary patients has been demonstrated in multiple studies. Blood lactate concentration is significantly elevated in many disease processes including septic peritonitis, immune-mediated hemolytic anemia, Babesiosis, trauma, gastric dilation and volvulus, and intracranial disease. Lactate clearance can be used to assess response to fluid therapy, cardiovascular therapeutics, and blood product transfusion in patients affected by type A lactic acidosis. Lactate concentration in peritoneal, pericardial, and synovial fluid can also be used as a diagnostic tool. Point of care analyzers such as the Lactate Pro, Lactate Scout, Accutrend, iSTAT, and Lactate Plus have been shown to be accurate lactate measurement instruments in small animal patients. PMID:27451047

  13. Attribution of Blame for Wife Abuse by Alcoholics and Nonalcoholics.

    ERIC Educational Resources Information Center

    Carducci, Bernardo J.; McNeely, Judith A.

    Several researchers have explored the role of alcohol in domestic violence and attributions of blame. To compare the amount of blame attributed to an incident of wife abuse, alcoholic (N=52) and nonalcoholic (N=159) subjects read an account of wife abuse and distributed a percentage of the blame to the man, the woman, and the situation.…

  14. Dimensions of Functioning in Alcoholic and Nonalcoholic Families.

    ERIC Educational Resources Information Center

    Johnson, Patrick

    2001-01-01

    Examines various dimensions of functioning in alcoholic and nonalcoholic families. Participants were 813 college students who completed a standardized measure of family functioning, demographic questions, and questions related to experiences in their families of origin. Results indicate that children raised in alcoholic families tend to experience…

  15. 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

  16. Inflammatory mediators in mastitis and lactation insufficiency.

    PubMed

    Ingman, Wendy V; Glynn, Danielle J; Hutchinson, Mark R

    2014-07-01

    Mastitis is a common inflammatory disease during lactation that causes reduced milk supply. A growing body of evidence challenges the central role of pathogenic bacteria in mastitis, with disease severity associated with markers of inflammation rather than infection. Inflammation in the mammary gland may be triggered by microbe-associated molecular patterns (MAMPs) as well as danger-associated molecular patterns (DAMPs) binding to pattern recognition receptors such as the toll-like receptors (TLRs) on the surface of mammary epithelial cells and local immune cell populations. Activation of the TLR4 signalling pathway and downstream nuclear factor kappa B (NFkB) is critical to mediating local mammary gland inflammation and systemic immune responses in mouse models of mastitis. However, activation of NFkB also induces epithelial cell apoptosis and reduced milk protein synthesis, suggesting that inflammatory mediators activated during mastitis promote partial involution. Perturbed milk flow, maternal stress and genetic predisposition are significant risk factors for mastitis, and could lead to a heightened TLR4-mediated inflammatory response, resulting in increased susceptibility and severity of mastitis disease in the context of low MAMP abundance. Therefore, heightened host inflammatory signalling may act in concert with pathogenic or commensal bacterial species to cause both the inflammation associated with mastitis and lactation insufficiency. Here, we present an alternate paradigm to the widely held notion that breast inflammation is driven principally by infectious bacterial pathogens, and suggest there may be other therapeutic strategies, apart from the currently utilised antimicrobial agents, that could be employed to prevent and treat mastitis in women. PMID:24961655

  17. Alcoholic and non-alcoholic steatohepatitis.

    PubMed

    Neuman, Manuela G; French, Samuel W; French, Barbara A; Seitz, Helmut K; Cohen, Lawrence B; Mueller, Sebastian; Osna, Natalia A; Kharbanda, Kusum K; Seth, Devanshi; Bautista, Abraham; Thompson, Kyle J; McKillop, Iain H; Kirpich, Irina A; McClain, Craig J; Bataller, Ramon; Nanau, Radu M; Voiculescu, Mihai; Opris, Mihai; Shen, Hong; Tillman, Brittany; Li, Jun; Liu, Hui; Thomes, Paul G; Ganesan, Murali; Malnick, Steve

    2014-12-01

    This paper is based upon the "Charles Lieber Satellite Symposia" organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human immunodeficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible

  18. Alcoholic and non-alcoholic steatohepatitis

    PubMed Central

    Neuman, Manuela G.; French, Samuel W.; French, Barbara A.; Seitz, Helmut K.; Cohen, Lawrence B.; Mueller, Sebastian; Osna, Natalia A.; Kharbanda, Kusum K.; Seth, Devanshi; Bautista, Abraham; Thompson, Kyle J.; McKillop, Iain H.; Kirpich, Irina A.; McClain, Craig J.; Bataller, Ramon; Nanau, Radu M.; Voiculescu, Mihai; Opris, Mihai; Shen, Hong; Tillman, Brittany; Li, Jun; Liu, Hui; Thomas, Paul G.; Ganesan, Murali; Malnick, Steve

    2015-01-01

    This paper is based upon the “Charles Lieber Satellite Symposia” organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its comorbidities with chronic viral hepatitis in the presence or absence of human deficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible

  19. Lactate metabolism by pediococci isolated from cheese.

    PubMed

    Thomas, T D; McKay, L L; Morris, H A

    1985-04-01

    Pediococcus pentosaceus is commonly found among the adventitious microflora of Cheddar cheese. When this organism was incubated with L-(+)-lactate under anaerobic conditions, L-(+)-lactate was rapidly converted to D-(-)-lactate until racemic (DL) lactate was present. Under aerobic conditions this initial reaction was followed by a slower reaction resulting in the use of both lactate isomers and in the production of acetate and CO2. With intact cells the lactate oxidation system had an optimum pH of 5 to 6, depending on the initial lactate concentration. Cells grown anaerobically possessed lactate-oxidizing activity which increased two- to fourfold as sugar was exhausted from the medium. Aerobic growth further increased specific activities. Cheddar cheese was made with the deliberate addition of P. pentosaceus. When the resulting cheese was grated to expose a large surface area to O2, lactate was converted to acetate at a rate which depended on the density of pediococci in the cheese. The lactate oxidation system remained active in cheese which had been ripened for 6 months. PMID:4004222

  20. Lactate metabolism in the fetal rabbit lung

    SciTech Connect

    Engle, M.J.; Brown, D.J.; Dooley, M.

    1986-05-01

    Lactate is frequently overlooked as a potential substrate for the fetal lung, even though it is present in the fetal circulation in concentrations as high as 8 mM. These high concentrations, coupled with the relatively low levels of glucose in the fetal blood, may indicate that lactate can substitute for glucose in pulmonary energy generation and phospholipid synthesis. A series of experiments was therefore undertaken in order to investigate the role of lactate in perinatal pulmonary development. Explants from 30 day gestation fetal rabbit lungs were incubated in Krebs-Ringer bicarbonate buffer supplemented with 3 mM (U-/sup 14/C)-glucose and varying levels of lactate. In the absence of medium lactate, fetal rabbit lung explants were capable of producing lactate at a rate of approximately 200 etamoles/mg protein/hour. The addition of lactate to the bathing medium immediately reduced net lactate production and above 4 mM, fetal rabbit lung explants became net utilizers of lactate. Media lactate concentrations of 2.5 mM, 5 mM and 10 mM also decreased glucose incorporation into total tissue disaturated phosphatidylcholine by approximately 20%, 35%, and 45%, respectively. Glucose incorporation into surfactant phosphatidylcholine was also reduced by approximately 50%, when lactate was present in the incubation medium at a concentration of 5 mM. Additional experiments also revealed that fetal lung lactate dehydrogenase activity was almost twice that found in the adult rabbit lung. These data indicate that lactate may be an important carbon source for the developing lung and could be a significant component in the manufacture of surfactant phosphatidylcholine during late gestation.

  1. [The role of lactate besides the lactic acidosis].

    PubMed

    Brucculeri, S; Urso, C; Caimi, G

    2013-01-01

    Lactic acidosis (LA) is the most common form of metabolic acidosis defined by values of lactate greater than 5 mmol / l and by a pH <7.34. The pathogenesis of LA involves hypoxic (type A) and non hypoxic (type B) causes which are often coexisting. Lactic acidosis is usual in hospitalized population especially in subjects in intensive care units, in which lactate levels on admission could be predictors of mortality even in the absence of organ dysfunction or shock. The outcome is mainly dependent on the cardiovascular effects of acidosis. In subjects with cardiogenic shock, the increased lactate/pyruvate ratio, detectable at onset, is correladed with mortality. An early assessment of blood and tissue lactate levels could play a role in the therapeutic management as well as in outcome. LA could be a unfavorable prognostic factor in cancer. The lactate would act also as "signal molecule" and as a promoting factor in angiogenesis and tumor progression. In the presence of risk factors for LA the role of metformin may be overrated. Despite the doctrinal progress to understand the pathogenesis and pathophysiology, there is not univocal consensus on the therapeutic treatment of LA. The identification and the attempt to remove the cause of acidosis are main aims; treatment with sodium bicarbonate is a matter of debate as the data on the cardiovascular effects and mortality are unclear. The therapy with carbicarb, dichloroacetate or THAM has shown no specific advantages in terms of mortality. In experimental models of LA and shock the use of sodium-hydrogen exchanger-1 (NHE1) selective inhibitors reduces cell damage and inflammatory cytokines synthesis; it also improves cardiac performance and decreases mortality. PMID:23868642

  2. Prevention of acute/severe hypoglycemia-induced neuron death by lactate administration.

    PubMed

    Won, Seok Joon; Jang, Bong Geom; Yoo, Byung Hoon; Sohn, Min; Lee, Min Woo; Choi, Bo Young; Kim, Jin Hee; Song, Hong Ki; Suh, Sang Won

    2012-06-01

    Hypoglycemia-induced cerebral neuropathy can occur in patients with diabetes who attempt tight control of blood glucose and may lead to cognitive dysfunction. Accumulating evidence from animal models suggests that hypoglycemia-induced neuronal death is not a simple result of glucose deprivation, but is instead the end result of a multifactorial process. In particular, the excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) consumes cytosolic nicotinamide adenine dinucleotide (NAD(+)), resulting in energy failure. In this study, we investigate whether lactate administration in the absence of cytosolic NAD(+) affords neuroprotection against hypoglycemia-induced neuronal death. Intraperitoneal injection of sodium L-lactate corrected arterial blood pH and blood lactate concentration after hypoglycemia. Lactate administered without glucose was not sufficient to promote electroencephalogram recovery from an isoelectric state during hypoglycemia. However, supplementation of glucose with lactate reduced neuronal death by ∼80% in the hippocampus. Hypoglycemia-induced superoxide production and microglia activation was also substantially reduced by administration of lactate. Taken together, these results suggest an intriguing possibility: that increasing brain lactate following hypoglycemia offsets the decrease in NAD(+) due to overactivation of PARP-1 by acting as an alternative energy substrate that can effectively bypass glycolysis and be fed directly to the citric acid cycle to maintain cellular ATP levels. PMID:22453629

  3. Exogenous lactate supply affects lactate kinetics of rainbow trout, not swimming performance

    PubMed Central

    Omlin, Teye; Langevin, Karolanne

    2014-01-01

    Intense swimming causes circulatory lactate accumulation in rainbow trout because lactate disposal (Rd) is not stimulated as strongly as lactate appearance (Ra). This mismatch suggests that maximal Rd is limited by tissue capacity to metabolize lactate. This study uses exogenous lactate to investigate what constrains maximal Rd and minimal Ra. Our goals were to determine how exogenous lactate affects: 1) Ra and Rd of lactate under baseline conditions or during graded swimming, and 2) exercise performance (critical swimming speed, Ucrit) and energetics (cost of transport, COT). Results show that exogenous lactate allows swimming trout to boost maximal Rd lactate by 40% and reach impressive rates of 56 μmol·kg−1·min−1. This shows that the metabolic capacity of tissues for lactate disposal is not responsible for setting the highest Rd normally observed after intense swimming. Baseline endogenous Ra (resting in normoxic water) is not significantly reduced by exogenous lactate supply. Therefore, trout have an obligatory need to produce lactate, either as a fuel for oxidative tissues and/or from organs relying on glycolysis. Exogenous lactate does not affect Ucrit or COT, probably because it acts as a substitute for glucose and lipids rather than extra fuel. We conclude that the observed 40% increase in Rd lactate is made possible by accelerating lactate entry into oxidative tissues via monocarboxylate transporters (MCTs). This observation together with the weak expression of MCTs and the phenomenon of white muscle lactate retention show that lactate metabolism of rainbow trout is significantly constrained by transmembrane transport. PMID:25121611

  4. 21 CFR 184.1207 - Calcium lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Calcium lactate. 184.1207 Section 184.1207 Food... GRAS § 184.1207 Calcium lactate. (a) Calcium lactate (C6H10CaO6.xH2O, where x is any integer up to 5, CAS Reg. No. 814-80-2) is prepared commercially by the neutralization of lactic acid with...

  5. 21 CFR 184.1207 - Calcium lactate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Calcium lactate. 184.1207 Section 184.1207 Food... Specific Substances Affirmed as GRAS § 184.1207 Calcium lactate. (a) Calcium lactate (C6H10CaO6.xH2O, where... lactic acid with calcium carbonate or calcium hydroxide. (b) The ingredient meets the specifications...

  6. 21 CFR 184.1207 - Calcium lactate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Calcium lactate. 184.1207 Section 184.1207 Food... Specific Substances Affirmed as GRAS § 184.1207 Calcium lactate. (a) Calcium lactate (C6H10CaO6.xH2O, where... lactic acid with calcium carbonate or calcium hydroxide. (b) The ingredient meets the specifications...

  7. 21 CFR 184.1207 - Calcium lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Calcium lactate. 184.1207 Section 184.1207 Food and... Substances Affirmed as GRAS § 184.1207 Calcium lactate. (a) Calcium lactate (C6H10CaO6.xH2O, where x is any... calcium carbonate or calcium hydroxide. (b) The ingredient meets the specifications of the Food...

  8. 21 CFR 184.1639 - Potassium lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Potassium lactate. 184.1639 Section 184.1639 Food... Specific Substances Affirmed as GRAS § 184.1639 Potassium lactate. (a) Potassium lactate (C3H5O3K, CAS Reg. No. 996-31-6) is the potassium salt of lactic acid. It is a hydroscopic, white, odorless solid and...

  9. 21 CFR 184.1639 - Potassium lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Potassium lactate. 184.1639 Section 184.1639 Food... GRAS § 184.1639 Potassium lactate. (a) Potassium lactate (C3H5O3K, CAS Reg. No. 996-31-6) is the potassium salt of lactic acid. It is a hydroscopic, white, odorless solid and is prepared commercially...

  10. 21 CFR 184.1639 - Potassium lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Potassium lactate. 184.1639 Section 184.1639 Food... Specific Substances Affirmed as GRAS § 184.1639 Potassium lactate. (a) Potassium lactate (C3H5O3K, CAS Reg. No. 996-31-6) is the potassium salt of lactic acid. It is a hydroscopic, white, odorless solid and...

  11. 21 CFR 184.1639 - Potassium lactate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Potassium lactate. 184.1639 Section 184.1639 Food... Specific Substances Affirmed as GRAS § 184.1639 Potassium lactate. (a) Potassium lactate (C3H5O3K, CAS Reg. No. 996-31-6) is the potassium salt of lactic acid. It is a hydroscopic, white, odorless solid and...

  12. 21 CFR 184.1639 - Potassium lactate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Potassium lactate. 184.1639 Section 184.1639 Food... Specific Substances Affirmed as GRAS § 184.1639 Potassium lactate. (a) Potassium lactate (C3H5O3K, CAS Reg. No. 996-31-6) is the potassium salt of lactic acid. It is a hydroscopic, white, odorless solid and...

  13. Cerebral Lactate Metabolism After Traumatic Brain Injury.

    PubMed

    Patet, Camille; Suys, Tamarah; Carteron, Laurent; Oddo, Mauro

    2016-04-01

    Cerebral energy dysfunction has emerged as an important determinant of prognosis following traumatic brain injury (TBI). A number of studies using cerebral microdialysis, positron emission tomography, and jugular bulb oximetry to explore cerebral metabolism in patients with TBI have demonstrated a critical decrease in the availability of the main energy substrate of brain cells (i.e., glucose). Energy dysfunction induces adaptations of cerebral metabolism that include the utilization of alternative energy resources that the brain constitutively has, such as lactate. Two decades of experimental and human investigations have convincingly shown that lactate stands as a major actor of cerebral metabolism. Glutamate-induced activation of glycolysis stimulates lactate production from glucose in astrocytes, with subsequent lactate transfer to neurons (astrocyte-neuron lactate shuttle). Lactate is not only used as an extra energy substrate but also acts as a signaling molecule and regulator of systemic and brain glucose use in the cerebral circulation. In animal models of brain injury (e.g., TBI, stroke), supplementation with exogenous lactate exerts significant neuroprotection. Here, we summarize the main clinical studies showing the pivotal role of lactate and cerebral lactate metabolism after TBI. We also review pilot interventional studies that examined exogenous lactate supplementation in patients with TBI and found hypertonic lactate infusions had several beneficial properties on the injured brain, including decrease of brain edema, improvement of neuroenergetics via a "cerebral glucose-sparing effect," and increase of cerebral blood flow. Hypertonic lactate represents a promising area of therapeutic investigation; however, larger studies are needed to further examine mechanisms of action and impact on outcome. PMID:26898683

  14. 21 CFR 184.1768 - Sodium lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Sodium lactate. 184.1768 Section 184.1768 Food and... Substances Affirmed as GRAS § 184.1768 Sodium lactate. (a) Sodium lactate (C3H5O3Na, CAS Reg. No. 72-17-3) is the sodium salt of lactic acid. It is prepared commercially by the neutralization of lactic acid...

  15. 21 CFR 184.1768 - Sodium lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Sodium lactate. 184.1768 Section 184.1768 Food and... Substances Affirmed as GRAS § 184.1768 Sodium lactate. (a) Sodium lactate (C3H5O3Na, CAS Reg. No. 72-17-3) is the sodium salt of lactic acid. It is prepared commercially by the neutralization of lactic acid...

  16. 21 CFR 184.1768 - Sodium lactate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Sodium lactate. 184.1768 Section 184.1768 Food and... Substances Affirmed as GRAS § 184.1768 Sodium lactate. (a) Sodium lactate (C3H5O3Na, CAS Reg. No. 72-17-3) is the sodium salt of lactic acid. It is prepared commercially by the neutralization of lactic acid...

  17. 21 CFR 184.1768 - Sodium lactate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Sodium lactate. 184.1768 Section 184.1768 Food and... Substances Affirmed as GRAS § 184.1768 Sodium lactate. (a) Sodium lactate (C3H5O3Na, CAS Reg. No. 72-17-3) is the sodium salt of lactic acid. It is prepared commercially by the neutralization of lactic acid...

  18. 21 CFR 184.1207 - Calcium lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... lactic acid with calcium carbonate or calcium hydroxide. (b) The ingredient meets the specifications of... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Calcium lactate. 184.1207 Section 184.1207 Food... Specific Substances Affirmed as GRAS § 184.1207 Calcium lactate. (a) Calcium lactate (C6H10CaO6.xH2O,...

  19. 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

  20. Lactation amenorrhea in Saudi women.

    PubMed Central

    Madani, K A; Khashoggi, R H; al-Nowaisser, A A; Nasrat, H A; Khalil, M H

    1994-01-01

    STUDY OBJECTIVE--The study aimed to investigate some aspects of breast feeding, namely-lactation amenorrhea, the average interval between pregnancies, and the extent of knowledge that an average Saudi woman has about breast feeding. DESIGN--This was a cross sectional study in which a pretested questionnaire was used to collect the information. SETTING--The study was conducted in the Taif area between January and April of 1990. Seventy nine primary health care centres participated. PARTICIPANTS--Altogether 1019 of 2400 women contacted who agreed to participate and met the criteria were studied. Eligible subjects were defined as Saudi women, between 16 and 40 years old, who came with their infants for vaccination, and had delivered between one week and 12 months previously. Each mother had at least one other child. MEASUREMENT AND MAIN RESULT--At birth, the percentage of infants who were initially breast fed was 98% but within three days of delivery over two thirds (68.9%) of the mothers gave other supplementary liquids to their infants. At the time of interview more than half (55.1%) of mothers had lactation amenorrhea. The mean (SD) lactation amenorrhea period and birth interval were 5.95 (5) and 26.8 (14.1) months, respectively. Mothers obtained information on breast feeding mainly from their doctors and television. Within families, husbands had the primary role in encouraging their wives to breast feed, followed by the mother and then by the mother in law. It was found that a high percentage (94.2%) of women had breast fed their previous child. CONCLUSION--The lack of adequate information on breast feeding and the short interval between births are local problems which should be considered by the health authorities. PMID:8051529

  1. Hemichannel-mediated release of lactate.

    PubMed

    Karagiannis, Anastassios; Sylantyev, Sergiy; Hadjihambi, Anna; Hosford, Patrick S; Kasparov, Sergey; Gourine, Alexander V

    2016-07-01

    In the central nervous system lactate contributes to the extracellular pool of readily available energy substrates and may also function as a signaling molecule which mediates communication between glial cells and neurons. Monocarboxylate transporters are believed to provide the main pathway for lactate transport across the membranes. Here we tested the hypothesis that lactate could also be released via opening of pannexin and/or functional connexin hemichannels. In acute slices prepared from the brainstem, hippocampus, hypothalamus and cortex of adult rats, enzymatic amperometric biosensors detected significant tonic lactate release inhibited by compounds, which block pannexin/connexin hemichannels and facilitated by lowering extracellular [Ca(2+)] or increased PCO2 Enhanced lactate release triggered by hypoxia was reduced by ∼50% by either connexin or monocarboxylate transporter blockers. Stimulation of Schaffer collateral fibers triggered lactate release in CA1 area of the hippocampus, which was facilitated in conditions of low extracellular [Ca(2+)], markedly reduced by blockade of connexin hemichannels and abolished by lactate dehydrogenase inhibitor oxamate. These results indicate that lactate transport across the membranes may occur via mechanisms other than monocarboxylate transporters. In the central nervous system, hemichannels may function as a conduit of lactate release, and this mechanism is recruited during hypoxia and periods of enhanced neuronal activity. PMID:26661210

  2. A20 Attenuates FFAs-induced Lipid Accumulation in Nonalcoholic Steatohepatitis

    PubMed Central

    Ai, Luoyan; Xu, Qingqing; Wu, Changwei; Wang, Xiaohan; Chen, Zhiwei; Su, Dazhi; Jiang, Xiaoke; Xu, Antao; Lin, Qing; Fan, Zhuping

    2015-01-01

    A20 is a ubiquitin-editing enzyme that attenuates the activity of proximal signaling complexes at pro-inflammatory receptors. It has been well documented that A20 protein plays an important role in response to liver injury and hepatocytes apoptosis in pro-inflammatory pathways. However, there was little evidence showing that A20 protein was involving in fatty-acid homeostasis except the up-regulation of two fatty acid metabolism regulatory genes at mRNA level (PPARa and CPT1a) by adenovirus-mediated A20 protein overexpression. In this study we found that: 1) the expression level of A20 protein was significantly higher in the steatotic liver from MCD-fed mice than the controls; 2) Overexpression of A20 protein suppressed FFAs-stimulated triglyceride deposition in HepG2 cells while under expression of A20 protein increased FFAs-stimulated triglyceride deposition; 3) Overexpression of A20 protein in HepG2 cells upregulated genes that promote β-oxidation and decreased the mRNA levels of key lipogenic genes such as fatty acid synthase (FAS), indicating A20 function as anti-steatotic factor by the activation of mitochondrial β-oxidation and attenuation of de novo lipogenesis; 4) Nonalcoholic steatohepatitis (NASH) patients showed significantly higher A20 expression level in liver compared with control individuals. Our results demonstrated that A20 protein plays an important role in fatty-acid homeostasis in human as well as animals. In addition, our data suggested that the pathological function of A20 protein in hepatocyte from lipotoxicity to NASH is by the alleviation of triglyceride accumulation in hepatocytes. Elevated expression of A20 protein could be a potential therapeutic strategy for preventing the progression of nonalcoholic steatohepatitis. PMID:26681923

  3. CXCR4 dysfunction in non-alcoholic steatohepatitis in mice and patients.

    PubMed

    Boujedidi, Hédia; Robert, Olivier; Bignon, Alexandre; Cassard-Doulcier, Anne-Marie; Renoud, Marie-Laure; Gary-Gouy, Hélène; Hemon, Patrice; Tharinger, Hugo; Prévot, Sophie; Bachelerie, Françoise; Naveau, Sylvie; Emilie, Dominique; Balabanian, Karl; Perlemuter, Gabriel

    2015-02-01

    Homing of inflammatory cells to the liver is key in the progression of non-alcoholic steatohepatitis (NASH). An abnormal response of CD4+ T-cells from obese mice to the chemotactic effect of CXCL12 has been reported but the mechanism involved in this process and relevance in patients are unknown. We aimed to explore the mechanism involved in the abnormal chemotaxis of CXC chemokine ligand 12 (CXCL12) in several mouse models of NASH and the relevance in the context of human non-alcoholic fatty liver disease (NAFLD). We assessed chemotactic responsiveness of CD4+ T-cells to CXCL12, the effect of AMD3100, a CXC chemokine receptor 4 (CXCR4) antagonist, in mice and lymphocytes from patients with NAFLD, and the affinity of CXCL12 for CXCR4. CXCL12-promoted migration of CD4+ T-cells from three different mouse models of NASH was increased and dependent of CXCR4. CD4+ T-cells from patients with NASH, but not from patients with pure steatosis, responded more strongly to the chemotactic effect of CXCL12, and this response was inhibited by AMD3100. Treatment with AMD3100 decreased the number of CD4+ T-cells to the liver in ob/ob mice. CXCL12 expression in the liver, CXCR4 and CXCR7 expression in CD4+ T-cells were not increased in three different mouse models of NASH. However, the affinity of CXCL12 for CXCR4 was increased in CD4+ T-cells of ob/ob mice. In conclusion, the CXCL12/CXCR4 pathway contributes in both mice and patients to the enhanced recruitment of CD4+ T-cells in NASH. An increased affinity of CXCL12 to CXCR4 rather than a higher expression of the chemokine or its receptors is involved in this process. PMID:25074471

  4. Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies

    PubMed Central

    Takeuchi, Masayoshi; Takino, Jun-ichi; Sakasai-Sakai, Akiko; Takata, Takanobu; Ueda, Tadashi; Tsutsumi, Mikihiro; Hyogo, Hideyuki; Yamagishi, Sho-ichi

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease around the world. It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, liver failure, and/or hepatocellular carcinoma. NAFLD is also associated with other medical conditions such as obesity, diabetes mellitus (DM), metabolic syndrome, hypertension, insulin resistance, hyperlipidemia, and cardiovascular disease (CVD). In diabetes, chronic hyperglycemia contributes to the development of both macro- and microvascular conditions through a variety of metabolic pathways. Thus, it can cause a variety of metabolic and hemodynamic conditions, including upregulated advanced glycation end-products (AGEs) synthesis. In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs, were found to make a significant contribution to the pathogenesis of DM-induced angiopathy. Furthermore, accumulating evidence suggests that the binding of TAGE with their receptor (RAGE) induces oxidative damage, promotes inflammation, and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells. All of these effects could facilitate the pathogenesis of hypertension, cancer, diabetic vascular complications, CVD, dementia, and NASH. Thus, inhibiting TAGE synthesis, preventing TAGE from binding to RAGE, and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH. Here, we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH. PMID:25544875

  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. Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame.

    PubMed

    Ibrahim, Samar H; Hirsova, Petra; Malhi, Harmeet; Gores, Gregory J

    2016-05-01

    With the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become a public health problem with increasing prevalence. The mechanism of disease progression remains obscure and effective therapy is lacking. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary, especially, since causative mechanistic studies of NAFLD are more difficult or unethical to perform in humans. A large number of studies regarding the pathophysiology and treatment of nonalcoholic steatohepatitis (NASH) have been undertaken in mice to model human NAFLD and NASH. This review discusses the known dietary, genetic, and inflammation-based animal models of NASH described in recent years, with a focus on the major advances made in this field. PMID:26626909

  7. 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

  8. 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

  9. Medical and Surgical Treatment Options for Nonalcoholic Steatohepatitis.

    PubMed

    Corey, Kathleen E; Rinella, Mary E

    2016-05-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in the USA with a growing prevalence worldwide. Nonalcoholic steatohepatitis (NASH), progressive form of NAFLD, can lead to the development of cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. Treatment of NASH may decrease the risk of progressive disease. Treatment for NAFLD should center around weight loss and exercise. Pharmacotherapy with vitamin E and pioglitazone should be considered for those with NASH, especially those with fibrosis. Weight loss surgery is also an effective treatment for NASH in individuals with other indications for surgery. In this review, we will discuss the currently available therapies for NASH including lifestyle, pharmacologic, and surgical options. PMID:26942734

  10. 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

  11. 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

  12. 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

  13. Disease progression in a patient with nonalcoholic steatohepatitis.

    PubMed

    Tseng, Ping-Huei; Liu, Chun-Jen; Kao, Jia-Horng; Shun, Chia-Tung; Chen, Pei-Jer; Chen, Ding-Shinn

    2008-10-01

    Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD). The prevalence and clinical significance of NAFLD/NASH have been increasingly recognized in Western countries but much less known in Asian countries, including Taiwan. Here, we report the case of a 43-year-old man who had abnormal liver tests for 18 years. Retrospective evaluation of his initial clinical, laboratory and histologic findings indicated that the hepatic disorder was compatible with the diagnosis of NASH. Although his liver biochemical tests improved after taking lipid-lowering agents, a liver biopsy 17 years later demonstrated histologic progression of intralobular necroinflammation and perivenular fibrosis. These facts suggest that NASH, albeit mild and slowly progressive, indeed exists in Taiwan. After the control of chronic hepatitis B and C and westernization of the lifestyle in Taiwan, an increasing burden of NAFLD/NASH is anticipated and active prophylactic measures should be implemented. PMID:18926950

  14. Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame

    PubMed Central

    Ibrahim, Samar H.; Hirsova, Petra; Malhi, Harmeet; Gores, Gregory J.

    2016-01-01

    With the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become a public health problem with increasing prevalence. The mechanism of disease progression remains obscure and effective therapy is lacking. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary, especially, since causative mechanistic studies of NAFLD are more difficult or unethical to perform in humans. A large number of studies regarding the pathophysiology and treatment of NASH have been undertaken in mice to model human NAFLD and nonalcoholic steatohepatitis (NASH). This review discusses the known dietary, genetic and inflammation based animal models of NASH described in recent years, with a focus on the major advances made in this field. PMID:26626909

  15. 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

  16. 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

  17. 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

  18. 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

  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. Enantioselective Regulation of Lactate Racemization by LarR in Lactobacillus plantarum

    PubMed Central

    Desguin, Benoît; Goffin, Philippe; Bakouche, Nordine; Diman, Aurélie; Viaene, Eric; Dandoy, Damien; Fontaine, Laetitia; Hallet, Bernard

    2014-01-01

    Lactobacillus plantarum is a lactic acid bacterium that produces a racemic mixture of l- and d-lactate from sugar fermentation. The interconversion of lactate isomers is performed by a lactate racemase (Lar) that is transcriptionally controlled by the l-/d-lactate ratio and maximally induced in the presence of l-lactate. We previously reported that the Lar activity depends on the expression of two divergently oriented operons: (i) the larABCDE operon encodes the nickel-dependent lactate racemase (LarA), its maturases (LarBCE), and a lactic acid channel (LarD), and (ii) the larR(MN)QO operon encodes a transcriptional regulator (LarR) and a four-component ABC-type nickel transporter [Lar(MN), in which the M and N components are fused, LarQ, and LarO]. LarR is a novel regulator of the Crp-Fnr family (PrfA group). Here, the role of LarR was further characterized in vivo and in vitro. We show that LarR is a positive regulator that is absolutely required for the expression of Lar activity. Using gel retardation experiments, we demonstrate that LarR binds to a 16-bp palindromic sequence (Lar box motif) that is present in the larR-larA intergenic region. Mutations in the Lar box strongly affect LarR binding and completely abolish transcription from the larA promoter (PlarA). Two half-Lar boxes located between the Lar box and the −35 box of PlarA promote LarR multimerization on DNA, and point mutations within one or both half-Lar boxes inhibit PlarA induction by l-lactate. Gel retardation and footprinting experiments indicate that l-lactate has a positive effect on the binding and multimerization of LarR, while d-lactate antagonizes the positive effect of l-lactate. A possible mechanism of LarR regulation by lactate enantiomers is proposed. PMID:25349156

  1. 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

  2. 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

  3. Best Prediction of Yields for Long Lactations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lactation records of any length now can be processed with the selection index methods known as best prediction (BP). Previous programs were limited to the 305-day standard used since 1935. Best prediction was implemented in 1998 to calculate lactation records in USDA genetic evaluations, replacing t...

  4. Lactation associated with herpes zoster pectoralis.

    PubMed

    Bhattacharya, S K; Girgla, H S

    1976-05-01

    The phenomenon of lactation associated with herpes zoster is unexpected. To our knowledge such an association has been reported only once. A case is reported in whom spontaneous lactation occurred in the ipsilateral breast following herpes zoster. It is believed to have resulted from stimulation of the intercostal nerve endings supplying the overlying skin of the breast. PMID:945354

  5. 21 CFR 184.1768 - Sodium lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ....1768 Sodium lactate. (a) Sodium lactate (C3H5O3Na, CAS Reg. No. 72-17-3) is the sodium salt of lactic acid. It is prepared commercially by the neutralization of lactic acid with sodium hydroxide. (b)...

  6. Brain lactate kinetics: Modeling evidence for neuronal lactate uptake upon activation.

    PubMed

    Aubert, Agnès; Costalat, Robert; Magistretti, Pierre J; Pellerin, Luc

    2005-11-01

    A critical issue in brain energy metabolism is whether lactate produced within the brain by astrocytes is taken up and metabolized by neurons upon activation. Although there is ample evidence that neurons can efficiently use lactate as an energy substrate, at least in vitro, few experimental data exist to indicate that it is indeed the case in vivo. To address this question, we used a modeling approach to determine which mechanisms are necessary to explain typical brain lactate kinetics observed upon activation. On the basis of a previously validated model that takes into account the compartmentalization of energy metabolism, we developed a mathematical model of brain lactate kinetics, which was applied to published data describing the changes in extracellular lactate levels upon activation. Results show that the initial dip in the extracellular lactate concentration observed at the onset of stimulation can only be satisfactorily explained by a rapid uptake within an intraparenchymal cellular compartment. In contrast, neither blood flow increase, nor extracellular pH variation can be major causes of the lactate initial dip, whereas tissue lactate diffusion only tends to reduce its amplitude. The kinetic properties of monocarboxylate transporter isoforms strongly suggest that neurons represent the most likely compartment for activation-induced lactate uptake and that neuronal lactate utilization occurring early after activation onset is responsible for the initial dip in brain lactate levels observed in both animals and humans. PMID:16260743

  7. 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

  8. Non-alcoholic steatohepatitis: the therapeutic challenge of a global epidemic

    PubMed Central

    Mouzaki, Marialena; Allard, Johane

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Nonalcoholic steatohepatitis (NASH) reflects severe liver disease within the NAFLD spectrum and can progress to end-stage liver disease. Within this manuscript we review the available evidence for the treatment of NASH as well as the newer therapeutic agents that are currently being investigated. PMID:24713803

  9. L-Lactate Protects Skin Fibroblasts against Aging-Associated Mitochondrial Dysfunction via Mitohormesis.

    PubMed

    Zelenka, Jaroslav; Dvořák, Aleš; Alán, Lukáš

    2015-01-01

    A moderate elevation of reactive oxygen species (ROS) production and a mild inhibition of mitochondrial respiratory chain have been associated with a health promotion and a lifespan extension in several animal models of aging. Here, we tested whether this phenomenon called mitohormesis could be mediated by L-lactate. The treatment with 5 mM L-lactate significantly increased H2O2 production and slightly inhibited the respiration in cultured skin fibroblasts and in isolated mitochondria. The L-lactate exposure was associated with oxidation of intracellular glutathione, phosphorylation of 5'AMP-activated protein kinase (AMPK), and induction of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) transcription. A replicative aging of fibroblasts (L0) with a constant (LC), or intermittent 5 mM L-lactate (LI) in media showed that the high-passage LI fibroblasts have higher respiration, lower H2O2 release, and lower secretion of L-lactate compared to L0 and LC. This protection against mitochondrial dysfunction in LI cells was associated with lower activity of mechanistic target of rapamycin complex 1 (mTORC1), less signs of cellular senescence, and increased autophagy compared to L0 and LC. In conclusion, we demonstrated that intermittent but not constant exposure to L-lactate triggers mitohormesis, prevents aging-associated mitochondrial dysfunction, and improves other markers of aging. PMID:26171114

  10. Inhibition of stress mediated cell death by human lactate dehydrogenase B in yeast.

    PubMed

    Sheibani, Sara; Jones, Natalie K; Eid, Rawan; Gharib, Nada; Arab, Nagla T T; Titorenko, Vladimir; Vali, Hojatollah; Young, Paul A; Greenwood, Michael T

    2015-08-01

    We report the identification of human L- lactate dehydrogenase B (LDHB) as a novel Bax suppressor. Yeast heterologously expressing LDHB is also resistant to the lethal effects of copper indicating that it is a general suppressor of stress mediated cell death. To identify potential LDHB targets, LDHB was expressed in yeast mutants defective in apoptosis, necrosis and autophagy. The absence of functional PCD regulators including MCA1, YBH3, cyclophilin (CPR3) and VMA3, as well as the absence of the pro-survival autophagic pathway (ATG1,7) did not interfere with the LDHB mediated protection against copper indicating that LDHB functions independently of known PCD regulators or by simply blocking or stimulating a common PCD promoting or inhibitory pathway. Measurements of lactate levels revealed that short-term copper stress (1.6 mM, 4 h), does not increase intracellular levels of lactate, instead a three-fold increase in extracellular lactate was observed. Thus, yeast cells resemble mammalian cells where different stresses are known to lead to increased lactate production leading to lactic acidosis. In agreement with this, we found that the addition of exogenous lactic acid to growth media was sufficient to induce cell death that could be inhibited by the expression of LDHB. Taken together our results suggest that lactate dehydrogenase is a general suppressor of PCD in yeast. PMID:26032856

  11. L-Lactate Protects Skin Fibroblasts against Aging-Associated Mitochondrial Dysfunction via Mitohormesis

    PubMed Central

    Zelenka, Jaroslav; Dvořák, Aleš; Alán, Lukáš

    2015-01-01

    A moderate elevation of reactive oxygen species (ROS) production and a mild inhibition of mitochondrial respiratory chain have been associated with a health promotion and a lifespan extension in several animal models of aging. Here, we tested whether this phenomenon called mitohormesis could be mediated by L-lactate. The treatment with 5 mM L-lactate significantly increased H2O2 production and slightly inhibited the respiration in cultured skin fibroblasts and in isolated mitochondria. The L-lactate exposure was associated with oxidation of intracellular glutathione, phosphorylation of 5′AMP-activated protein kinase (AMPK), and induction of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) transcription. A replicative aging of fibroblasts (L0) with a constant (LC), or intermittent 5 mM L-lactate (LI) in media showed that the high-passage LI fibroblasts have higher respiration, lower H2O2 release, and lower secretion of L-lactate compared to L0 and LC. This protection against mitochondrial dysfunction in LI cells was associated with lower activity of mechanistic target of rapamycin complex 1 (mTORC1), less signs of cellular senescence, and increased autophagy compared to L0 and LC. In conclusion, we demonstrated that intermittent but not constant exposure to L-lactate triggers mitohormesis, prevents aging-associated mitochondrial dysfunction, and improves other markers of aging. PMID:26171114

  12. Parental perceptions regarding lifestyle interventions for obese children and adolescents with nonalcoholic fatty liver disease

    PubMed Central

    Iñiguez, Ingrid Rivera; Yap, Jason; Mager, Diana R

    2014-01-01

    BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) affects 30% of obese children globally. The main treatment for NAFLD is to promote gradual weight loss through lifestyle modification. Very little is known regarding parental perspectives about the barriers and facilitators that influence the ability to promote healthy lifestyle behaviours in children with NAFLD. OBJECTIVES: To explore and describe parental perspectives regarding barriers to and facilitators of implementing lifestyle modification in children with NAFLD. METHODS: A mixed-methods approach, including qualitative methodology (focus groups) and validated questionnaires (Lifestyle Behaviour Checklist), was used to assess parental perceptions regarding barriers to and facilitators of lifestyle change in parents of children with healthy body weights (control parents) and in parents of children with NAFLD (NAFLD parents). RESULTS: NAFLD parents identified more problem behaviours related to food portion size and time spent in nonsedentary physical activity, and lower parental self-efficacy than parents of controls (P<0.05). Major barriers to lifestyle change cited by NAFLD parents were lack of time, self-motivation and role modelling of healthy lifestyle behaviours. In contrast, control parents used a variety of strategies to elicit healthy lifestyle behaviours in their children including positive role modelling, and inclusion of the child in food preparation and meal purchasing decisions, and perceived few barriers to promoting healthy lifestyles. Internet sources were the main form of nutrition information used by parents. CONCLUSIONS: Lifestyle modification strategies focused on promoting increased parental self-efficacy and parental motivation to promote healthy lifestyle behaviour are important components in the treatment of obese children with NAFLD. PMID:24855432

  13. The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism.

    PubMed

    Chambel, Sílvia S; Santos-Gonçalves, Andreia; Duarte, Tiago L

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease with ever-growing incidence in the industrialized world. It starts with the simple accumulation of lipids in the hepatocyte and can progress to the more severe nonalcoholic steatohepatitis (NASH), which is associated with inflammation, fibrosis, and cirrhosis. There is increasing awareness that reactive oxygen species and electrophiles are implicated in the pathogenesis of NASH. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a positive regulator of the expression of a battery of genes involved in the protection against oxidative/electrophilic stress. In rodents, Nrf2 is also known to participate in hepatic fatty acid metabolism, as a negative regulator of genes that promote hepatosteatosis. We review relevant evidence in the literature that these two mechanisms may contribute to the protective role of Nrf2 in the development of hepatic steatosis and in the progression to steatohepatitis, particularly in young animals. We propose that age may be a key to explain contradictory findings in the literature. In summary, Nrf2 mediates the crosstalk between lipid metabolism and antioxidant defense mechanisms in experimental models of NAFLD, and the nutritional or pharmacological induction of Nrf2 represents a promising potential new strategy for its prevention and treatment. PMID:26120584

  14. Genome-based nutrition: An intervention strategy for the prevention and treatment of obesity and nonalcoholic steatohepatitis

    PubMed Central

    Roman, Sonia; Ojeda-Granados, Claudia; Ramos-Lopez, Omar; Panduro, Arturo

    2015-01-01

    Obesity and nonalcoholic steatohepatitis are increasing in westernized countries, regardless of their geographic location. In Latin America, most countries, including Mexico, have a heterogeneous admixture genome with Amerindian, European and African ancestries. However, certain high allelic frequencies of several nutrient-related polymorphisms may have been achieved by past gene-nutrient interactions. Such interactions may have promoted the positive selection of variants adapted to regional food sources. At present, the unbalanced diet composition of the Mexicans has led the country to a 70% prevalence rate of overweightness and obesity due to substantial changes in food habits, among other factors. International guidelines and intervention strategies may not be adequate for all populations worldwide because they do not consider disparities in genetic and environmental factors, and thus there is a need for differential prevention and management strategies. Here, we provide the rationale for an intervention strategy for the prevention and management of obesity-related diseases such as non-alcoholic steatohepatitis based on a regionalized genome-based diet. The components required to design such a diet should focus on the specific ancestry of each population around the world and the convenience of consuming traditional ethnic food. PMID:25834309

  15. An in vitro model of the horse gut microbiome enables identification of lactate-utilizing bacteria that differentially respond to starch induction.

    PubMed

    Biddle, Amy S; Black, Samuel J; Blanchard, Jeffrey L

    2013-01-01

    Laminitis is a chronic, crippling disease triggered by the sudden influx of dietary starch. Starch reaches the hindgut resulting in enrichment of lactic acid bacteria, lactate accumulation, and acidification of the gut contents. Bacterial products enter the bloodstream and precipitate systemic inflammation. Hindgut lactate levels are normally low because specific bacterial groups convert lactate to short chain fatty acids. Why this mechanism fails when lactate levels rapidly rise, and why some hindgut communities can recover is unknown. Fecal samples from three adult horses eating identical diets provided bacterial communities for this in vitro study. Triplicate microcosms of fecal slurries were enriched with lactate and/or starch. Metabolic products (short chain fatty acids, headspace gases, and hydrogen sulfide) were measured and microbial community compositions determined using Illumina 16S rRNA sequencing over 12-hour intervals. We report that patterns of change in short chain fatty acid levels and pH in our in vitro system are similar to those seen in in vivo laminitis induction models. Community differences between microcosms with disparate abilities to clear excess lactate suggest profiles conferring resistance of starch-induction conditions. Where lactate levels recover following starch induction conditions, propionate and acetate levels rise correspondingly and taxa related to Megasphaeraelsdenii reach levels exceeding 70% relative abundance. In lactate and control cultures, taxa related to Veillonellamontpellierensis are enriched as lactate levels fall. Understanding these community differences and factors promoting the growth of specific lactate utilizing taxa may be useful to prevent acidosis under starch-induction conditions. PMID:24098591

  16. Current trends in lactate metabolism: introduction.

    PubMed

    Gladden, L Bruce

    2008-03-01

    In September 2006, at the Integrative Physiology of Exercise meeting in Indianapolis, IN, a symposium entitled "Current Trends in Lactate Metabolism" was presented. This short paper introduces two papers from that symposium. The first paper by L. Bruce Gladden briefly summarizes key pieces of evidence that support the cell-to-cell lactate shuttle, a concept that is no longer an hypothesis but that, instead, is now an established theory that provides the context for discussions of whole body metabolism. Gladden also offers a critical appraisal of the intracellular lactate shuttle and evaluates an ongoing controversy relative to the role of lactate in acid-base balance. In the second paper, Hashimoto and Brooks provide their evidence in support of the intracellular lactate shuttle and a lactate oxidation complex in the inner mitochondrial membrane. They also postulate that lactate is a cell-signaling molecule, "lactormone," that can upregulate gene and protein expression. Both papers have been updated since their original presentations and represent the current state of knowledge. PMID:18379209

  17. Etiology and therapeutic approach to elevated lactate

    PubMed Central

    Andersen, Lars W.; Mackenhauer, Julie; Roberts, Jonathan C.; Berg, Katherine M.; Cocchi, Michael N.; Donnino, Michael W.

    2014-01-01

    Lactate levels are commonly evaluated in acutely ill patients. Although most commonly used in the context of evaluating shock, lactate can be elevated for many reasons. While tissue hypoperfusion is probably the most common cause of elevation, many other etiologies or contributing factors exist. Clinicians need to be aware of the many potential causes of lactate elevation as the clinical and prognostic importance of an elevated lactate varies widely by disease state. Moreover, specific therapy may need to be tailored to the underlying cause of elevation. The current review is based on a comprehensive PubMed search and contains an overview of the pathophysiology of lactate elevation followed by an in-depth look at the varied etiologies, including medication-related causes. The strengths and weaknesses of lactate as a diagnostic/prognostic tool and its potential use as a clinical endpoint of resuscitation will be discussed. The review ends with some general recommendations on management of patients with elevated lactate. PMID:24079682

  18. Lactate as a Biomarker for Sleep

    PubMed Central

    Naylor, Erik; Aillon, Daniel V.; Barrett, Brian S.; Wilson, George S.; Johnson, David A.; Johnson, Donna A.; Harmon, Hans P.; Gabbert, Seth; Petillo, Peter A.

    2012-01-01

    Study Objectives: An ideal biomarker for sleep should change rapidly with sleep onset, remain at a detectably differential level throughout the sleep period, and exhibit a rapid change with waking. Currently, no molecular marker has been identified that exhibits all three properties. This study examined three substances (lactate, glucose, and glutamate) for suitability as a sleep biomarker. Design: Using amperometric biosensor technology in conjunction with electroencephalograph (EEG) and electromyograph (EMG) monitoring, extracellular concentrations of lactate and glucose (Cohort 1) as well as lactate and glutamate (Cohort 2) were recorded over multiple sleep/wake cycles. Patients or Participants: There were 12 C57Bl/6J male mice (3-5 mo old). Interventions: Sleep and waking transitions were identified using EEG recordings. Extracellular concentrations of lactate, glucose, and glutamate were evaluated before and during transition events as well as during extended sleep and during a 6-h sleep deprivation period. Measurements and Results: Rapid and sustained increases in cortical lactate concentration (approximately 15 μM/min) were immediately observed upon waking and during rapid eye movement sleep. Elevated lactate concentration was also maintained throughout a 6-h period of continuous waking. A persistent and sustained decline in lactate concentration was measured during nonrapid eye movement sleep. Glutamate exhibited similar patterns, but with a much slower rise and decline (approximately 0.03 μM/min). Glucose concentration changes did not demonstrate a clear correlation with either sleep or wake. Conclusions: These findings indicate that extracellular lactate concentration is a reliable sleep/wake biomarker and can be used independently of the EEG signal. Citation: Naylor E; Aillon DV; Barrett BS; Wilson GS; Johnson DA; Johnson DA; Harmon HP; Gabbert S; Petillo PA. Lactate as a biomarker for sleep. SLEEP 2012;35(9):1209-1222. PMID:22942499

  19. Lactational mastitis caused by Streptococcus lactarius.

    PubMed

    Tena, Daniel; Fernández, Cristina; López-Garrido, Beatriz; Pérez-Balsalobre, Mercedes; Losa, Cristina; Medina-Pascual, María José; Sáez-Nieto, Juan Antonio

    2016-08-01

    Human infections caused by Streptococcus lactarius have not been previously reported. In the present report, we describe a lactational mastitis caused by this organism. The infection occurred in a 28-year-old breast-feeding female, with a 10-days history of moderate pain on the right breast. The patient was cured after antibiotic treatment with levofloxacin for 21 days. Our case shows that S. lactarius should be considered as a cause of lactational mastitis. The introduction of molecular microbiology techniques can be extremely useful for knowing the implication of streptococci in lactational mastitis. PMID:27220606

  20. 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

  1. Safety of dermatologic medications in pregnancy and lactation: Part II. Lactation.

    PubMed

    Butler, Daniel C; Heller, Misha M; Murase, Jenny E

    2014-03-01

    Dermatologists are frequently faced with questions from women who are breastfeeding about the safety of commonly prescribed topical and systemic medications during lactation. Safety data in lactation, particularly regarding medications that are unique to dermatology, are limited and can be difficult to locate. We have consolidated the available safety data in a single reference guide for clinicians. We review literature pertaining to the safety of common dermatologic therapies in lactation and offer recommendations based on the available evidence. PMID:24528912

  2. 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

  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. 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

  5. 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

  6. Genetics Home Reference: lactate dehydrogenase deficiency

    MedlinePlus

    ... dehydrogenase-B pieces (subunits) of the lactate dehydrogenase enzyme. This enzyme is found throughout the body and is important ... cells. There are five different forms of this enzyme, each made up of four protein subunits. Various ...

  7. Phyllodes Tumor in a Lactating Breast

    PubMed Central

    Murthy, Sudha S.; Raju, K. V. V. N.; Nair, Haripreetha G.

    2016-01-01

    Phyllodes tumor is attributed to a small fraction of primary tumors of the breast. Such tumors occur rarely in pregnancy and lactation. We report a case of a 25-year-old lactating mother presenting with a lump in the left breast. Core needle biopsy was opined as phyllodes tumor with lactational changes, and subsequent wide local excision confirmed the diagnosis of benign phyllodes tumor with lactational changes. The characteristic gross and microscopic findings of a well-circumscribed lesion with leaf-like fibroepithelial growth pattern and typical nonuniform or diffuse stromal proliferation with periductal accentuation even in the absence of mitotic figures can help clinch the diagnosis. Benign phyllodes is known for its recurrence and requires wide excision and close follow-up. It is vital to identify these lesions even on limited biopsies as therapeutic options differ. This case is presented for its rarity and the diagnostic challenge it poses in limited biopsy. PMID:27081326

  8. Phyllodes Tumor in a Lactating Breast.

    PubMed

    Murthy, Sudha S; Raju, K V V N; Nair, Haripreetha G

    2016-01-01

    Phyllodes tumor is attributed to a small fraction of primary tumors of the breast. Such tumors occur rarely in pregnancy and lactation. We report a case of a 25-year-old lactating mother presenting with a lump in the left breast. Core needle biopsy was opined as phyllodes tumor with lactational changes, and subsequent wide local excision confirmed the diagnosis of benign phyllodes tumor with lactational changes. The characteristic gross and microscopic findings of a well-circumscribed lesion with leaf-like fibroepithelial growth pattern and typical nonuniform or diffuse stromal proliferation with periductal accentuation even in the absence of mitotic figures can help clinch the diagnosis. Benign phyllodes is known for its recurrence and requires wide excision and close follow-up. It is vital to identify these lesions even on limited biopsies as therapeutic options differ. This case is presented for its rarity and the diagnostic challenge it poses in limited biopsy. PMID:27081326

  9. Regulation of bone mineral loss during lactation

    NASA Technical Reports Server (NTRS)

    Brommage, R.; Deluca, H. F.

    1985-01-01

    The effects of varyng dietary calcium and phosphorous levels, vitamin D deficiency, oophorectomy, adrenalectomy, and simultaneous pregnancy on bone mineral loss during lactation in rats are studied. The experimental procedures and evaluations are described. The femur ash weight of lactating and nonlactating rats are calculated. The data reveals that a decrease in dietary calcium of 0.02 percent results in an increased loss of bone mineral, an increase in calcium to 1.4 percent does not lessen bone mineral loss, and bone mineral loss in vitamin D deficient rats is independent of calcium levels. It is observed that changes in dietary phosphorous level, oophorectomy, adrenalectomy, and simultaneous pragnancy do not reduce bone mineral loss during lactation. The analysis of various hormones to determine the mechanism that triggers bone mineral loss during lactation is presented.

  10. 21 CFR 184.1311 - Ferrous lactate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... lactic acid with iron filings, reaction of ferrous chloride with sodium lactate, or reaction of ferrous...) and 1 CFR part 51. Copies are available from the National Academy Press, 2101 Constitution Ave....

  11. 21 CFR 184.1311 - Ferrous lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... lactic acid with iron filings, reaction of ferrous chloride with sodium lactate, or reaction of ferrous...) and 1 CFR part 51. Copies are available from the National Academy Press, 2101 Constitution Ave....

  12. 21 CFR 184.1311 - Ferrous lactate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... lactic acid with iron filings, reaction of ferrous chloride with sodium lactate, or reaction of ferrous...) and 1 CFR part 51. Copies are available from the National Academy Press, 2101 Constitution Ave....

  13. Efficiency of Energy Utilization by Lactating Alpine Goats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Thirty-six lactating Alpine does (50.5 ± 1.2 kg BW) were used to determine the effect of stage of lactation on energy utilization. Twelve does were assigned for measurement periods in early, mid-, and late lactation (28-35, 91-98, and 189 to 196 d of lactation). For six does of each group, after m...

  14. Lactation: historical patterns and potential for manipulation.

    PubMed

    Blackburn, D G

    1993-10-01

    The advent of biotechnology has made data on undomesticated mammals relevant to dairy science. Such data indicate the potential of lactation for modification, reveal genetic material available for use through bioengineering, help distinguish adaptive features from historical artifacts, and clarify limits on lactational diversity that date from early evolution. Evolutionary analysis indicates that a complex degree of lactation preceded divergence of the extant mammalian lineages during the Mesozoic Era. Although aspects of monotreme lactation appear to be ancestral for extant mammals, the marsupials and eutherians exhibit divergent specializations. Evidence is consistent with the idea that protolacteal glands evolved by combining features of skin gland populations into a new functional complex. Secretions of these ancestral glands may have had antimicrobial properties that protected the eggs or hatchlings and organic components that supplemented offspring nutrition. Following development of highly nutritious milks, evolution produced diversity in milk composition and function, milk output, length of lactation, mammary gland anatomy, and contributions of lactation to offspring nutrition. Certain marsupials are specialized in terms of functional independence and temporal plasticity of mammary tissues. Mammalian diversity indicates that artificial selection and physiological manipulation of domestic artiodactyls has only modestly exploited the potential of mammary glands as a nutritional source for humans. PMID:8227641

  15. Clinical use of lactate monitoring in critically ill patients

    PubMed Central

    2013-01-01

    Increased blood lactate levels (hyperlactataemia) are common in critically ill patients. Although frequently used to diagnose inadequate tissue oxygenation, other processes not related to tissue oxygenation may increase lactate levels. Especially in critically ill patients, increased glycolysis may be an important cause of hyperlactataemia. Nevertheless, the presence of increased lactate levels has important implications for the morbidity and mortality of the hyperlactataemic patients. Although the term lactic acidosis is frequently used, a significant relationship between lactate and pH only exists at higher lactate levels. The term lactate associated acidosis is therefore more appropriate. Two recent studies have underscored the importance of monitoring lactate levels and adjust treatment to the change in lactate levels in early resuscitation. As lactate levels can be measured rapidly at the bedside from various sources, structured lactate measurements should be incorporated in resuscitation protocols. PMID:23663301

  16. Lactate production by the mammalian blastocyst: Manipulating the microenvironment for uterine implantation and invasion?

    PubMed Central

    Gardner, David K

    2015-01-01

    The mammalian blastocyst exhibits a high capacity for aerobic glycolysis, a metabolic characteristic of tumours. It has been considered that aerobic glycolysis is a means to ensure a high carbon flux to fulfil biosynthetic demands. Here, alternative explanations for this pattern of metabolism are considered. Lactate creates a microenvironment of low pH around the embryo to assist the disaggregation of uterine tissues to facilitate trophoblast invasion. Further it is proposed that lactate acts as a signalling molecule (especially at the reduced oxygen tension present at implantation) to elicit bioactive VEGF recruitment from uterine cells, to promote angiogenesis. Finally it is suggested that the region of high lactate/low pH created by the blastocyst modulates the activity of the local immune response, helping to create immune tolerance. Consequently, the mammalian blastocyst offers a model to study the role of microenvironments, and how metabolites and pH are used in signalling. PMID:25619853

  17. 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

  18. Cost-Utility Analysis of Nonalcoholic Steatohepatitis Screening

    PubMed Central

    Zhang, Eric; Wartelle-Bladou, Claire; Lepanto, Luigi; Lachaine, Jean; Cloutier, Guy; Tang, An

    2016-01-01

    OBJECTIVES Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. No studies have examined the cost-effectiveness of screening for nonalcoholic steatohepatitis (NASH), its advanced form. METHODS We performed a cost-utility analysis of annual non-invasive screening strategies using third-party payer perspective in a general population and compared it to screening in a high-risk obese or diabetic population. Screening algorithms involved well-studied techniques including NAFLD fibrosis score, transient elastography (TE), and acoustic radiation force impulse (ARFI) imaging for detecting advanced fibrosis (≥ F3); and plasma cytokeratin (CK)-18 for NASH detection. Liver biopsy and magnetic resonance elastography (MRE) were compared as confirmation methods. Canadian dollar costs were adjusted for inflation and discounted at 5%. Incremental cost-effectiveness ratio (ICER) of ≤$C50,000 was considered cost-effective. RESULTS Compared with no screening, screening with NAFLD fibrosis score/TE/CK-18 algorithm with MRE as confirmation for advanced fibrosis had an ICER of $C26,143 per quality-adjusted life year (QALY) gained. Screening in high-risk obese or diabetic populations was more cost-effective, with an ICER of $C9,051 and $C7,991 per QALY gained respectively. Liver biopsy confirmation was not found to be cost-effective. CONCLUSIONS Our model suggests that annual NASH screening in high-risk obese or diabetic populations can be cost-effective. PMID:25994191

  19. Nonalcoholic steatohepatitis: emerging targeted therapies to optimize treatment options

    PubMed Central

    Milic, Sandra; Mikolasevic, Ivana; Krznaric-Zrnic, Irena; Stanic, Marija; Poropat, Goran; Stimac, Davor; Vlahovic-Palcevski, Vera; Orlic, Lidija

    2015-01-01

    Diet and lifestyle changes have led to worldwide increases in the prevalences of obesity and metabolic syndrome, resulting in substantially greater incidence of nonalcoholic fatty liver disease (NAFLD). NAFLD is considered a hepatic manifestation of metabolic syndrome and is related to diabetes, insulin resistance, central obesity, hyperlipidemia, and hypertension. Nonalcoholic steatohepatitis (NASH) is an entity that describes liver inflammation due to NAFLD. Growing evidence suggests that NAFLD is a multisystem disease with a clinical burden that is not only confined to liver-related morbidity and mortality, but that also affects several extra-hepatic organs and regulatory pathways. Thus, NAFLD is considered an important public health issue, but there is currently no effective therapy for all NAFLD patients in the general population. Studies seeking optimal therapy for NAFLD and NASH have not yet led to development of a universal protocol for treating this growing problem. Several pharmacological agents have been studied in an effort to improve insulin resistance and the proinflammatory mediators that may be responsible for NASH progression. Cardiovascular risk factors are highly prevalent among NASH patients, and the backbone of treatment regimens for these patients still comprises general lifestyle interventions, including dietary changes and increased physical activity. Vitamin E and thiazolidinedione derivatives are currently the most evidence-based therapeutic options, but only limited clinical evidence is available regarding their long-term efficacy and safety. Vitamin D and renin–angiotensin–aldosterone system blockers are promising drugs that are currently being intensively investigated for use in NAFLD/NASH patients. PMID:26316717

  20. 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

  1. Questionnaire survey on lifestyle of patients with nonalcoholic steatohepatitis.

    PubMed

    Noto, Haruka; Tokushige, Katsutoshi; Hashimoto, Etsuko; Taniai, Makiko; Shiratori, Keiko

    2014-11-01

    Lack of exercise and excessive food intake are known to be the important causes of nonalcoholic steatohepatitis (NASH). To elucidate the relationship between lifestyle and NASH, we surveyed exercise and dietary habits, comparing them among 171 biopsy-proven NASH patients, 29 nonalcoholic fatty liver (NAFL) patients and 49 normal subjects. Dietary habits including the duration of dinner time, amount of rice at dinner, and weekly frequencies of meat, fries, Chinese noodles, sweets, and instant food consumption were significantly different in male NASH patients compared to normal male subjects. In women, differences were seen in the amount of rice at dinner, frequency of eating out, and proclivity for sweets. In male NASH patients, the frequency of physical exercise was significantly lower. The lifestyle tendencies of NASH were almost similar to those of NAFL. In the comparison between obese NASH and non-obese NASH, no clear lifestyle differences were found. In conclusion, the most striking result of this survey was that the lifestyle of males contributed significantly to the development of NASH. These results point to treatment of NASH in males. In female NASH patients, lifestyle differences were minimal, and the effects of other factors such as genetic background will need to be investigated. PMID:25411525

  2. 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

  3. 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

  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. 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

  6. 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

  7. 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

  8. Clinical spectrum and therapy of non-alcoholic steatohepatitis.

    PubMed

    Day, Christopher Paul

    2012-01-01

    Non-alcoholic fatty liver disease is increasingly being diagnosed worldwide and considered to be the commonest liver disorder in Western countries. It comprises a disease spectrum ranging from simple steatosis (fatty liver) through non-alcoholic steatohepatitis (NASH) to fat with fibrosis and, ultimately, cirrhosis. Simple steatosis is largely benign and non-progressive, whereas NASH can lead to cirrhosis, liver failure and hepatocellular carcinoma. Therapeutic strategies can be divided into those directed at components of the metabolic syndrome with potential beneficial liver effects and those directed specifically at the liver. Recent data suggest that diet and exercise improve NASH, particular in those achieving >7% weight loss. Obesity surgery has been shown to improve steatosis in all studies and inflammation and fibrosis in some. With respect to anti-diabetic drugs, results for metformin have not been convincing and concerns over the safety of glitazones have reduced the initial enthusiasm for their use. ACE inhibitors and angiotensin II receptor blockers hold the most promise as anti-hypertensive agents for patients with NASH and hypertension. With respect to more specific liver-directed therapies, there have been promising studies of antioxidants, including betaine and probucol, and vitamin E may improve NASH in adults and children. The TNF-α-lowering agent pentoxifylline may have beneficial effects on NASH. Liver transplantation is successful, but the disease recurrence rate is high in the absence of treatment of the underlying metabolic syndrome. PMID:23075871

  9. Non-Alcoholic Steatohepatitis: From Pathophysiology to Novel Therapies.

    PubMed

    Jahn, Daniel; Rau, Monika; Wohlfahrt, Julia; Hermanns, Heike M; Geier, Andreas

    2016-01-01

    Non-alcoholic fatty liver (NAFL) disease is defined by an accumulation of liver fat exceeding 5% of its weight in the absence of significant alcoholic intake. In 5-20%, there is a progression from NAFL to non-alcoholic steatohepatitis (NASH). Until now, it is not well understood why only some patients develop NASH, and currently, no drugs are licensed for this indication. Different T-cell populations such as T-regulatory, Th1 and Th17 cells play a central role in the immunopathogenesis of fatty liver disease and open the option of future interleukin (IL)-17-based therapeutics. The inflammatory process underlying NASH is furthermore characterized by elevated expression of pro-inflammatory cytokines such as TNFα and IL-1β. Anakinra, a recombinant version of IL-1Ra shows promising metabolic effects with improved hyperglycemia and beta-cell secretory function in a double-blind placebo controlled randomized trial in type 2 diabetic patients but such studies are still in their preliminary stages for NASH. Several studies point out that bile acid farnesoid X receptor (FXR)-mediated signals (such as the enterohepatic hormone fibroblast growth factor 15/19) are involved in the regulation of triglyceride and glucose metabolism. Recent clinical trials have revealed a beneficial impact of the FXR agonist obeticholic acid on body weight, insulin sensitivity and liver histology in patients with NASH. Further potential novel therapeutic targets in NASH are currently in phase II clinical development. PMID:27170389

  10. 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

  11. A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats

    PubMed Central

    Svegliati-Baroni, Gianluca; Candelaresi, Cinzia; Saccomanno, Stefania; Ferretti, Gianna; Bachetti, Tiziana; Marzioni, Marco; De Minicis, Samuele; Nobili, Liliana; Salzano, Renata; Omenetti, Alessia; Pacetti, Deborah; Sigmund, Soeren; Benedetti, Antonio; Casini, Alessandro

    2006-01-01

    Insulin resistance induces nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). We used a high-fat, high-calorie solid diet (HFD) to create a model of insulin resistance and NASH in nongenetically modified rats and to study the relationship between visceral adipose tissue and liver. Obesity and insulin resistance occurred in HFD rats, accompanied by a progressive increase in visceral adipose tissue tumor necrosis factor (TNF)-α mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-α expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-α-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor substrate-1Ser307 phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinflammation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis at 6 months. Supplementation of n-3 polyunsaturated fatty acid, a PPARα ligand, to HFD-treated animals restored hepatic adiponectin and PPARα expression, reduced TNF-α hepatic levels, and ameliorated fatty liver and the degree of liver injury. Thus, our model mimics the most common features of NASH in humans and provides an ideal tool to study the role of individual pathogenetic events (as for PPARα down-regulation) and to define any future experimental therapy, such as n-3 polyunsaturated fatty acid, which ameliorated the degree of liver injury. PMID:16936261

  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. 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

  14. 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

  15. 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

  16. 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

  17. Development of a Representative Mouse Model with Nonalcoholic Steatohepatitis.

    PubMed

    Verbeek, Jef; Jacobs, Ans; Spincemaille, Pieter; Cassiman, David

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the Western world. It represents a disease spectrum ranging from isolated steatosis to non-alcoholic steatohepatitis (NASH). In particular, NASH can evolve to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The development of novel treatment strategies is hampered by the lack of representative NASH mouse models. Here, we describe a NASH mouse model, which is based on feeding non-genetically manipulated C57BL6/J mice a 'Western style' high-fat/high-sucrose diet (HF-HSD). HF-HSD leads to early obesity, insulin resistance, and hypercholesterolemia. After 12 weeks of HF-HSD, all mice exhibit the complete spectrum of features of NASH, including steatosis, hepatocyte ballooning, and lobular inflammation, together with fibrosis in the majority of mice. Hence, this model closely mimics the human disease. Implementation of this mouse model will lead to a standardized setup for the evaluation of (i) underlying mechanisms that contribute to the progression of NAFLD to NASH, and (ii) therapeutic interventions for NASH. © 2016 by John Wiley & Sons, Inc. PMID:27248435

  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. 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

  20. Nonalcoholic Steatohepatitis: A Search for Factual Animal Models

    PubMed Central

    Sanches, Sheila Cristina L.; Ramalho, Leandra Naira Z.; Augusto, Marlei Josiele; da Silva, Deisy Mara; Ramalho, Fernando Silva

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, which occurs in the absence of alcohol abuse. NAFLD can evolve into progressive liver injury and fibrosis in the form of nonalcoholic steatohepatitis (NASH). Several animal models have been developed to attempt to represent the morphological, biochemical, and clinical features of human NASH. The actual review presents a critical analysis of the most commonly used experimental models of NAFLD/NASH development. These models can be classified into genetic, nutritional, and a combination of genetic and nutritional factors. The main genetic models are ob/ob and db/db mutant mice and Zucker rats. The principal nutritional models employ methionine- and choline-deficient, high-fat, high-cholesterol and high-cholate, cafeteria, and high-fructose diets. Currently, associations between high-fructose and various compositions of high-fat diets have been widely studied. Previous studies have encountered significant difficulties in developing animal models capable of reproducing human NASH. Some models produce consistent morphological findings, but the induction method differs significantly compared with the pathophysiology of human NASH. Other models precisely represent the clinical and etiological contexts of this disease but fail to provide accurate histopathological representations mainly in the progression from steatosis to liver fibrosis. PMID:26064924

  1. 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

  2. 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

  3. Questionnaire survey on lifestyle of patients with nonalcoholic steatohepatitis

    PubMed Central

    Noto, Haruka; Tokushige, Katsutoshi; Hashimoto, Etsuko; Taniai, Makiko; Shiratori, Keiko

    2014-01-01

    Lack of exercise and excessive food intake are known to be the important causes of nonalcoholic steatohepatitis (NASH). To elucidate the relationship between lifestyle and NASH, we surveyed exercise and dietary habits, comparing them among 171 biopsy-proven NASH patients, 29 nonalcoholic fatty liver (NAFL) patients and 49 normal subjects. Dietary habits including the duration of dinner time, amount of rice at dinner, and weekly frequencies of meat, fries, Chinese noodles, sweets, and instant food consumption were significantly different in male NASH patients compared to normal male subjects. In women, differences were seen in the amount of rice at dinner, frequency of eating out, and proclivity for sweets. In male NASH patients, the frequency of physical exercise was significantly lower. The lifestyle tendencies of NASH were almost similar to those of NAFL. In the comparison between obese NASH and non-obese NASH, no clear lifestyle differences were found. In conclusion, the most striking result of this survey was that the lifestyle of males contributed significantly to the development of NASH. These results point to treatment of NASH in males. In female NASH patients, lifestyle differences were minimal, and the effects of other factors such as genetic background will need to be investigated. PMID:25411525

  4. 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

  5. Prevalence of anemia and its risk factors among lactating mothers in Myanmar.

    PubMed

    Zhao, Ai; Zhang, Yumei; Li, Bo; Wang, Peiyu; Li, Jiayin; Xue, Yong; Gao, Hongchong

    2014-05-01

    In Myanmar, 60% of the population consists of mothers and children, and they are the groups most vulnerable to anemia. The objectives of this study are to determine (1) the anemia prevalence among lactating women and (2) the risk factors associated with anemia. Convenience sampling was used to select three villages in two different regions (Kachin and Shan) in Myanmar. Hemoglobin and anthropometric indicators were measured for 733 lactating women. Logistic regression analyses were used to determine factors associated with anemia. The anemia prevalence rate was 60.3% in lactating women, with 20.3% of lactating women having severe anemia. Factors of malnutrition (P = 0.026), self-reported symptoms of night blindness or poor dark adaptation (P < 0.001), lack of primary education experience (P < 0.001), low family annual capita income (< 800 MMK; P < 0.001), drinking spring or river water (P < 0.001), and drinking unboiled water (P = 0.016) were associated with anemia. To promote health in lactating women, a comprehensive intervention is needed in these regions. PMID:24639302

  6. Prevalence of Anemia and Its Risk Factors Among Lactating Mothers in Myanmar

    PubMed Central

    Zhao, Ai; Zhang, Yumei; Li, Bo; Wang, Peiyu; Li, Jiayin; Xue, Yong; Gao, Hongchong

    2014-01-01

    In Myanmar, 60% of the population consists of mothers and children, and they are the groups most vulnerable to anemia. The objectives of this study are to determine (1) the anemia prevalence among lactating women and (2) the risk factors associated with anemia. Convenience sampling was used to select three villages in two different regions (Kachin and Shan) in Myanmar. Hemoglobin and anthropometric indicators were measured for 733 lactating women. Logistic regression analyses were used to determine factors associated with anemia. The anemia prevalence rate was 60.3% in lactating women, with 20.3% of lactating women having severe anemia. Factors of malnutrition (P = 0.026), self-reported symptoms of night blindness or poor dark adaptation (P < 0.001), lack of primary education experience (P < 0.001), low family annual capita income (< 800 MMK; P < 0.001), drinking spring or river water (P < 0.001), and drinking unboiled water (P = 0.016) were associated with anemia. To promote health in lactating women, a comprehensive intervention is needed in these regions. PMID:24639302

  7. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism.

    PubMed

    Lauritzen, Knut H; Morland, Cecilie; Puchades, Maja; Holm-Hansen, Signe; Hagelin, Else Marie; Lauritzen, Fredrik; Attramadal, Håvard; Storm-Mathisen, Jon; Gjedde, Albert; Bergersen, Linda H

    2014-10-01

    The G-protein-coupled lactate receptor, GPR81 (HCA1), is known to promote lipid storage in adipocytes by downregulating cAMP levels. Here, we show that GPR81 is also present in the mammalian brain, including regions of the cerebral neocortex and hippocampus, where it can be activated by physiological concentrations of lactate and by the specific GPR81 agonist 3,5-dihydroxybenzoate to reduce cAMP. Cerebral GPR81 is concentrated on the synaptic membranes of excitatory synapses, with a postsynaptic predominance. GPR81 is also enriched at the blood-brain-barrier: the GPR81 densities at endothelial cell membranes are about twice the GPR81 density at membranes of perivascular astrocytic processes, but about one-seventh of that on synaptic membranes. There is only a slight signal in perisynaptic processes of astrocytes. In synaptic spines, as well as in adipocytes, GPR81 immunoreactivity is located on subplasmalemmal vesicular organelles, suggesting trafficking of the protein to and from the plasma membrane. The results indicate roles of lactate in brain signaling, including a neuronal glucose and glycogen saving response to the supply of lactate. We propose that lactate, through activation of GPR81 receptors, can act as a volume transmitter that links neuronal activity, cerebral energy metabolism and energy substrate availability. PMID:23696276

  8. Lactate Activates HIF-1 in Oxidative but Not in Warburg-Phenotype Human Tumor Cells

    PubMed Central

    De Saedeleer, Christophe J.; Copetti, Tamara; Porporato, Paolo E.; Verrax, Julien

    2012-01-01

    Cancer can be envisioned as a metabolic disease driven by pressure selection and intercellular cooperativeness. Together with anaerobic glycolysis, the Warburg effect, formally corresponding to uncoupling glycolysis from oxidative phosphorylation, directly participates in cancer aggressiveness, supporting both tumor progression and dissemination. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key contributor to glycolysis. It stimulates the expression of glycolytic transporters and enzymes supporting high rate of glycolysis. In this study, we addressed the reverse possibility of a metabolic control of HIF-1 in tumor cells. We report that lactate, the end-product of glycolysis, inhibits prolylhydroxylase 2 activity and activates HIF-1 in normoxic oxidative tumor cells but not in Warburg-phenotype tumor cells which also expressed lower basal levels of HIF-1α. These data were confirmed using genotypically matched oxidative and mitochondria-depleted glycolytic tumor cells as well as several different wild-type human tumor cell lines of either metabolic phenotype. Lactate activates HIF-1 and triggers tumor angiogenesis and tumor growth in vivo, an activity that we found to be under the specific upstream control of the lactate transporter monocarboxylate transporter 1 (MCT1) expressed in tumor cells. Because MCT1 also gates lactate-fueled tumor cell respiration and mediates pro-angiogenic lactate signaling in endothelial cells, MCT1 inhibition is confirmed as an attractive anticancer strategy in which a single drug may target multiple tumor-promoting pathways. PMID:23082126

  9. Staphylococcus aureus lactate- and malate-quinone oxidoreductases contribute to nitric oxide resistance and virulence.

    PubMed

    Spahich, Nicole A; Vitko, Nicholas P; Thurlow, Lance R; Temple, Brenda; Richardson, Anthony R

    2016-06-01

    Staphylococcus aureus is a Gram-positive pathogen that resists many facets of innate immunity including nitric oxide (NO·). Staphylococcus aureus NO-resistance stems from its ability to evoke a metabolic state that circumvents the negative effects of reactive nitrogen species. The combination of l-lactate and peptides promotes S. aureus growth at moderate NO-levels, however, neither nutrient alone suffices. Here, we investigate the staphylococcal malate-quinone and l-lactate-quinone oxidoreductases (Mqo and Lqo), both of which are critical during NO-stress for the combined utilization of peptides and l-lactate. We address the specific contributions of Lqo-mediated l-lactate utilization and Mqo-dependent amino acid consumption during NO-stress. We show that Lqo conversion of l-lactate to pyruvate is required for the formation of ATP, an essential energy source for peptide utilization. Thus, both Lqo and Mqo are essential for growth under these conditions making them attractive candidates for targeted therapeutics. Accordingly, we exploited a modelled Mqo/Lqo structure to define the catalytic and substrate-binding residues.We also compare the S. aureus Mqo/Lqo enzymes to their close relatives throughout the staphylococci and explore the substrate specificities of each enzyme. This study provides the initial characterization of the mechanism of action and the immunometabolic roles for a newly defined staphylococcal enzyme family. PMID:26851155

  10. Glycolysis and the significance of lactate in traumatic brain injury

    PubMed Central

    Carpenter, Keri L. H.; Jalloh, Ibrahim; Hutchinson, Peter J.

    2015-01-01

    In traumatic brain injury (TBI) patients, elevation of the brain extracellular lactate concentration and the lactate/pyruvate ratio are well-recognized, and are associated statistically with unfavorable clinical outcome. Brain extracellular lactate was conventionally regarded as a waste product of glucose, when glucose is metabolized via glycolysis (Embden-Meyerhof-Parnas pathway) to pyruvate, followed by conversion to lactate by the action of lactate dehydrogenase, and export of lactate into the extracellular fluid. In TBI, glycolytic lactate is ascribed to hypoxia or mitochondrial dysfunction, although the precise nature of the latter is incompletely understood. Seemingly in contrast to lactate's association with unfavorable outcome is a growing body of evidence that lactate can be beneficial. The idea that the brain can utilize lactate by feeding into the tricarboxylic acid (TCA) cycle of neurons, first published two decades ago, has become known as the astrocyte-neuron lactate shuttle hypothesis. Direct evidence of brain utilization of lactate was first obtained 5 years ago in a cerebral microdialysis study in TBI patients, where administration of 13C-labeled lactate via the microdialysis catheter and simultaneous collection of the emerging microdialysates, with 13C NMR analysis, revealed 13C labeling in glutamine consistent with lactate utilization via the TCA cycle. This suggests that where neurons are too damaged to utilize the lactate produced from glucose by astrocytes, i.e., uncoupling of neuronal and glial metabolism, high extracellular levels of lactate would accumulate, explaining the association between high lactate and poor outcome. Recently, an intravenous exogenous lactate supplementation study in TBI patients revealed evidence for a beneficial effect judged by surrogate endpoints. Here we review the current state of knowledge about glycolysis and lactate in TBI, how it can be measured in patients, and whether it can be modulated to achieve better

  11. 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

  12. Prevention of Hepatic Fibrosis in a Murine Model of Metabolic Syndrome with Nonalcoholic Steatohepatitis

    PubMed Central

    DeLeve, Laurie D.; Wang, Xiangdong; Kanel, Gary C.; Atkinson, Roscoe D.; McCuskey, Robert S.

    2008-01-01

    The endocannabinoid pathway plays an important role in the regulation of appetite and body weight, hepatic lipid metabolism, and fibrosis. Blockade of the endocannabinoid receptor CB1 with SR141716 promotes weight loss, reduces hepatocyte fatty acid synthesis, and is antifibrotic. D-4F, an apolipoprotein A-1 mimetic with antioxidant properties, is currently in clinical trials for the treatment of atherosclerosis. C57BL/6J mice were fed a high-fat diet for 7 months, followed by a 2.5-month treatment with either SR141716 or D-4F. SR141716 markedly improved body weight, liver weight, serum transaminases, insulin resistance, hyperglycemia, hypercholesterolemia, hyperleptinemia, and oxidative stress, accompanied by the significant prevention of fibrosis progression. D-4F improved hypercholesterolemia and hyperleptinemia without improvement in body weight, steatohepatitis, insulin resistance, or oxidative stress, and yet, there was significant prevention of fibrosis. D-4F prevented culture-induced activation of stellate cells in vitro. In summary, C57BL/6J mice given a high-fat diet developed features of metabolic syndrome with nonalcoholic steatohepatitis and fibrosis. Both SR141716 and D-4F prevented progression of fibrosis after onset of steatohepatitis, ie, a situation comparable to a common clinical scenario, with D-4F seeming to have a more general antifibrotic effect. Either compound therefore has the potential to be of clinical benefit. PMID:18772330

  13. 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

  14. 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

  15. Recent advances in mouse models of obesity- and nonalcoholic steatohepatitis-associated hepatocarcinogenesis

    PubMed Central

    Nakagawa, Hayato

    2015-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer, and obesity has been established as a risk factor for HCC development. Nonalcoholic steatohepatitis (NASH) is apparently the key link between obesity and hepatocarcinogenesis, and obesity also accelerates HCC development synergistically with other risk factors, such as hepatitis virus infection and alcohol consumption. As an explanation for the pathogenesis of NASH, the so-called “two-hit” theory has been widely accepted, but recently, a better model, the so-called “multiple-hits hypothesis” was proposed, which states that many disease-promoting factors may occur in parallel, rather than consecutively. However, the overall mechanism remains largely unknown. Various cell-cell and organ-organ interactions are involved in the pathogenesis of NASH, and thus appropriate in vivo disease models are essential for a deeper understanding. However, replicating the full spectrum of human NASH has been difficult, as NASH involves obesity, insulin resistance, steatohepatitis, fibrosis, and ultimately HCC, and the lack of an appropriate mouse model has been a considerable barrier to determining the missing links among obesity, NASH, and HCC. In recent years, several innovative mouse models presenting obesity- and NASH-associated HCC have been established by modified diets, chemotoxic agents, genetic manipulation, or a combination of these factors, shedding some light on this complex network and providing new therapeutic strategies. Thus, in this paper, I review the mouse models of obesity- and NASH-associated HCC, especially focusing on recent advances and their clinical relevance. PMID:26301053

  16. 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

  17. 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

  18. 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

  19. Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible?

    PubMed Central

    Lytle, Kelli A.; Jump, Donald B.

    2016-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative. Methods We evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice. Results Mice fed WD for 22–24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7–8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 ≥ 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (PUFA) content. Conclusion These studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD

  20. Voluntary exercise during pregnancy and lactation and its effect on lactational performance in mice.

    PubMed

    Karasawa, K; Suwa, J; Kimura, S

    1981-01-01

    The amount of voluntary exercise during pregnancy and lactation and its effect on the lactational performance in mice were investigated. Female mice were housed in exercise cages with treadwheels during periods of growth, pregnancy and lactation and the amounts of exercise were measured. It was observed that growing female mice exercised voluntarily at a level of approximately 5,000 rotations (diameter of treadwheel; 13.5 cm) per day during the 4-week growth period. After conception, the amount of exercise gradually decreased and in late pregnancy running activity decreased markedly. Throughout the lactational period dams exercised lightly. As indices of lactational performance, the body weights of pups nursed in litters of 8, milk yield and cellular development of abdominal-inguinal mammary glands were examined. There were no significant differences in the final body weights of pups, milk yield per day or development of mammary glands between exercise and non-exercise groups. PMID:7328442

  1. [Interference of ethylene glycol on lactate assays].

    PubMed

    Graïne, H; Toumi, K; Roullier, V; Capeau, J; Lefèvre, G

    2007-01-01

    Ethylene glycol is broken down to three main organic acids: glycolic acid, glyoxylic acid and oxalic acid which cause severe metabolic acidosis. Effect of these three acids on lactate assays was evaluated in five blood gas analysers and two clinical chemistry analysers. For all systems, no influence of oxalic acid on lactate results could be demonstrated. No interference of glycolic acid could be observed on lactate assay performed with Rapid Lab 1265 (R: 104,9 +/- 12,1%), Vitros 950 (R: 105,7 +/- 5,3 %) and Architect ci8200 (R: 104,9 +/- 4,7%), but on the contrary, CCX 4, OMNI S, ABL 725 and 825 demonstrated a concentration-dependent interference. No interference of glyoxylic acid could be observed with Vitros 950, but a positive interference could be observed with ABL 725 and 825, OMNI S, CCX4 and Architect ci8200 A linear relationship between apparent lactate concentration found with ABL 725 and 825, OMNI S, CCX 4, and glyoxylic acid could be observed (0,94 < r < 0,99), a weaker interference being observed with Rapid Lab 1265 and Architect ci 8200. Our results demonstrated that in case of ethylene glycol poisoning, cautious interpretation of lactate assay should be done, since wrong results of lactacidemia could lead to misdiagnostic and delay patient treatment. PMID:17627925

  2. 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

  3. Marital Interaction in Alcoholic and Nonalcoholic Couples: Alcoholic Subtype Variations and Wives’ Alcoholism Status

    PubMed Central

    Floyd, Frank J.; Daugherty, Michelle Klotz; Fitzgerald, Hiram H.; Cranford, James A.; Zucker, Robert A.

    2008-01-01

    The authors examined problem-solving marital interactions of alcoholic and nonalcoholic couples (N = 132). Four alcoholic groups (husband alcoholic with antisocial personality disorder or not, paired with alcoholic or nonalcoholic wives) were compared with each other and with a both-spouses-nonalcoholic group. Consistent with the alcoholic subtypes hypothesis, couples with an antisocial alcoholic husband had higher levels of hostile behavior regardless of wives’ alcoholism status. In contrast, rates of positive behaviors and the ratio of positive to negative behaviors were greatest among couples in which either both or neither of the spouses had alcoholic diagnoses and were lowest among alcoholic husbands with nonalcoholic wives. Discussion focuses on possible mechanisms linking antisocial alcoholism and discrepant alcoholic diagnoses to poorer marital outcomes. PMID:16492103

  4. Prelacteal feeding: influencing factors and relation to establishment of lactation.

    PubMed

    Ahmed, F U; Rahman, M E; Alam, M S

    1996-08-01

    This study was carried out with a view to finding out factors influencing prelacteal feeding and its relation to establishment of lactation in rural Bangladesh. 420 mothers in early post-partum period were interviewed at home. Prelacteal feeding was given to 77% of the babies, and honey was given to 72% of them. The common methods of prelacteal feeding were by finger (41%) and spoon (40%). Twelve socio-demographic and health care variables were studied for their probable influence on prelacteal feeding. Nine of them accounted for 22% of the variability in giving prelacteal feeding. Reasons of giving prelacteal feeding and the time of first breast feeding influenced the practice significantly (P < 0.05). Type and duration of prelacteal feeding had significant negative influence on "coming in" of milk (P < 0.05). Prelacteal feeding accounted for 44% of variations in coming in of milk. Prelacteal feeding and coming in of milk formed a vicious cycle: the former delayed initiation of lactation and on the other hand delay in coming in of milk encouraged prelacteal feeding. These observation emphasized the need for coordinated efforts for promotion of proper infant feeding practices in our rural community. PMID:9103657

  5. [Relevance of lactate determination in sports medicine].

    PubMed

    Schwaberger, G; Pessenhofer, H; Schmid, P

    1985-05-31

    In the last years increasing attention has been paid to specific changes of muscle metabolism during physical exertion in the diagnosis of physical performance. Lactate resp. lactic acid, being the terminal product of anaerobic glycolysis, has gained a central position in that field of sports medicine. Measuring lactate concentration level in arterialized capillary blood (drawn from the earlobe) one can investigate both the onset of anaerobic-lactic energy production during increasing work load (aerobic-anaerobic transition) and the maximal amount of anaerobic energy formation during short periods of exhausting work. In this way, using suitable work load protocols, the aerobic capacity (endurance capacity) on the one hand and the anaerobic capacity on the other hand can be determined. Therefore the most prominent components of energy production in working muscle and physical performance in general are accessible by measurement of blood lactate concentration level. PMID:4036145

  6. Elevated Lactate Secondary to Gastrointestinal Beriberi.

    PubMed

    Duca, James; Lum, Corey J; Lo, Angela M

    2016-01-01

    Thiamine deficiency usually occurs with prolonged nutritional deficiency and is almost universally identified with Wernicke's encephalopathy or beriberi. It is also, however, a rare cause of elevated lactate and gastroenterological symptoms. This case report describes a 30-year-old man with 2 weeks of gastroenterological symptoms and intermittent oral intake, who was found to have an elevated lactate level. Neurological exam was normal and an extensive workup was negative, but after being treated with thiamine, his lactate level improved overnight and all of his symptoms resolved. Thiamine levels returned low at 44 nmol/L (normal 78-185 nmol/L). Lack of recognition of this phenomenon, while rare, can lead to unnecessary tests and procedures and increased morbidity and mortality. PMID:25876741

  7. 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

  8. 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

  9. Metabolic Imaging: A link between Lactate Dehydrogenase A, Lactate and Tumor Phenotype

    PubMed Central

    Thakur, Sunitha B.; Vider, Jelena; Russell, James; Blasberg, Ronald; Koutcher, Jason A.

    2014-01-01

    Purpose We compared the metabolic profiles and the association between LDH-A expression and lactate production in two isogenic murine breast cancer cell lines and tumors (67NR and 4T1). These cell lines were derived from a single mammary tumor and have different growth and metabolic phenotypes. Experimental Design LDH-A expression, lactate concentration, glucose utilization and oxygen consumption were measured in cells, and the potential relationship between tumor lactate levels (measured by magnetic resonance spectroscopic imaging (MRSI)) and tumor glucose utilization (measured by [18F] 2-deoxy-2-fluoro-D-glucose positron emission tomography ([18F]FDG-PET)) was assessed in orthotopic breast tumors derived from these cell lines. Results We show a substantial difference in LDH-A expression between 67NR and 4T1 cells under normoxia and hypoxia. We also show that small orthotopic 4T1 tumors generate tenfold more lactate than corresponding 67NR tumors. The high lactate levels in small primary 4T1 tumors are associated with intense pimonidazole staining (a hypoxia indicator). Less intense hypoxia staining was observed in the larger 67NR tumors, and is consistent with the gradual increase and plateau of lactate concentration in enlarging 67NR tumors. Conclusions Lactate-MRSI has a greater dynamic range than [18F]FDG-PET and may be a more sensitive measure with which to evaluate the aggressive and metastatic potential of primary breast tumors. PMID:21844011

  10. The Effectiveness of Lactation Consultants and Lactation Counselors on Breastfeeding Outcomes.

    PubMed

    Patel, Sanjay; Patel, Shveta

    2016-08-01

    Breastfeeding for all infants starting at birth and continuing until at least 6 months of age has been recommended by the World Health Organization and the American Academy of Pediatrics. The health benefits to infants and mothers have been demonstrated in many studies. Dedicated lactation specialists may play a role in providing education and support to pregnant women and new mothers wishing to breastfeed to improve breastfeeding outcomes. The objective of this review was to assess if lactation education or support programs using lactation consultants or lactation counselors would improve rates of initiation and duration of any breastfeeding and exclusive breastfeeding compared with usual practice. A systematic literature review of the evidence was conducted using electronic databases. The review was limited to randomized trials and yielded 16 studies with 5084 participants. It was found that breastfeeding interventions using lactation consultants and counselors increase the number of women initiating breastfeeding (odds ratio [OR] for any initiation vs not initiating breastfeeding = 1.35; 95% confidence interval [CI], 1.10-1.67). The interventions improve any breastfeeding rates (OR for any breastfeeding up to 1 month vs not breastfeeding = 1.49; 95% CI, 1.09-2.04). In addition, there were beneficial effects on exclusive breastfeeding rates (OR for exclusive breastfeeding up to 1 month vs not exclusive breastfeeding = 1.71; 95% CI, 1.20-2.44). Most of the evidence would suggest developing and improving postpartum support programs incorporating lactation consultants and lactation counselors. PMID:26644419

  11. Diet for a Healthy Lactating Woman.

    PubMed

    Kolasa, Kathryn M; Firnhaber, Gina; Haven, Kelley

    2015-12-01

    The nutrient and caloric requirements for lactation are set by the Institute of Medicine. The dietary pattern to meet those needs is found in the Dietary Guidelines for Americans. Only deficiency states for selected nutrients and/or prolonged inadequate caloric intake appear to affect the volume and quality of breast milk. Other dietary concerns of lactating women include "dieting" to return to prepregnancy weight; low maternal intake of selected nutrients due to health conditions or food choices; need for supplementation of calcium, vitamin D, and fatty acids; and use of non-nutritive sweeteners, caffeine, herbal supplements, and alcohol. PMID:26398295

  12. Calcium metabolism in pregnancy and lactation

    PubMed Central

    White, C P

    2009-01-01

    Homeostatic adaptation to maternal calcium metabolism is a prerequisite for optimal delivery of sufficient calcium to the fetus and neonate during pregnancy and lactation, respectively. This article outlines the major adaptations known to occur and the physiological regulators likely to be principally involved. Importantly, different adaptive responses are used in pregnancy and lactation. The rarity of calcium disorders in pregnancy underscores the successful implementation of these adaptations in most women. For those few women with either pre-existing or pregnancy-acquired disorders of calcium metabolism, a knowledge of normal physiology is essential to understand the implications for managing these disorders in pregnant women.

  13. 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

  14. 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

  15. Gender-specific drinking styles in alcoholics and nonalcoholics.

    PubMed

    Olenick, N L; Chalmers, D K

    1991-07-01

    This study examined sex differences in drinking style when considering both alcoholics and nonalcoholics (controls). The Alcohol Use Inventory was employed as a descriptive instrument. Of the 16 primary scales two results of significant interaction were obtained indicating sex differences in problem drinking practices corrected, as it were, for sex differences in normal drinking practices. Female alcoholics used alcohol to alter their mood more than did the alcoholic men, whereas women in the control group used it less for this purpose than did the male controls. The second interaction effect indicated that female alcoholics drank in response to marital difficulties much more than did male alcoholics. The control women, by contrast, demonstrated less of a likelihood to drink for this reason than did male controls. PMID:1875705

  16. 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

  17. 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

  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. Current complications and challenges in nonalcoholic steatohepatitis screening and diagnosis.

    PubMed

    Golabi, Pegah; Sayiner, Mehmet; Fazel, Yousef; Koenig, Aaron; Henry, Linda; Younossi, Zobair M

    2016-01-01

    Nonalcoholic steatohepatitis (NASH) can lead to complications such as liver failure, cirrhosis and hepatocellular carcinoma. The diagnostic gold standard for NASH is liver biopsy; however, other noninvasive methods have been developed. In this article, the authors evaluate current methods in NASH screening and diagnosis. Routine radiologic modalities were found to detect hepatic steatosis accurately, but were unable to establish the diagnosis of NASH or stage of fibrosis. Newly developed elastography based techniques seem promising to estimate liver fibrosis. Other noninvasive tests such as FibroTest, ELF, Hepascore, FIB-4, NFS, FLI and ION (biochemical panels) have AUROCs ranging between 0.80-0.98 for detecting advanced fibrosis but lack specificity for detecting mild fibrosis. Noninvasive tools, especially elastography, identify NASH associated advanced fibrosis potentially reducing liver biopsies. More research is needed to validate the clinical utility of these tests. PMID:26469309

  20. Mechanisms of Liver Injury in Non-Alcoholic Steatohepatitis.

    PubMed

    Duwaerts, Caroline C; Maher, Jacquelyn J

    2014-06-01

    Non-alcoholic steatohepatitis (NASH) is a disorder marked by alterations in hepatic lipid homeostasis as well as liver injury in the form of cell death, inflammation and fibrosis. Research into the pathophysiology of NASH is dynamic. New concepts from the fields of cell biology, microbiology, immunology and genetics are being tested for their applicability to NASH; discoveries in each of these areas are enriching our understanding of this complex disease. This review summarizes how recent developments from the bench and bedside are merging with more traditional concepts to reshape our view of NASH pathogenesis. Highlights include human studies that emphasize the role of de novo lipogenesis in NASH and experimental work uncovering a role for the inflammasome in NASH. Genetic predispositions to NASH are being clarified, and intestinal microbiome is emerging as a determinant of fatty liver. These unique ideas are now taking their place within an integrated picture of NASH pathogenesis. PMID:25045618

  1. 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

  2. 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

  3. 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

  4. NASH (Nonalcoholic steatohepatitis): A case of multiorganelle failure.

    PubMed

    Caldwell, Stephen

    2014-10-01

    The clinical term 'multiorgan failure' lends itself, modified to 'multiorganelle failure', to the cascading events in cellular systems leading to hepatocyte injury, cell death, inflammation and fibrosis and ultimately to cirrhosis in NASH (non-alcoholic steatohepatitis). NASH is one of the most common forms of liver disease and constitutes the severe form of NAFLD (non-alcoholic fatty liver disease). The key features that distinguish potentially progressive NASH from relatively stable non-NASH fatty liver (NNFL, often referred to as simple steatosis) are cellular ballooning, inflammation and fibrosis. These findings, together with steatosis or accumulation of greater than normal hepatic lipid, usually constitute histological NASH seen on liver biopsy or in laboratory samples. Cellular ballooning is not specific to NASH but it is perhaps the most emblematic finding on histological samples. The ballooned hepatocyte has evidence of cytoskeletal injury (depletion and condensation as Mallory-Denk bodies), accumulation of partially oxidized small fat droplets, mitochondrial morphological changes presumably related to organelle dysfunction, dilated endoplasmic reticulum and autophagosomes - an attempt at cellular repair. Ballooning itself likely results from a combination of cytoskeletal injury resulting in loss of normal cell shape and from accumulation of injured and somewhat derelict small fat droplets and dilated endoplasmic reticulum. Cellular injury in NASH and especially cellular ballooning can be viewed as a process of 'multi-organelle failure' beginning with generation of super oxide and failure to contain the subsequent oxidative injury and by-products in an environment rich in lipid fuel. These events lead to activation of imunologic pathways. Dysfunction of the small fat droplet appears to be a central mechanism and the oxidative injury can be viewed as the process of rancidification - the chemical decomposition of oils, lipids and fats. PMID:26461413

  5. Effect of resveratrol on experimental non-alcoholic steatohepatitis.

    PubMed

    Heebøll, Sara; Thomsen, Karen Louise; Clouston, Andrew; Sundelin, Elias Immanuel; Radko, Yulia; Christensen, Lars Porskjær; Ramezani-Moghadam, Mehdi; Kreutzfeldt, Martin; Pedersen, Steen Bønløkke; Jessen, Niels; Hebbard, Lionel; George, Jacob; Grønbæk, Henning

    2015-01-01

    Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are increasing clinical problems for which effective treatments are required. The polyphenol resveratrol prevents the development of fatty liver disease in a number of experimental studies. We hypothesized that it could revert steatohepatitis, including hepatic inflammation and fibrosis, in an experimental NASH model. To induce hepatic steatohepatitis, a 65% fat, 2% cholesterol and 0.5% cholate (HFC) diet was fed to rats for 1 or 16 weeks, prior to treatment. Subsequently, the diet was supplemented with resveratrol (approx. 100mg/rat/day) to three intervention groups; week 2-4, 2-7 or 17-22. Treated animals were sacrificed at the end of each intervention period with appropriate control and HFC diet controls. Blood and liver were harvested for analysis. When commenced early, resveratrol treatment partially mitigated transaminase elevations, hepatic enlargement and TNFα induced protein-3 protein expression, but generally resveratrol treatment had no effect on elevated hepatic triglyceride levels, histological steatohepatitis or fibrosis. We observed a slight reduction in Collagen1α1 mRNA expression and no reduction in the mRNA expression of other markers of fibrosis, inflammation or steatosis (TGFβ, TNFα, α2-MG, or SREBP-1c). Resveratrol metabolites were detected in serum, including trans-resveratrol-3-O-sulphate/trans-resveratrol-4'-O-sulphate (mean concentration 7.9 μg/ml). Contrary to the findings in experimental steatosis, resveratrol treatment had no consistent therapeutic effect in alleviating manifest experimental steatohepatitis. PMID:25814186

  6. 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

  7. Differential Intrahepatic Phospholipid Zonation in Simple Steatosis and Nonalcoholic Steatohepatitis

    PubMed Central

    Wattacheril, Julia; Seeley, Erin H.; Angel, Peggi; Chen, Heidi; Bowen, Benjamin P.; Lanciault, Christian; M.Caprioli, Richard; Abumrad, Naji; Flynn, Charles Robb

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) occurs frequently in a setting of obesity, dyslipidemia and insulin resistance, but the etiology of the disease, particularly the events favoring progression to nonalcoholic steatohepatitis (NASH) as opposed to simple steatosis (SS), are not fully understood. Based on known zonation patterns in protein, glucose and lipid metabolism, coupled with evidence that phosphatidylcholine may play a role in NASH pathogenesis, we hypothesized that phospholipid zonation exists in liver and that specific phospholipid abundance and distribution may be associated with histologic disease. A survey of normal hepatic protein expression profiles in the Human Protein Atlas revealed pronounced zonation of enzymes involved in lipid utilization and storage, particularly those facilitating phosphatidylcholine (PC) metabolism. Immunohistochemistry of obese normal, SS and NASH liver specimens with anti-phosphatidylethanomine N-methyltransferase (PEMT) antibodies showed a progressive decrease in the zonal distribution of this PC biosynthetic enzyme. Phospholipid quantitation by liquid chromatography mass spectrometry (LC-MS) in hepatic extracts of Class III obese patients with increasing NAFLD severity revealed that most PC species with 32, 34 and 36 carbons as well as total PC abundance was decreased with SS and NASH. Matrix assisted laser desorption ionization - imaging mass spectrometry (MALDI-IMS) imaging revealed strong zonal distributions for 32, 34 and 36 carbon PCs in controls (minimal histologic findings) and SS that was lost in NASH specimens. Specific lipid species such as PC 34∶1 and PC 36∶2 best illustrated this phenomenon. These findings suggest that phospholipid zonation may be associated with the presence of an intrahepatic proinflammatory phenotype and thus have broad implications in the etiopathogenesis of NASH. PMID:23451176

  8. Effect of chronic psychosocial stress on nonalcoholic steatohepatitis in mice

    PubMed Central

    Czech, Barbara; Neumann, Inga D; Müller, Martina; Reber, Stefan O; Hellerbrand, Claus

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which may progress towards inflammation (nonalcoholic steatohepatitis (NASH)). NAFLD is regarded as a consequence of a sedentary, food-abundant lifestyle which, in the modern world, often coincides with chronically high levels of perceived psychosocial stress. Here, we aimed to characterize the effect of chronic psychosocial stress on the development of NAFLD/NASH in male mice either fed with standard chow or NASH-inducing high fat diet. Chronic psychosocial stress was induced by chronic subordinate colony housing (CSC), a pre-clinically validated paradigm relevant for human affective and somatic disorders. Single housed (SHC) mice served as controls. Under standard chow conditions CSC mice revealed lower hepatic triglyceride levels but higher hepatic TNFα, MCP-1 and HMOX mRNA expression, while serum transaminase levels did not significantly differ from SHC mice. Under the NASH-inducing high-fat diet CSC and SHC mice showed similar body weight-gain and serum levels of glucose and adiponectin. Moreover, liver histology as well as TNFα, MCP-1 and HMOX expression were similar in CSC and SHC mice fed with HFD. Surprisingly, CSC showed even significantly lower transaminase levels than SHC mice fed with the same NASH-inducing diet. Together, these data indicate that under normal dietary conditions the CSC model induces noticeable hepatic oxidative stress and inflammation without causing manifest hepatocellular injury. In contrast, CSC exhibited a protective effect on hepatocellular injury in a dietary NASH-model. Identification of the underlying mechanisms of this phenomenon may lead to novel therapeutic strategies to prevent progression of NAFLD. PMID:23923077

  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. 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

  11. Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability

    PubMed Central

    Luther, Jay; Garber, John J.; Khalili, Hamed; Dave, Maneesh; Bale, Shyam Sundhar; Jindal, Rohit; Motola, Daniel L.; Luther, Sanjana; Bohr, Stefan; Jeoung, Soung Won; Deshpande, Vikram; Singh, Gurminder; Turner, Jerrold R.; Yarmush, Martin L.; Chung, Raymond T.; Patel, Suraj J.

    2015-01-01

    BACKGROUND & AIMS Emerging data suggest that changes in intestinal permeability and increased gut microbial translocation contribute to the inflammatory pathway involved in nonalcoholic steatohepatitis (NASH) development. Numerous studies have investigated the association between increased intestinal permeability and NASH. Our meta-analysis of this association investigates the underlying mechanism. METHODS A meta-analysis was performed to compare the rates of increased intestinal permeability in patients with NASH and healthy controls. To further address the underlying mechanism of action, we studied changes in intestinal permeability in a diet-induced (methionine-and-choline-deficient; MCD) murine model of NASH. In vitro studies were also performed to investigate the effect of MCD culture medium at the cellular level on hepatocytes, Kupffer cells, and intestinal epithelial cells. RESULTS Nonalcoholic fatty liver disease (NAFLD) patients, and in particular those with NASH, are more likely to have increased intestinal permeability compared with healthy controls. We correlate this clinical observation with in vivo data showing mice fed an MCD diet develop intestinal permeability changes after an initial phase of liver injury and tumor necrosis factor-α (TNFα) induction. In vitro studies reveal that MCD medium induces hepatic injury and TNFα production yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFα in altering intestinal permeability, we found that mice genetically resistant to TNFα-myosin light chain kinase (MLCK)–induced intestinal permeability changes fed an MCD diet still develop increased permeability and liver injury. CONCLUSIONS Our clinical and experimental results strengthen the association between intestinal permeability increases and NASH and also suggest that an early phase of hepatic injury and inflammation contributes to altered intestinal permeability in a fashion independent of TNF

  12. 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

  13. Novel Membrane Based Process for Producing Lactate Esters

    SciTech Connect

    1999-02-01

    Lactate Esters from Renewable Carbohydrate Feedstocks can Replace Petroleum-Derived Solvents. Lactate esters are versatile solvents that are biodegradable, nontoxic, and applicable to a wide range of industrial and consumer uses.

  14. LactMed: New NLM Database on Drugs and Lactation

    MedlinePlus

    ... Issues Research News From NIH LactMed: New NLM Database on Drugs and Lactation Past Issues / Summer 2006 ... Javascript on. Photo: Comstock LactMed, a free online database with information on drugs and lactation, is one ...

  15. LactMed: New NLM Database on Drugs and Lactation

    MedlinePlus

    ... Current Issue Past Issues Research News From NIH LactMed: New NLM Database on Drugs and Lactation Past ... milk, infant levels in blood, potential effects in breast-feeding infants and on lactation itself. The American Academy ...

  16. IBFAN Africa training initiatives: code implementation and lactation management.

    PubMed

    Mbuli, A

    1994-01-01

    As part of an ongoing effort to halt the decline of breast feeding rates in Africa, 35 representatives of 12 different African countries met in Mangochi, Malawi, in February 1994. The Code of Marketing of Breastmilk Substitutes was scrutinized. National codes were drafted based on the "Model Law" of the IBFAN Code Documentation Centre (ICDC), Penang. Mechanisms of implementation, specific to each country, were developed. Strategies for the promotion, protection, and support of breast feeding, which is very important to child survival in Africa, were discussed. The training course was organized by ICDC, in conjunction with IBFAN Africa, and with the support of the United Nations Children's Fund (UNICEF) and the World Health Organization (WHO). Countries in eastern, central, and southern Africa were invited to send participants, who included professors, pediatricians, nutritionists, MCH personnel, nurses, and lawyers. IBFAN Africa has also been conducting lactation management workshops for a number of years in African countries. 26 health personnel (pediatricians, nutritionists, senior nursing personnel, and MCH workers), representing 7 countries in the southern African region, attended a training of trainers lactation management workshop in Swaziland in August, 1993 with the support of their UNICEF country offices. The workshop included lectures, working sessions, discussions, and slide and video presentations. Topics covered included national nutrition statuses, the importance of breast feeding, the anatomy and physiology of breast feeding, breast feeding problems, the International Code of Marketing, counseling skills, and training methods. The field trip to a training course covering primary health care that was run by the Traditional Healers Organization (THO) in Swaziland was of particular interest because of the strong traditional medicine sector in many African countries. IBFAN Africa encourages use of community workers (traditional healers, Rural Health

  17. Increased Serum Levels of LIGHT/TNFSF14 in Nonalcoholic Fatty Liver Disease: Possible Role in Hepatic Inflammation

    PubMed Central

    Otterdal, Kari; Haukeland, John Willy; Yndestad, Arne; Dahl, Tuva B; Holm, Sverre; Segers, Filip M; Gladhaug, Ivar P; Konopski, Zbigniew; Damås, Jan Kristian; Halvorsen, Bente; Aukrust, Pål

    2015-01-01

    Objectives: The tumor necrosis factor superfamily member 14, LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes), has been involved in various autoimmune disorders and has been shown to influence hepatic lipid metabolism. We hypothesized that LIGHT could also have a pathogenic role in nonalcoholic fatty liver disease (NAFLD). Methods: Serum levels of LIGHT in NAFLD patients and control subjects, as well as LIGHT and interleukin (IL)-8 released from Huh7 (human hepatoma cell line) hepatocytes, were determined by enzyme-linked immunosorbent assay. The mRNA expression of LIGHT in the liver tissue and mRNA levels of LIGHT and IL-8 in Huh7 hepatocytes were assessed by real-time quantitative reverse transcription-PCR. Results: (i) Serum levels of LIGHT were significantly elevated in NAFLD patients (n=66) as compared with healthy controls (n=16), with no differences between simple steatosis (n=34) and nonalcoholic steatohepatitis (NASH) (n=32). (ii) Within the liver, NAFLD patients (n=14) had significantly increased mRNA levels of the two LIGHT receptors, herpes virus entry mediator and lymphotoxin β receptor (LTβR), as compared with controls (n=7), with no difference between simple steatosis (n=8) and NASH (n=6). (iii) LIGHT markedly increased the release of IL-8 in Huh7 hepatocytes in a time- and dose-dependent manner. (iv) The reactive oxygen species (ROS) H2O2 (hydrogen peroxide) enhanced the LIGHT-mediated release of IL-8 in Huh7 hepatocytes. Conclusion: We show increased levels of LIGHT and its two membrane-bound receptors in NAFLD, potentially promoting hepatic inflammation through ROS interaction. Our findings should encourage further studies on the role of LIGHT in NAFLD development and progression. PMID:26133108

  18. 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...

  19. 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

  20. 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

  1. 21 CFR 73.165 - Ferrous lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Ferrous lactate. 73.165 Section 73.165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL LISTING OF...

  2. 21 CFR 582.1207 - Calcium lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Calcium lactate. 582.1207 Section 582.1207 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE General Purpose...

  3. ENERGY REQUIREMENTS DURING PREGNANCY AND LACTATION

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: To estimate the energy requirements of pregnant and lactating women consistent with optimal pregnancy outcome and adequate milk production. Design: Total energy cost of pregnancy was estimated using the factorial approach from pregnancy-induced increments in basal metabolic rate measured...

  4. 21 CFR 582.5311 - Ferrous lactate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Ferrous lactate. 582.5311 Section 582.5311 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or...

  5. 21 CFR 582.5311 - Ferrous lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Ferrous lactate. 582.5311 Section 582.5311 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or...

  6. Microbial production of lactate-containing polyesters

    PubMed Central

    Yang, Jung Eun; Choi, So Young; Shin, Jae Ho; Park, Si Jae; Lee, Sang Yup

    2013-01-01

    Due to our increasing concerns on environmental problems and limited fossil resources, biobased production of chemicals and materials through biorefinery has been attracting much attention. Optimization of the metabolic performance of microorganisms, the key biocatalysts for the efficient production of the desired target bioproducts, has been achieved by metabolic engineering. Metabolic engineering allowed more efficient production of polyhydroxyalkanoates, a family of microbial polyesters. More recently, non-natural polyesters containing lactate as a monomer have also been produced by one-step fermentation of engineered bacteria. Systems metabolic engineering integrating traditional metabolic engineering with systems biology, synthetic biology, protein/enzyme engineering through directed evolution and structural design, and evolutionary engineering, enabled microorganisms to efficiently produce natural and non-natural products. Here, we review the strategies for the metabolic engineering of microorganisms for the in vivo biosynthesis of lactate-containing polyesters and for the optimization of whole cell metabolism to efficiently produce lactate-containing polyesters. Also, major problems to be solved to further enhance the production of lactate-containing polyesters are discussed. PMID:23718266

  7. Biomonitoring Polybrominated Diphenyl Ethers in Lactating Women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Breast milk is a valuable biological specimen for biomonitoring lipid-soluble polybrominated diphenyl ethers (PBDEs). The goal of this project was to determine the levels of PBDEs in breast milk of lactating women from the Seacoast region of New Hampshire and to examine potential relationships betw...

  8. Studying Reliability Using Identical Handheld Lactate Analyzers

    ERIC Educational Resources Information Center

    Stewart, Mark T.; Stavrianeas, Stasinos

    2008-01-01

    Accusport analyzers were used to generate lactate performance curves in an investigative laboratory activity emphasizing the importance of reliable instrumentation. Both the calibration and testing phases of the exercise provided students with a hands-on opportunity to use laboratory-grade instrumentation while allowing for meaningful connections…

  9. 21 CFR 73.165 - Ferrous lactate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are... availability of this material at NARA, call 202-741-6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html. (c) Uses and restrictions. Ferrous lactate may...

  10. 21 CFR 73.165 - Ferrous lactate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are... availability of this material at NARA, call 202-741-6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html. (c) Uses and restrictions. Ferrous lactate may...

  11. Cloning and nucleotide sequence of the Lactobacillus casei lactate dehydrogenase gene.

    PubMed Central

    Kim, S F; Baek, S J; Pack, M Y

    1991-01-01

    An allosteric L-(+)-lactate dehydrogenase gene of Lactobacillus casei ATCC 393 was cloned in Escherichia coli, and the nucleotide sequence of the gene was determined. The gene was composed of an open reading frame of 981 bp, starting with a GTG codon and ending with a TAA codon. The sequences for the promoter and ribosome binding site were identified, and a sequence for a structure resembling a rho-independent transcription terminator was also found. Images PMID:1768113

  12. Nonalcoholic Hepatic Steatosis Is a Strong Predictor of High-Risk Coronary-Artery Plaques as Determined by Multidetector CT

    PubMed Central

    Osawa, Kazuhiro; Miyoshi, Toru; Yamauchi, Kentarou; Koyama, Yasushi; Nakamura, Kazufumi; Sato, Shuhei; Kanazawa, Susumu; Ito, Hiroshi

    2015-01-01

    Background Nonalcoholic fatty liver disease is associated with a risk of coronary artery disease (e.g., diabetes mellitus, dyslipidemia, metabolic syndrome). We evaluated whether nonalcoholic hepatic steatosis is associated with high-risk plaques as assessed by multidetector computed tomography (CT). Methods This retrospective study involved 414 participants suspected of having coronary artery disease. Nonalcoholic hepatic steatosis was defined as a liver-to-spleen fat ratio of <1.0 and the presence and appropriate characteristics of coronary-artery plaques as assessed by coronary CT angiography. High-risk plaques were identified, as were low-density plaques, positive remodeling, and spotty calcification. Results Compared with patients who did not have nonalcoholic hepatic steatosis, patients with nonalcoholic hepatic steatosis had more low-density plaques (21% vs. 44%, p<0.01), positive remodeling (41% vs. 58%, p = 0.01), and spotty calcification (12% vs. 36%, p<0.01). The number of high-risk plaques in patients with nonalcoholic hepatic steatosis was greater than in those without nonalcoholic hepatic steatosis (p<0.01). Patients with nonalcoholic hepatic steatosis were more likely to have high-risk plaques than were those with only an elevated level of visceral adipose tissue (≥86 cm2; 35% vs. 16%, p<0.01). Multivariate analyses that included nonalcoholic hepatic steatosis, amount of visceral adipose tissue, and the presence/absence of traditional risk factors demonstrated that nonalcoholic hepatic steatosis was an independent predictor of high-risk plaques (odds ratio: 4.60; 95% confidence interval: 1.94–9.07, p<0.01). Conclusions Diagnosis of nonalcoholic hepatic steatosis may be of value when assessing the risk of coronary artery disease. PMID:26125952

  13. 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

  14. L-Lactate transport into rat heart mitochondria and reconstruction of the L-lactate/pyruvate shuttle.

    PubMed Central

    Valenti, Daniela; de Bari, Lidia; Atlante, Anna; Passarella, Salvatore

    2002-01-01

    In vitro reconstruction of the L-lactate/pyruvate shuttle has been performed, which allows NADH oxidation outside rat heart mitochondria. Such a shuttle occurs due to the combined action of the novel mitochondrial L-lactate/pyruvate antiporter, which differs from the monocarboxylate carrier, and the mitochondrial L-lactate dehydrogenase. The rate of L-lactate/pyruvate antiport proved to regulate the shuttle in vitro. PMID:11988081

  15. L-Lactate transport into rat heart mitochondria and reconstruction of the L-lactate/pyruvate shuttle.

    PubMed

    Valenti, Daniela; de Bari, Lidia; Atlante, Anna; Passarella, Salvatore

    2002-05-15

    In vitro reconstruction of the L-lactate/pyruvate shuttle has been performed, which allows NADH oxidation outside rat heart mitochondria. Such a shuttle occurs due to the combined action of the novel mitochondrial L-lactate/pyruvate antiporter, which differs from the monocarboxylate carrier, and the mitochondrial L-lactate dehydrogenase. The rate of L-lactate/pyruvate antiport proved to regulate the shuttle in vitro. PMID:11988081

  16. D-Lactate transport and metabolism in rat liver mitochondria.

    PubMed Central

    de Bari, Lidia; Atlante, Anna; Guaragnella, Nicoletta; Principato, Giovanni; Passarella, Salvatore

    2002-01-01

    In the present study we investigated whether isolated rat liver mitochondria can take up and metabolize D-lactate. We found the following: (1) externally added D-lactate causes oxygen uptake by mitochondria [P/O ratio (the ratio of mol of ATP synthesized to mol of oxygen atoms reduced to water during oxidative phosphorylation)=2] and membrane potential (Delta(psi)) generation in processes that are rotenone-insensitive, but inhibited by antimycin A and cyanide, and proton release from coupled mitochondria inhibited by alpha-cyanocinnamate, but not by phenylsuccinate; (2) the activity of the putative flavoprotein (D-lactate dehydrogenase) was detected in inside-out submitochondrial particles, but not in mitochondria and mitoplasts, as it is localized in the matrix phase of the mitochondrial inner membrane; (3) three novel separate translocators exist to mediate D-lactate traffic across the mitochondrial inner membrane: the D-lactate/H(+) symporter, which was investigated by measuring fluorimetrically the rate of endogenous flavin reduction, the D-lactate/oxoacid antiporter (which mediates both the D-lactate/pyruvate and D-lactate/oxaloacetate exchanges) and D-lactate/malate antiporter studied by monitoring photometrically the appearance of the D-lactate counteranions outside mitochondria. The D-lactate translocators, in the light of their different inhibition profiles separate from the monocarboxylate carrier, were found to differ from each other in the V(max) values and in the inhibition and pH profiles and were shown to regulate mitochondrial D-lactate metabolism in vitro. The D-lactate translocators and the D-lactate dehydrogenase could account for the removal of the toxic methylglyoxal from cytosol, as well as for D-lactate-dependent gluconeogenesis. PMID:11955284

  17. Effect of lactation number, year, and season of initiation of lactation on milk yield of cows hormonally induced into lactation and treated with recombinant bovine somatotropin.

    PubMed

    Mellado, M; Antonio-Chirino, E; Meza-Herrera, C; Veliz, F G; Arevalo, J R; Mellado, J; de Santiago, A

    2011-09-01

    Records representing data from 1,500 barren Holstein cows over an 8-yr period from a large commercial dairy farm in northern Mexico were analyzed to determine the effects of lactation number and season and year of initiation of lactation on milk production of cows induced hormonally into lactation and treated with recombinant bovine somatotropin (rbST) throughout lactation. Peak and 305-d milk yields were also assessed as predictors of total milk yield in cows induced into lactation. A significant quadratic relationship was found between 305-d milk yield and number of lactation [7,607±145 and 9,548±181 kg for first- and ≥6-lactation cows, respectively; mean ± standard error of the mean (SEM)] with the highest production occurring in the fifth lactation. Total milk yields of cows with ≤2 lactations were approximately 4,500 kg less than milk yields of adult cows (the overall average ± standard milk yield was 13,544±5,491 kg per lactation and the average lactation length was 454±154 d). Moreover, 305-d milk production was depressed in cows induced into lactation in spring (8,804±153 kg; mean ± SEM) and summer (8,724±163 kg) than in fall (9,079±151 kg) and winter (9,085±143 kg). Partial regression coefficients for 305-d milk yield and peak milk yield indicated an increment of 157 kg of milk per lactation per 1-kg increase in peak milk yield (r(2)=0.69). Neither peak milk yield (r(2)=0.18) nor 305-d milk yield (r(2)=0.29) was accurate for predicting total milk yield per lactation. Year, parity, and season effects had significant influence on milk yield of cows induced into lactation and treated with rbST throughout lactation, and peak milk yield can assist in the prediction of 305-d milk yield but not total milk yield. This study also showed that hormonal induction of lactation in barren high-yielding cows is a reliable, practical, and affordable technique in countries where rbST treatment and prolonged steroid administration of dairy cows are legally

  18. Tin-containing silicates: alkali salts improve methyl lactate yield from sugars.

    PubMed

    Tolborg, Søren; Sádaba, Irantzu; Osmundsen, Christian M; Fristrup, Peter; Holm, Martin S; Taarning, Esben

    2015-02-01

    This study focuses on increasing the selectivity to methyl lactate from sugars using stannosilicates as heterogeneous catalyst. All group I ions are found to have a promoting effect on the resulting methyl lactate yield. Besides, the alkali ions can be added both during the preparation of the catalyst or directly to the solvent mixture to achieve the highest reported yield of methyl lactate (ca. 75 %) from sucrose at 170 °C in methanol. The beneficial effect of adding alkali to the reaction media applies not only to highly defect-free Sn-Beta prepared through the fluoride route, but also to materials prepared by post-treatment of dealuminated commercial Beta zeolites, as well as ordered mesoporous stannosilicates, in this case Sn-MCM-41 and Sn-SBA-15. These findings open the door to the possibility of using other preparation methods or different Sn-containing silicates with equally high methyl lactate yields as Sn-Beta. PMID:25605624

  19. Targeting metabolic flexibility by simultaneously inhibiting respiratory complex I and lactate generation retards melanoma progression

    PubMed Central

    Chaube, Balkrishna; Malvi, Parmanand; Singh, Shivendra Vikram; Mohammad, Naoshad; Meena, Avtar Singh; Bhat, Manoj Kumar

    2015-01-01

    Melanoma is a largely incurable skin malignancy owing to the underlying molecular and metabolic heterogeneity confounded by the development of resistance. Cancer cells have metabolic flexibility in choosing either oxidative phosphorylation (OXPHOS) or glycolysis for ATP generation depending upon the nutrient availability in tumor microenvironment. In this study, we investigated the involvement of respiratory complex I and lactate dehydrogenase (LDH) in melanoma progression. We show that inhibition of complex I by metformin promotes melanoma growth in mice via elevating lactate and VEGF levels. In contrast, it leads to the growth arrest in vitro because of enhanced extracellular acidification as a result of increased glycolysis. Inhibition of LDH or lactate generation causes decrease in glycolysis with concomitant growth arrest both in vitro and in vivo. Blocking lactate generation in metformin-treated melanoma cells results in diminished cell proliferation and tumor progression in mice. Interestingly, inhibition of either LDH or complex I alone does not induce apoptosis, whereas inhibiting both together causes depletion in cellular ATP pool resulting in metabolic catastrophe induced apoptosis. Overall, our study suggests that LDH and complex I play distinct roles in regulating glycolysis and cell proliferation. Inhibition of these two augments synthetic lethality in melanoma. PMID:26484566

  20. Best prediction of yields for long lactations.

    PubMed

    Cole, J B; Null, D J; Vanraden, P M

    2009-04-01

    Lactation records of any reasonable length now can be processed with the selection index method known as best prediction (BP). Previous prediction programs were limited to the 305-d standard used since 1935. Best prediction was implemented in 1998 to calculate lactation records in USDA genetic evaluations, replacing the test interval method used since 1969 to calculate lactation records. Best prediction is more complex but also more accurate, particularly when testing is less frequent. Programs were reorganized to output better graphics, give users simpler access to options, and provide additional output, such as BP of daily yields. Test-day data for 6 breeds were extracted from the national dairy database, and lactation lengths were required to be > or =500 d (Ayrshire, Milking Shorthorn) or > or =800 d (all others). Average yield and SD at any day in milk (DIM) were estimated by fitting 3-parameter Wood's curves (milk, fat, protein) and 4-parameter exponential functions (somatic cell score) to means and SD of 15- (< or =300 DIM) and 30-d (>300 DIM) intervals. Correlations among TD yields were estimated using an autoregressive matrix to account for biological changes and an identity matrix to model daily measurement error. Autoregressive parameters (r) were estimated separately for first (r = 0.998) and later parities (r = 0.995). These r values were slightly larger than previous estimates due to the inclusion of the identity matrix. Correlations between traits were modified so that correlations between somatic cell score and other traits may be nonzero. The new lactation curves and correlation functions were validated by extracting TD data from the national database, estimating 305-d yields using the original and new programs, and correlating those results. Daily BP of yield were validated using daily milk weights from on-farm meters in university research herds. Correlations ranged from 0.900 to 0.988 for 305-d milk yield. High correlations ranged from 0.844 to

  1. Mustard bran in lactating dairy cow diets.

    PubMed

    Maiga, H A; Bauer, M L; Dahlen, C R; Badaruddin, M; Scholljegerdes, E J

    2011-06-01

    Two trials using lactating Holstein cows were conducted to evaluate effects of a diet containing oriental mustard bran on dry matter intake (DMI), milk production, milk components, and organoleptic properties. In experiment 1, 34 lactating cows (24 multiparous and 10 primiparous; days in milk ≥ 50 d) were used in a switchback design to determine the lactational response and organoleptic quality of milk when the diet contained 8% oriental mustard bran (MB) versus a control diet (CON). Mustard bran replaced a portion of soybean meal and all the beet pulp in the CON diet. Milk yields were greater for cows fed the MB diet; however, no differences were found in DMI, 3.5% fat- (FCM) or solids-corrected milk. Milk components and components production were not affected by treatment. Milk organoleptic qualities were not affected by diet. In experiment 2, 22 lactating cows (16 multiparous and 6 primiparous; days in milk ≥ 21 d) were assigned randomly within parity to receive MB or CON from wk 4 to 19 postpartum in a randomized complete block design. Cows were fed CON wk 1 to 3 postpartum. The MB diet contained the same ingredients as the CON, except sunflower seed and a portion of soybean meal were replaced with mustard bran. Milk and components data were collected during wk 3 postpartum and used as covariates to adjust treatment means. Intake was greater for cows fed the MB diet; however, daily milk, 3.5% FCM, and solids-corrected milk yields were not different between diets. Milk components and component yields were not affected by treatment. Milk urea concentration was less for cows fed the MB diet. Although cows fed the MB diet had greater DMI, this was not translated into a higher milk 3.5% FCM/DMI production efficiency ratio. During experiment 2, many cows fed MB experienced minor to severe hemolysis with bloody urine. This hemolysis believed to be caused by the S-methyl-cysteine sulfoxide contained in mustard bran could have affected milk production efficiency

  2. 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

  3. 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...

  4. [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

  5. 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

  6. Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis

    PubMed Central

    Heinrichs, Daniel; Berres, Marie-Luise; Coeuru, Melanie; Knauel, Meike; Nellen, Andreas; Fischer, Petra; Philippeit, Claudia; Bucala, Richard; Trautwein, Christian; Wasmuth, Hermann E.; Bernhagen, Jürgen

    2014-01-01

    MIF is an inflammatory cytokine but is hepatoprotective in models of hepatotoxin-induced liver fibrosis. Hepatic fibrosis can also develop from metabolic liver disease, such as nonalcoholic fatty liver disease (NASH). We investigated the role of MIF in high-fat or methionine- and choline-deficient diet mouse models of NASH. Mif−/− mice showed elevated liver triglyceride levels (WT, 53±14 mg/g liver; Mif−/−, 103±7 mg/g liver; P<0.05) and a 2–3-fold increased expression of lipogenic genes. Increased fatty degeneration in the livers of Mif−/−mice was associated with increased hepatic inflammatory cells (1.6-fold increase in F4/80+ macrophages) and proinflammatory cytokines (e.g., 2.3-fold increase in Tnf-α and 2-fold increase in Il-6 expression). However, inflammatory cells and cytokines were decreased by 50–90% in white adipose tissue (WAT) of Mif−/− mice. Subset analysis showed that macrophage phenotypes in livers of Mif−/− mice were skewed toward M2 (e.g., 1.7-fold and 2.5-fold increase in Arg1 and Il-13, respectively, and 2.5-fold decrease in iNos), whereas macrophages were generally reduced in WAT of these mice (70% reduction in mRNA expression of F4/80+ macrophages). The protective MIF effect was scrutinized in isolated hepatocytes. MIF reversed inflammation-induced triglyceride accumulation in Hepa1-6 cells and primary hepatocytes and also attenuated oleic acid-elicited triglyceride increase in 3T3-L1 adipocytes. Protection from fatty hepatocyte degeneration was paralleled by a 2- to 3-fold reduction by MIF of hepatocyte proinflammatory cytokine production. Blockade of MIF receptor cluster of differentiation 74 (CD74) but not of CXCR2 or CXCR4 fully reverted the protective effect of MIF, comparable to AMPK inhibition. In summary, we demonstrate that MIF mediates hepatoprotection through the CD74/AMPK pathway in hepatocytes in metabolic models of liver injury.—Heinrichs, D., Berres, M.-L., Coeuru, M., Knauel, M., Nellen, A., Fischer

  7. The energetics of lactation in cooperatively breeding meerkats Suricata suricatta.

    PubMed

    Scantlebury, M; Russell, A F; McIlrath, G M; Speakman, J R; Clutton-Brock, T H

    2002-10-22

    Species may become obligate cooperative breeders when parents are unable to raise their offspring unassisted. We measured the daily energy expenditure of mothers, helpers and offspring during peak lactation in cooperatively breeding meerkats Suricata suricatta using the doubly labelled water technique. Lactating mothers expended more energy per day than allo-lactating subordinate females, non-lactating females or suckling offspring. Metabolizable energy intakes of lactating mothers were calculated from isotope-based estimates of offspring milk energy intake, and were not significantly different from the previously suggested maximal limit for mammals. Allo-lactating females were the only category of animals that lost weight during the period of study, probably because they spent more time babysitting than non-lactating females. Daily energy expenditure (DEE) of lactating mothers increased with litter size but decreased with the number of helpers. Calculations show that for every 10 helpers, even in the absence of allo-lactators, mothers are able to reduce their DEE during peak lactation by an amount equivalent to the energy cost of one pup. These results indicate that helpers have beneficial energetic consequences for lactating mothers in an obligate cooperatively breeding mammal. PMID:12396490

  8. The energetics of lactation in cooperatively breeding meerkats Suricata suricatta.

    PubMed Central

    Scantlebury, M; Russell, A F; McIlrath, G M; Speakman, J R; Clutton-Brock, T H

    2002-01-01

    Species may become obligate cooperative breeders when parents are unable to raise their offspring unassisted. We measured the daily energy expenditure of mothers, helpers and offspring during peak lactation in cooperatively breeding meerkats Suricata suricatta using the doubly labelled water technique. Lactating mothers expended more energy per day than allo-lactating subordinate females, non-lactating females or suckling offspring. Metabolizable energy intakes of lactating mothers were calculated from isotope-based estimates of offspring milk energy intake, and were not significantly different from the previously suggested maximal limit for mammals. Allo-lactating females were the only category of animals that lost weight during the period of study, probably because they spent more time babysitting than non-lactating females. Daily energy expenditure (DEE) of lactating mothers increased with litter size but decreased with the number of helpers. Calculations show that for every 10 helpers, even in the absence of allo-lactators, mothers are able to reduce their DEE during peak lactation by an amount equivalent to the energy cost of one pup. These results indicate that helpers have beneficial energetic consequences for lactating mothers in an obligate cooperatively breeding mammal. PMID:12396490

  9. The effect of dietary energy source during mid to late lactation on liver triglyceride and lactation performance of dairy cows.

    PubMed

    Vazquez-Añon, M; Bertics, S J; Grummer, R R

    1997-10-01

    Control [1.61 Mcal of net energy for lactation (NEL)/kg of dry matter (DM)], high grain (1.70 Mcal of NEL)/kg of DM), or high fat [1.70 Mcal of NEL/kg of DM with 2.3% tallow (DM basis)] diets were fed to 43 cows (150 +/- 3.1 d in milk) during mid to late lactation to determine effects on performance characteristics, metabolic parameters, or both during mid to late lactation, the dry period, and the first 100 d of the next lactation. All cows received identical diets during the dry period and during early lactation. Increasing the energy density of the diets during mid to late lactation increased DM intake (DMI), plasma nonesterified fatty acid concentration, milk production, and milk protein yield. Compared with the high grain diets, fat supplementation decreased DMI and the percentage of milk protein but increased plasma nonesterified fatty acid concentration without causing elevation of liver triglyceride at the end of mid to late lactation. Increased energy density of the diets did not affect body condition score during mid to late lactation. There were no residual effects for any of the treatments on DMI, lactation performance, or body weight in the subsequent lactation. However, energy supplementation during mid to late lactation increased liver triglyceride content after calving. Compared with high fat diets, high grain diets fed during mid to late lactation increased plasma beta-hydroxy-butyrate concentration in the subsequent lactation. High energy diets fed during mid to late lactation may influence lipid metabolism during the following lactation. PMID:9361222

  10. 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

  11. 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

  12. Lactation Biology Symposium: circadian clocks as mediators of the homeorhetic response to lactation.

    PubMed

    Casey, T M; Plaut, K

    2012-03-01

    The transition from pregnancy to lactation is the most stressful period in the life of a cow. During this transition, homeorhetic adaptations are coordinated across almost every organ and are marked by changes in hormones and metabolism to accommodate the increased energetic demands of lactation. Recent data from our laboratory showed that changes in circadian clocks occur in multiple tissues during the transition period in rats and indicate that the circadian system coordinates changes in the physiology of the dam needed to support lactation. Circadian rhythms coordinate the timing of physiological processes and synchronize these processes with the environment of the animal. Circadian rhythms are generated by molecular circadian clocks located in the hypothalamus (the master clock) and peripherally in every organ of the body. The master clock receives environmental and physiological cues and, in turn, synchronizes internal physiology by coordinating endocrine rhythms and metabolism through peripheral clocks. The effect of the circadian clock on lactation may be inferred by the photoperiod effect on milk production, which is accompanied by coordinated changes in the endocrine system and metabolic capacity of the dam to respond to changes in day length. We have shown that bovine mammary epithelial cells possess a functional clock that can be synchronized by external stimuli, and the expression of the aryl hydrocarbon receptor nuclear translocator-like gene, a positive limb of the core clock, is responsive to prolactin in bovine mammary explants. Others showed that 7% of genes expressed in breasts of lactating women had circadian patterns of expression, and we report that the diurnal variation of composition of bovine milk is associated with changes in expression of mammary core clock genes. Together these studies indicate that the circadian system coordinates the metabolic and hormonal changes needed to initiate and sustain lactation, and we believe that the

  13. Major Role of NAD-Dependent Lactate Dehydrogenases in Aerobic Lactate Utilization in Lactobacillus plantarum during Early Stationary Phase

    PubMed Central

    Goffin, Philippe; Lorquet, Frédérique; Kleerebezem, Michiel; Hols, Pascal

    2004-01-01

    NAD-independent lactate dehydrogenases are commonly thought to be responsible for lactate utilization during the stationary phase of aerobic growth in Lactobacillus plantarum. To substantiate this view, we constructed single and double knockout mutants for the corresponding genes, loxD and loxL. Lactate-to-acetate conversion was not impaired in these strains, while it was completely blocked in mutants deficient in NAD-dependent lactate dehydrogenase activities, encoded by the ldhD and ldhL genes. We conclude that NAD-dependent but not NAD-independent lactate dehydrogenases are involved in this process. PMID:15375150

  14. The primary pathway for lactate oxidation in Desulfovibrio vulgaris

    PubMed Central

    Vita, Nicolas; Valette, Odile; Brasseur, Gaël; Lignon, Sabrina; Denis, Yann; Ansaldi, Mireille; Dolla, Alain; Pieulle, Laetitia

    2015-01-01

    The ability to respire sulfate linked to lactate oxidation is a key metabolic signature of the Desulfovibrio genus. Lactate oxidation by these incomplete oxidizers generates reductants through lactate dehydrogenase (LDH) and pyruvate-ferredoxin oxidoreductase (PFOR), with the latter catalyzing pyruvate conversion into acetyl-CoA. Acetyl-CoA is the source of substrate-level phosphorylation through the production of ATP. Here, we show that these crucial steps are performed by enzymes encoded by a nonacistronic transcriptional unit named now as operon luo (for lactate utilization operon). Using a combination of genetic and biochemical techniques, we assigned a physiological role to the operon genes DVU3027-28 and DVU3032-33. The growth of mutant Δ26-28 was highly disrupted on D-lactate, whereas the growth of mutant Δ32-33 was slower on L-lactate, which could be related to a decrease in the activity of D-lactate or L-lactate oxidase in the corresponding mutants. The DVU3027-28 and DVU3032-33 genes thus encode functional D-LDH and L-LDH enzymes, respectively. Scanning of the genome for lactate utilization revealed several lactate permease and dehydrogenase homologs. However, transcriptional compensation was not observed in any of the mutants except for lactate permease. Although there is a high degree of redundancy for lactate oxidase, it is not functionally efficient in LDH mutants. This result could be related to the identification of several operon enzymes, including LDHs, in the PFOR activity bands, suggesting the occurrence of a lactate-oxidizing supermolecular structure that can optimize the performance of lactate utilization in Desulfovibrio species. PMID:26167158

  15. Chronic pain management in pregnancy and lactation.

    PubMed

    Coluzzi, F; Valensise, H; Sacco, M; Allegri, M

    2014-02-01

    During pregnancy most of women will experience some kind of pain, either as a result of a pre-existing condition (low back pain, headache, fibromyalgia, and rheumatoid arthritis) or as a direct consequence of pregnancy (weight gain, postural changes, pelvic floor dysfunction, hormonal factors). However, chronic pain management during pregnancy and lactation remains a challenge for clinicians and pregnant women are at risk of undertreatment for painful conditions, because of fear about use of drugs during pregnancy. Few analgesic drugs have been demonstrated to be absolutely contraindicated during pregnancy and breastfeeding, but studies in pregnant women are not available for most of pain medications. The aim of this paper is to review the safety profile in pregnancy or lactation of the commonly prescribed pain medications and non-pharmacological treatments. In addition to the conventional classifications from the Food and Drug Administration and the American Academy of Paediatrics, authors analyzed the currently available clinical data from literature. PMID:23857445

  16. Lipid Transport in the Lactating Mammary Gland

    PubMed Central

    McManaman, James L.

    2015-01-01

    Mammalian cells depend on phospholipid (PL) and fatty acid (FA) transport to maintain membrane structure and organization, and to fuel and regulate cellular functions. In mammary glands of lactating animals, copious milk secretion, including large quantities of lipid in some species, requires adaptation and integration of PL and FA synthesis and transport processes to meet secretion demands. At present few details exist about how these processes are regulated within the mammary gland. However, recent advances in our understanding of the structural and molecular biology of membrane systems and cellular lipid trafficking provide insights into the mechanisms underlying the regulation and integration of PL and FA transport processes the lactating mammary gland. This review discusses the PL and FA transport processes required to maintain the structural integrity and organization of the mammary gland and support its secretory functions within the context of current molecular and cellular models of their regulation. PMID:24567110

  17. Reduction of d-lactate content in sauerkraut using starter cultures of recombinant Leuconostoc mesenteroides expressing the ldhL gene.

    PubMed

    Jin, Qing; Li, Ling; Moon, Jin Seok; Cho, Seung Kee; Kim, Yu Jin; Lee, Soo Jin; Han, Nam Soo

    2016-05-01

    The d-form of lactate, which causes metabolic stress upon excessive dietary intake, is mainly produced by Leuconostoc sp., the predominant species in sauerkraut. To shift the metabolic flux of d-lactate from pyruvate to l-lactate, we expressed the l-lactate dehydrogenase (ldhL) gene in Leuconostoc mesenteroides ATCC 8293. The ldhL gene from Lactobacillus plantarum was introduced into L. mesenteroides using the shuttle vectors pLeuCM and pLeuCM42. To elevate the expression level of ldhL in L. mesenteroides, the nucleotides for pyruvate kinase promoter were fused to ldhL and cloned into above vectors to construct pLC18pkL and pLC42pkL. As results, introduction of pLC42pkL in L. mesenteroides significantly improved both l-LDH activity and l-lactate productivity during fermentation, decreasing the d-/l-lactate ratio. When used as a starter culture for sauerkraut fermentation, recombinant L. mesenteroides harboring pLC42pkL increased l-lactate concentration and decreased d-lactate concentration compared to the wild type strain. We newly developed a recombinant L. mesenteroides which has high l-lactate dehydrogenase activity and applied this strain to minimize the harmful effect of d-lactate during the sauerkraut fermentation. To the best of our knowledge, we demonstrate for the first time the effective use of recombinant Leuconostoc sp. for quality improvement of fermented foods. PMID:26472127

  18. Spectrophotometric determination of ethacridine lactate in infusion

    PubMed Central

    Jain, Pritam S.; Surana, S. J.

    2011-01-01

    Aim: A simple, rapid, selective, accurate, and precise UV spectrophotometric method has been developed for the estimation of ethacridine lactate from bulk and pharmaceutical formulation. Materials and Methods: Appropriate aliquot portions of stock standard solution of ethacridine lactate were transferred into five separate 10 ml volumetric flasks, and the volume was adjusted to the mark with double distilled water to obtain concentrations of 0.2, 0.4, 0.6, 0.8, 1.0, and 1.2 μg/ml. The λmax of ethacridine lactate in double distill water was found to be 271 nm with an apparent molar absorptivity of 59.781 × 103 l/mol cm. The drug follows linearity in the concentration range 2–12 μg/ml with a correlation coefficient value of 0.998. Results: The proposed method was applied to pharmaceutical formulation and % amount of drug estimated 99.71% was found to be in good agreement with the label claim. The accuracy of the method was checked by recovery experiment performed at three different levels, i.e., 80%, 100%, and 120%. The % recovery was found to be in the range 99.26–100.25%. The low values of % RSD are indicative of the accuracy and reproducibility of the method. The precision of the method was studied as intraday, interday variations and repeatability. The % RSD value less than 2 indicates that the method is precise. Ruggedness of the proposed method was studied with the help of two analysts. Conclusion: The results indicated that the method could be used for the routine estimation of ethacridine lactate from tablet formulations. PMID:23781454

  19. Peafowl lactate dehydrogenase: problem of isoenzyme identification.

    PubMed

    Rose, R G; Wilson, A C

    1966-09-16

    Peafowl, like other vertebrates, contain multiple forms of lactate dehydrogenase. The electrophoretic properties of the peafowl isoenzymes are unusual in that the isoenzyme from heart tissue can be either more or less anodic than that of muscle, depending on the pH. This finding focuses attention on the problem of isoenzyme identification. It is suggested that isoenzymes be identified on the basis of properties that are chemically and biologically more significant than electrophoretic mobility. PMID:5917779

  20. 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

  1. 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

  2. Berberine Reduces Neurotoxicity Related to Nonalcoholic Steatohepatitis in Rats

    PubMed Central

    Ghareeb, Doaa A.; Khalil, Sofia; Hafez, Hani S.; Bajorath, Jürgen; Ahmed, Hany E. A.; Sarhan, Eman; Elwakeel, Eiman; El-Demellawy, Maha A.

    2015-01-01

    Berberine is a plant alkaloid that has several pharmacological effects such as antioxidant, antilipidemic, and anti-inflammatory effects. Nonalcoholic steatohepatitis (NASH) triggers different aspects of disorders such as impaired endogenous lipid metabolism, hypercholesterolemia, oxidative stress, and neurotoxicity. In this study, we examined the mechanism by which NASH induces neurotoxicity and the protective effect of berberine against both NASH and its associated neurotoxicity. NASH induced rats showed significant impairments in lipid metabolism with increased serum triglycerides, cholesterol, and low-density lipoprotein (LDL). The NASH induced group also demonstrated a significant oxidative stress which is characterized by increased TBARs level and decreased antioxidant capacity such as GSH and SOD levels. Moreover, the NASH induction was associated with inflammation which was demonstrated by increased TNFα and nitric oxide levels. Hyperglycemia and hyperinsulinemia were observed in the NASH induced group. Also, our results showed a significant increase in the expression of the acetylcholine esterase (AChE) and amyloid beta precursor protein (AβPP). These changes were significantly correlated with decreased insulin degrading enzyme (IDE) and beta-amyloid40 (Aβ40) and increased beta-amyloid42 (Aβ42) in the hippocampal region. Daily administration of berberine (50 mg/kg) for three weeks ameliorated oxidative stress, inflammation, hyperlipidemia, hyperglycemia, hyperinsulinemia, and the observed neurotoxicity. PMID:26576191

  3. Liver transplantation for nonalcoholic steatohepatitis in young patients.

    PubMed

    Alkhouri, Naim; Hanouneh, Ibrahim A; Zein, Nizar N; Lopez, Rocio; Kelly, Dympna; Eghtesad, Bijan; Fung, John J

    2016-04-01

    Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of obesity and insulin resistance. The aim of this study was to determine the frequency of NASH as an indication for liver transplantation (LT) in children and young adults and to characterize patient and graft survival. The study included all children and young adult patients (up to the age of 40 years) who underwent LT in the United States for NASH cirrhosis from the 1987 to 2012 United Network for Organ Sharing (UNOS) database. Kaplan-Meier analysis was used to assess patient and graft survival. A total of 330 patients were included, 68% were Caucasian, and the mean BMI was 33.6 ± 6.3. Age at time of LT ranged between 4 and 40 years (mean 33.9 ± 6.6 years). Fourteen subjects were <18 years of age at time of LT and 20 were between the ages of 18 and 25 years. Median follow-up after 1st LT was 45.8 months [10.7, 97.3]. During this time, 30% of subjects (n = 100) died and 11.5% (n = 38) were retransplanted including 13 for NASH recurrence. In conclusion, NASH can progress to end-stage liver disease requiring LT in childhood and early adulthood. A significant number of young patients transplanted for NASH cirrhosis required retransplantation. PMID:26402655

  4. Extract of a polyherbal formulation ameliorates experimental nonalcoholic steatohepatitis

    PubMed Central

    Azeemuddin, Mohammed; Rafiq, Mohamed; Anturlikar, Suryakanth Dattatraya; Sharath Kumar, Lakkavalli Mohan; Patki, Pralhad Sadashiv; Babu, Uddagiri Venkanna; Shyam, Ramakrishnan

    2015-01-01

    The objective of the present study is to evaluate the effect of the extract of a well-known hepatospecific polyherbal formulation, Liv.52, in an experimental model of high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) in rats. Feeding a HFD for 15 weeks resulted in significant impairment of the lipid profile, elevation of hepatic enzyme markers, and insulin resistance in rats. The histological examination of the liver furthermore indicated fibrotic changes and fat deposition in hepatic tissues. The treatment with Liv.52 extract [125 mg/kg body weight per os (b.wt. p.o.)], which was administered from week 9 onward, reversed the HFD-induced changes to a statistically significant extent, compared to the untreated positive control animals. The effect observed with Liv.52 extract was comparable to that of pioglitazone (4 mg/kg b.wt.), a standard drug that is useful in the management of NASH. The treatment with Liv.52 extract significantly reduced steatosis, collagen deposition, and necrosis in hepatic tissues, which indicates its antifibrotic and antinecrotic properties. The results obtained in the present set of experiments indicate that Liv.52 extract effectively reverses metabolic and histological changes associated with HFD-induced NASH. PMID:27114939

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. Nonalcoholic Steatohepatitis: Involvement of the Telomerase and Proinflammatory Mediators

    PubMed Central

    Serhal, Rim; Hilal, George; Boutros, George; Sidaoui, Joseph; Wardi, Layal; Ezzeddine, Salah; Alaaeddine, Nada

    2015-01-01

    Nonalcoholic steatohepatitis or NASH is an excessive accumulation of fat in hepatocytes accompanied by inflammation and hepatic injury. Proinflammatory molecules such as IL-17, CCL20, S100A8, S100A9, and S100A8/A9 have been shown to be implicated in many types of cancer. Telomerase activity has been found to be associated with chronic inflammation and cancer. NASH can progress to fibrosis then cirrhosis and finally to hepatocellular carcinoma (HCC). Our objective is to try to find a relation between inflammation and the progression of NASH into HCC. We found that there was a significant elevation in the telomerase activity, detected by real-time PCR, between NASH and fibrotic NASH in the liver biopsies of patients. The expression of S100A8, S100A9, S100A8/A9, CCL20, and IL-17, detected by ELISA, is significantly increased in NASH patients with fibrosis in comparison with controls. But, in NASH patients, S100A9, S100A8/A9, and IL-17 only are significantly elevated in comparison with controls. The same, on the mRNA level, expression of IL-17, detected by RT-PCR, is significantly elevated in NASH patients in comparison with controls. Therefore, there is a direct link between the expression of IL-17, CCL20, telomerase, S100A8, and S100A9 in the fibrotic condition and the progression towards cancer. PMID:26273651

  15. 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

  16. Histological study of alcoholic, nonalcoholic, and obstructive chronic pancreatitis.

    PubMed

    De Angelis, C; Valente, G; Spaccapietra, M; Angonese, C; Del Favero, G; Naccarato, R; Andriulli, A

    1992-01-01

    Pancreatic tissue obtained from 26 patients with alcoholic chronic pancreatitis (ACP), nine patients with nonalcoholic idiopathic chronic pancreatitis (NAICP), and seven patients with obstructive chronic pancreatitis (OCP) was studied in an attempt to determine whether clinical or etiologic differences have a morphologic counterpart. Histologically it was easy to distinguish ACP from OCP occurring distal to an obstruction of the pancreatic duct. Nine patients with NAICP showed histological features similar to those found in ACP. Plugs and calcifications were found as frequently in NAICP as in ACP, suggesting that NAICP, whatever the etiology, is truly pancreatolithiasis, which leads to slowly progressive fibrosis and acinar atrophy in the obstructed pancreatic lobule. Nerve fibers were found to be more numerous in all disease categories. Inflammatory foci of lymphocytes associated with nerves were observed in 57 and 35% of cases with OCP and ACP, respectively, but only in one patient with NAICP. These findings may constitute a pathological basis for the existing clinical data showing that NAICP frequently runs a pain-free course. PMID:1553368

  17. 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

  18. Treatment of Nonalcoholic Steatohepatitis in Adults: Present and Future

    PubMed Central

    Gitto, S.; Vitale, G.; Villa, E.; Andreone, P.

    2015-01-01

    Nonalcoholic steatohepatitis has become one of the most common liver-related health problems. This condition has been linked to an unhealthy diet and weight gain, but it can also be observed in nonobese people. The standard of care is represented by the lifestyle intervention. However, because this approach has several limitations, such as a lack of compliance, the use of many drugs has been proposed. The first-line pharmacological choices are vitamin E and pioglitazone, both showing a positive effect on transaminases, fat accumulation, and inflammation. Nevertheless, vitamin E has no proven effect on fibrosis and on long-term morbidity and mortality and pioglitazone has a negative impact on weight. Other drugs have been studied such as metformin, ursodeoxycholic acid, statins, pentoxiphylline, and orlistat with only partially positive results. Among the emerging treatments, telmisartan is particularly interesting as it seems to have an impact on insulin resistance, liver steatosis, inflammation, and fibrosis. However, the pathogenesis of steatohepatitis is highly complex and is determined by different parallel hits; indeed, the association of different drugs that act on various levels has been suggested. In conclusion, lifestyle intervention should be optimised and the associations of different drugs should be tested in large studies with long-term outcomes. PMID:25866507

  19. 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

  20. Characterization of Lactate Sensors Based on Lactate Oxidase and Palladium Benzoporphyrin Immobilized in Hydrogels.

    PubMed

    Andrus, Liam P; Unruh, Rachel; Wisniewski, Natalie A; McShane, Michael J

    2015-01-01

    An optical biosensor for lactate detection is described. By encapsulating enzyme-phosphor sensing molecules within permeable hydrogel materials, lactate-sensitive emission lifetimes were achieved. The relative amount of monomer was varied to compare three homo- and co-polymer materials: poly(2-hydroxyethyl methacrylate) (pHEMA) and two copolymers of pHEMA and poly(acrylamide) (pAam). Diffusion analysis demonstrated the ability to control lactate transport by varying the hydrogel composition, while having a minimal effect on oxygen diffusion. Sensors displayed the desired dose-variable response to lactate challenges, highlighting the tunable, diffusion-controlled nature of the sensing platform. Short-term repeated exposure tests revealed enhanced stability for sensors comprising hydrogels with acrylamide additives; after an initial "break-in" period, signal retention was 100% for 15 repeated cycles. Finally, because this study describes the modification of a previously developed glucose sensor for lactate analysis, it demonstrates the potential for mix-and-match enzyme-phosphor-hydrogel sensing for use in future multi-analyte sensors. PMID:26198251

  1. Characterization of Lactate Sensors Based on Lactate Oxidase and Palladium Benzoporphyrin Immobilized in Hydrogels

    PubMed Central

    Andrus, Liam P.; Unruh, Rachel; Wisniewski, Natalie A.; McShane, Michael J.

    2015-01-01

    An optical biosensor for lactate detection is described. By encapsulating enzyme-phosphor sensing molecules within permeable hydrogel materials, lactate-sensitive emission lifetimes were achieved. The relative amount of monomer was varied to compare three homo- and co-polymer materials: poly(2-hydroxyethyl methacrylate) (pHEMA) and two copolymers of pHEMA and poly(acrylamide) (pAam). Diffusion analysis demonstrated the ability to control lactate transport by varying the hydrogel composition, while having a minimal effect on oxygen diffusion. Sensors displayed the desired dose-variable response to lactate challenges, highlighting the tunable, diffusion-controlled nature of the sensing platform. Short-term repeated exposure tests revealed enhanced stability for sensors comprising hydrogels with acrylamide additives; after an initial “break-in” period, signal retention was 100% for 15 repeated cycles. Finally, because this study describes the modification of a previously developed glucose sensor for lactate analysis, it demonstrates the potential for mix-and-match enzyme-phosphor-hydrogel sensing for use in future multi-analyte sensors. PMID:26198251

  2. Increased Brain Lactate Concentrations Without Increased Lactate Oxidation During Hypoglycemia in Type 1 Diabetic Individuals

    PubMed Central

    De Feyter, Henk M.; Mason, Graeme F.; Shulman, Gerald I.; Rothman, Douglas L.; Petersen, Kitt Falk

    2013-01-01

    Previous studies have reported that brain metabolism of acetate is increased more than twofold during hypoglycemia in type 1 diabetic (T1D) subjects with hypoglycemia unawareness. These data support the hypothesis that upregulation of blood-brain barrier monocarboxylic acid (MCA) transport may contribute to the maintenance of brain energetics during hypoglycemia in subjects with hypoglycemia unawareness. Plasma lactate concentrations are ∼10-fold higher than acetate concentrations, making lactate the most likely alternative MCA as brain fuel. We therefore examined transport of [3-13C]lactate across the blood-brain barrier and its metabolism in the brains of T1D patients and nondiabetic control subjects during a hypoglycemic clamp using 13C magnetic resonance spectroscopy. Brain lactate concentrations were more than fivefold higher (P < 0.05) during hypoglycemia in the T1D subjects compared with the control subjects. Surprisingly, we observed no increase in the oxidation of blood-borne lactate in the T1D subjects, as reflected by similar 13C fractional enrichments in brain glutamate and glutamine. Taken together, these data suggest that in addition to increased MCA transport at the blood-brain barrier, there may be additional metabolic adaptations that contribute to hypoglycemia unawareness in patients with T1D. PMID:23715622

  3. 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

  4. [Study of clinical efficiency of essential phospholipids and silymarin combination in nonalcoholic and alcoholic steatohepatitis].

    PubMed

    Iakimchuk, G N; Gendrikson, L N

    2011-01-01

    The issues of steatohepatitis treatment in the pathogenesis of which a major role plays lipid accumulation in hepatocyte and increased processes of free radical oxidation of lipids. Developed a method of treatment of patients with alcoholic and nonalcoholic steatohepatitis with the inclusion of a combination of essential phospholipids (EPL) and silymarin (SM). A comparative assessment of results of treatment with the inclusion of a combination of EPL and SM, Essentiale and Carsil in 60 patients with alcoholic and nonalcoholic steatohepatitis. Revealed the preferential efficiency of combination EPL and SM in these patients in regard of shortening the time clinical manifestations of disease, reducing transaminase activity, normalization of the cholestasis and cholesterol. Given practical recommendations of treatment patients with alcoholic and nonalcoholic steatohepatitis with the inclusion of a combination of EPL and CM. PMID:22364002

  5. Interleukin-15-mediated inflammation promotes non-alcoholic fatty liver disease.

    PubMed

    Cepero-Donates, Yuneivy; Lacraz, Grégory; Ghobadi, Farnaz; Rakotoarivelo, Volatiana; Orkhis, Sakina; Mayhue, Marian; Chen, Yi-Guang; Rola-Pleszczynski, Marek; Menendez, Alfredo; Ilangumaran, Subburaj; Ramanathan, Sheela

    2016-06-01

    Interleukin-15 (IL-15) is essential for the homeostasis of lymphoid cells particularly memory CD8(+) T cells and NK cells. These cells are abundant in the liver, and are implicated in obesity-associated pathogenic processes. Here we characterized obesity-associated metabolic and cellular changes in the liver of mice lacking IL-15 or IL-15Rα. High fat diet-induced accumulation of lipids was diminished in the livers of mice deficient for IL-15 or IL-15Rα. Expression of enzymes involved in the transport of lipids in the liver showed modest differences. More strikingly, the liver tissues of IL15-KO and IL15Rα-KO mice showed decreased expression of chemokines CCl2, CCL5 and CXCL10 and reduced infiltration of mononuclear cells. In vitro, IL-15 stimulation induced chemokine gene expression in wildtype hepatocytes, but not in IL15Rα-deficient hepatocytes. Our results show that IL-15 is implicated in the high fat diet-induced lipid accumulation and inflammation in the liver, leading to fatty liver disease. PMID:26868085

  6. Extended lactation in dairy cows: effects of milking frequency, calving season and nutrition on lactation persistency and milk quality.

    PubMed

    Sorensen, Annette; Muir, D Donald; Knight, Christopher H

    2008-02-01

    Twelve spring-calving and twelve winter-calving cows were managed for extended lactation cycles of 18-months duration, with the former group then completing a second extended lactation. Half of the cows were fed according to standard management practice for the herd; the other half received supplementary concentrate from week 9 of lactation onwards. Commencing at the same time, half of the udder of each cow was subjected to increased milking frequency (thrice daily rather than twice daily). Lactation persistency (and hence total milk yield) was significantly increased by frequent milking. Winter calving cows and supplemented cows also exhibited better persistency, but this was only evident up until the point of re-breeding, at around lactation week 33. Milk composition was measured in the spring-calving cows in both their first and second extended lactations. Composition altered during the course of the lactation, protein and fat percentages increasing and lactose percentage decreasing, irrespective of treatment. The quality of the milk for processing into cheese, fermented products, heat-treated products and cream liqueurs was assessed by calculation of casein number (casein protein as a proportion of total protein). Processing quality declined across the course of lactation in those groups that showed poor persistency but not in those that maintained a persistent lactation. Milk hygienic quality (somatic cell counts) showed parallel changes. Body condition score increased during the course of lactation but was not affected by supplementation; none of the cows became excessively fat. All cows remained healthy throughout the extended lactations and the majority (33/36) re-bred successfully. By demonstrating that lactation persistency is plastic and can be improved by simple management interventions, the results lend support to the economic arguments in favour of extended lactation cycles. The likely welfare benefits of extended lactation are also discussed. PMID

  7. Lactate Produced by Glycogenolysis in Astrocytes Regulates Memory Processing

    PubMed Central

    Newman, Lori A.; Korol, Donna L.; Gold, Paul E.

    2011-01-01

    When administered either systemically or centrally, glucose is a potent enhancer of memory processes. Measures of glucose levels in extracellular fluid in the rat hippocampus during memory tests reveal that these levels are dynamic, decreasing in response to memory tasks and loads; exogenous glucose blocks these decreases and enhances memory. The present experiments test the hypothesis that glucose enhancement of memory is mediated by glycogen storage and then metabolism to lactate in astrocytes, which provide lactate to neurons as an energy substrate. Sensitive bioprobes were used to measure brain glucose and lactate levels in 1-sec samples. Extracellular glucose decreased and lactate increased while rats performed a spatial working memory task. Intrahippocampal infusions of lactate enhanced memory in this task. In addition, pharmacological inhibition of astrocytic glycogenolysis impaired memory and this impairment was reversed by administration of lactate or glucose, both of which can provide lactate to neurons in the absence of glycogenolysis. Pharmacological block of the monocarboxylate transporter responsible for lactate uptake into neurons also impaired memory and this impairment was not reversed by either glucose or lactate. These findings support the view that astrocytes regulate memory formation by controlling the provision of lactate to support neuronal functions. PMID:22180782

  8. Brain lactate metabolism: the discoveries and the controversies

    PubMed Central

    Dienel, Gerald A

    2012-01-01

    Potential roles for lactate in the energetics of brain activation have changed radically during the past three decades, shifting from waste product to supplemental fuel and signaling molecule. Current models for lactate transport and metabolism involving cellular responses to excitatory neurotransmission are highly debated, owing, in part, to discordant results obtained in different experimental systems and conditions. Major conclusions drawn from tabular data summarizing results obtained in many laboratories are as follows: Glutamate-stimulated glycolysis is not an inherent property of all astrocyte cultures. Synaptosomes from the adult brain and many preparations of cultured neurons have high capacities to increase glucose transport, glycolysis, and glucose-supported respiration, and pathway rates are stimulated by glutamate and compounds that enhance metabolic demand. Lactate accumulation in activated tissue is a minor fraction of glucose metabolized and does not reflect pathway fluxes. Brain activation in subjects with low plasma lactate causes outward, brain-to-blood lactate gradients, and lactate is quickly released in substantial amounts. Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an ‘opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain. PMID:22186669

  9. Intestinal calcium absorption of women during lactation and after weaning.

    PubMed

    Kalkwarf, H J; Specker, B L; Heubi, J E; Vieira, N E; Yergey, A L

    1996-04-01

    We investigated whether intestinal calcium absorption and serum 1,25-dihydroxycholecalciferol (calcitriol) concentrations are higher in women during lactation and after weaning to compensate for calcium lost in breast milk. Measurements were obtained at 4.6 mo postpartum in 24 lactating women and 24 nonlactating women, at 9.6 mo postpartum in 24 lactating women (2.6 mo after complete weaning) and 24 nonlactating women. One-half of the women in each group were randomly assigned to receive 1 g supplemental Ca/d as calcium carbonate. Fractional calcium absorption was measured by using stable isotopic tracers 42Ca and 44Ca. Fractional absorption was 0.32+/-0.02 (+/-SEM) in both lactating and nonlactating women, but was higher in lactating women after weaning (0.37+/-0.02) compared with nonlactating postpartum control subjects (0.31+/-0.02). These effects were independent of calcium intake. Changes in serum calcitriol paralleled changes in fractional absorption. There were no differences in calcitriol concentrations between lactating and nonlactating women, but calcitriol was greater in women after weaning compared with postpartum control subjects. Lactating women who had resumed menses had higher fractional absorption and serum calcitriol than did lactating women who had not. Serum calcium and phosphorus concentrations were greater in lactating compared with nonlactating women; there were no differences between groups after weaning. We conclude that lactation stimulates increases in fractional calcium absorption and serum calcitriol, but the responses are only apparent after weaning or the resumption of menses. PMID:8599316

  10. Cloning, nucleotide sequence, and transcriptional analysis of the Pediococcus acidilactici L-(+)-lactate dehydrogenase gene.

    PubMed Central

    Garmyn, D; Ferain, T; Bernard, N; Hols, P; Delcour, J

    1995-01-01

    Recombinant plasmids containing the Pediococcus acidilactici L-(+)-lactate dehydrogenase gene (ldhL) were isolated by complementing for growth under anaerobiosis of an Escherichia coli lactate dehydrogenase-pyruvate formate lyase double mutant. The nucleotide sequence of the ldhL gene predicted a protein of 323 amino acids showing significant similarity with other bacterial L-(+)-lactate dehydrogenases and especially with that of Lactobacillus plantarum. The ldhL transcription start points in P. acidilactici were defined by primer extension, and the promoter sequence was identified as TCAAT-(17 bp)-TATAAT. This sequence is closely related to the consensus sequence of vegetative promoters from gram-positive bacteria as well as from E. coli. Northern analysis of P. acidilactici RNA showed a 1.1-kb ldhL transcript whose abundance is growth rate regulated. These data, together with the presence of a putative rho-independent transcriptional terminator, suggest that ldhL is expressed as a monocistronic transcript in P. acidilactici. PMID:7887607

  11. Positive long-term outcomes from presuckling calcium supplementation in lactating rats and the offspring.

    PubMed

    Suntornsaratoon, Panan; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2015-06-01

    Adequate dietary calcium intake and the enhanced intestinal calcium absorption in lactating mothers have long been postulated to prevent maternal bone loss and benefit neonatal bone growth. We recently showed that calcium supplementation just before breastfeeding efficiently alleviated lactation-induced bone loss in dams as well as increased milk calcium concentration, which led to higher bone mineral density (BMD) in the newborns. Herein, we further elaborated in detail how presuckling calcium supplements worked in lactating rats and how they benefited bone growth in the offspring. As revealed by bone histomorphometry, presuckling supplement with calcium alone reduced the osteoclast surface and active erosion surface, leading to an increase in trabecular thickness without changes in trabecular separation or number in dams. The beneficial effects of presuckling calcium supplements, particularly the regimen containing glucose and galactose that enhanced intestinal calcium absorption, were found to last for 3 mo postweaning, although it could not restore estrogen-deficient osteopenia induced by ovariectomy. Regarding the neonatal benefits, pups nursed by calcium-supplemented dams exhibited increases in trabecular BMD, which could be observed even at the age of 27 wk. Bone elongation was also greater in pups of calcium-supplemented dams, which was due possibly to accelerated growth plate chondrocyte turnover. It could be concluded that calcium supplements markedly diminished the lactation-induced osteopenia in dams and positively affected BMD and bone elongation in growing rats. Therefore, presuckling calcium supplementation in lactating mothers is an effective strategy for promoting a long-lasting high bone density for both mother and the offspring. PMID:25852004

  12. Increased plasma leptin attenuates adaptive metabolism in early lactating dairy cows.

    PubMed

    Ehrhardt, Richard A; Foskolos, Andreas; Giesy, Sarah L; Wesolowski, Stephanie R; Krumm, Christopher S; Butler, W Ronald; Quirk, Susan M; Waldron, Matthew R; Boisclair, Yves R

    2016-05-01

    Mammals meet the increased nutritional demands of lactation through a combination of increased feed intake and a collection of adaptations known as adaptive metabolism (e.g., glucose sparing via insulin resistance, mobilization of endogenous reserves, and increased metabolic efficiency via reduced thyroid hormones). In the modern dairy cow, adaptive metabolism predominates over increased feed intake at the onset of lactation and develops concurrently with a reduction in plasma leptin. To address the role of leptin in the adaptive metabolism of early lactation, we asked which adaptations could be countered by a constant 96-h intravenous infusion of human leptin (hLeptin) starting on day 8 of lactation. Compared to saline infusion (Control), hLeptin did not alter energy intake or milk energy output but caused a modest increase in body weight loss. hLeptin reduced plasma glucose by 9% and hepatic glycogen content by 73%, and these effects were associated with a 17% increase in glucose disposal during an insulin tolerance test. hLeptin attenuated the accumulation of triglyceride in the liver by 28% in the absence of effects on plasma levels of the anti-lipolytic hormone insulin or plasma levels of free fatty acids, a marker of lipid mobilization from adipose tissue. Finally, hLeptin increased the plasma concentrations of T4 and T3 by nearly 50% without affecting other neurally regulated hormones (i.e., cortisol and luteinizing hormone (LH)). Overall these data implicate the periparturient reduction in plasma leptin as one of the signals promoting conservation of glucose and energy at the onset of lactation in the energy-deficient dairy cow. PMID:26957637

  13. Serotonin Regulates Calcium Homeostasis in Lactation by Epigenetic Activation of Hedgehog Signaling

    PubMed Central

    Laporta, Jimena; Keil, Kimberly P.; Weaver, Samantha R.; Cronick, Callyssa M.; Prichard, Austin P.; Crenshaw, Thomas D.; Heyne, Galen W.; Vezina, Chad M.; Lipinski, Robert J.

    2014-01-01

    Calcium homeostasis during lactation is critical for maternal and neonatal health. We previously showed that nonneuronal/peripheral serotonin [5-hydroxytryptamine (5-HT)] causes the lactating mammary gland to synthesize and secrete PTHrP in an acute fashion. Here, using a mouse model, we found that genetic inactivation of tryptophan hydroxylase 1 (Tph1), which catalyzes the rate-limiting step in peripheral 5-HT synthesis, reduced circulating and mammary PTHrP expression, osteoclast activity, and maternal circulating calcium concentrations during the transition from pregnancy to lactation. Tph1 inactivation also reduced sonic hedgehog signaling in the mammary gland during lactation. Each of these deficiencies was rescued by daily injections of 5-hydroxy-L-tryptophan (an immediate precursor of 5-HT) to Tph1-deficient dams. We used immortalized mouse embryonic fibroblasts to demonstrate that 5-HT induces PTHrP through a sonic hedgehog-dependent signal transduction mechanism. We also found that 5-HT altered DNA methylation of the Shh gene locus, leading to transcriptional initiation at an alternate start site and formation of a variant transcript in mouse embryonic fibroblasts in vitro and in mammary tissue in vivo. These results support a new paradigm of 5-HT-mediated Shh regulation involving DNA methylation remodeling and promoter switching. In addition to having immediate implications for lactation biology, identification and characterization of a novel functional regulatory relationship between nonneuronal 5-HT, hedgehog signaling, and PTHrP offers new avenues for the study of these important factors in development and disease. PMID:25192038

  14. Parity, Lactation, and Breast Cancer Subtypes in African American Women: Results from the AMBER Consortium

    PubMed Central

    Viscidi, Emma; Troester, Melissa A.; Hong, Chi-Chen; Schedin, Pepper; Bethea, Traci N.; Bandera, Elisa V.; Borges, Virginia; McKinnon, Craig; Haiman, Christopher A.; Lunetta, Kathryn; Kolonel, Laurence N.; Rosenberg, Lynn; Olshan, Andrew F.; Ambrosone, Christine B.

    2014-01-01

    Background African American (AA) women have a disproportionately high incidence of estrogen receptor–negative (ER-) breast cancer, a subtype with a largely unexplained etiology. Because childbearing patterns also differ by race/ethnicity, with higher parity and a lower prevalence of lactation in AA women, we investigated the relation of parity and lactation to risk of specific breast cancer subtypes. Methods Questionnaire data from two cohort and two case-control studies of breast cancer in AA women were combined and harmonized. Case patients were classified as ER+ (n = 2446), ER- (n = 1252), or triple negative (ER-, PR-, HER2-; n = 567) based on pathology data; there were 14180 control patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in polytomous logistic regression analysis with adjustment for study, age, reproductive and other risk factors. Results ORs for parity relative to nulliparity was 0.92 (95% CI = 0.81 to 1.03) for ER+, 1.33 (95% CI = 1.11 to 1.59) for ER-, and 1.37 (95% CI = 1.06 to 1.70) for triple-negative breast cancer. Lactation was associated with a reduced risk of ER- (OR = 0.81, 95% CI = 0.69 to 0.95) but not ER+ cancer. ER- cancer risk increased with each additional birth in women who had not breastfed, with an OR of 1.68 (95% CI = 1.15 to 2.44) for 4 or more births relative to one birth with lactation. Conclusions The findings suggest that parous women who have not breastfed are at increased risk of ER- and triple-negative breast cancer. Promotion of lactation may be an effective tool for reducing occurrence of the subtypes that contribute disproportionately to breast cancer mortality. PMID:25224496

  15. 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

  16. Cognitive function in patients with alcoholic and nonalcoholic chronic liver disease.

    PubMed

    Brodersen, Carlos; Koen, Eduardo; Ponte, Alicia; Sánchez, Silvina; Segal, Eduardo; Chiapella, Alberto; Fernández, Maria; Torres, Maria; Tripodi, Valeria; Lemberg, Abraham

    2014-01-01

    The aim of the present study was to characterize the neurophysiological profile of cognitive impairment associated with patients with chronic alcoholic and nonalcoholic liver disease. The authors evaluated 43 patients with cirrhotic liver disease: 19 patients with chronic alcohol ingestion and 24 nonalcoholic patients who had been infected with hepatitis B or C virus. Eleven healthy subjects were included as control subjects. A battery of 12 psychological tests was used to investigate cognitive deficits in the patients with chronic liver disease. It was observed that alcoholic patients with chronic liver disease showed a more important cognitive deterioration than those affected by hepatitis B or C virus. PMID:25093764

  17. 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

  18. 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

  19. 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

  20. Mancozeb, a fungicide routinely used in agriculture, worsens nonalcoholic fatty liver disease in the human HepG2 cell model.

    PubMed

    Pirozzi, Anna Virginia Adriana; Stellavato, Antonietta; La Gatta, Annalisa; Lamberti, Monica; Schiraldi, Chiara

    2016-05-13

    Mancozeb, a manganese/zinc ethylene-bis-dithiocarbamate, is a fungicide routinely used in pest control programs. However, it has been found to have deleterious effects on human health and on the environment. Indeed, its massive use has raised the issue of possible health risks for agrarian communities; the molecule can also reach human cells via the food chain and alter metabolism, endocrine activity and cell survival. In particular, mancozeb induces many toxic effects on hepatic cell metabolism. For this reason, we investigated its effect in an in vitro model of hepatic damage, namely fatty acid-induced nonalcoholic fatty liver disease in the HepG2 cell line. We found that the hepatic toxicity of the fungicide exacerbated fatty acid-induced steatosis, as manifested by an increase in intracellular lipid droplet accumulation. Furthermore, mancozeb altered cell metabolism and induced cell death through upregulation of lactate dehydrogenase and cytochrome c, respectively, in dose-dependent manners. Therefore, mancozeb may play an important role in the pathogenesis and progression of chronic disease in humans and represents a danger for human health in high doses. PMID:27016407

  1. Essential role for a novel population of binucleated mammary epithelial cells in lactation.

    PubMed

    Rios, Anne C; Fu, Nai Yang; Jamieson, Paul R; Pal, Bhupinder; Whitehead, Lachlan; Nicholas, Kevin R; Lindeman, Geoffrey J; Visvader, Jane E

    2016-01-01

    The mammary gland represents a unique tissue to study organogenesis as it predominantly develops in the post-natal animal and undergoes dramatic morphogenetic changes during puberty and the reproductive cycle. The physiological function of the mammary gland is to produce milk to sustain the newborn. Here we view the lactating gland through three-dimensional confocal imaging of intact tissue. We observed that the majority of secretory alveolar cells are binucleated. These cells first arise in very late pregnancy due to failure of cytokinesis and are larger than mononucleated cells. Augmented expression of Aurora kinase-A and Polo-like kinase-1 at the lactogenic switch likely mediates the formation of binucleated cells. Our findings demonstrate an important physiological role for polyploid mammary epithelial cells in lactation, and based on their presence in five different species, suggest that binucleated cells evolved to maximize milk production and promote the survival of offspring across all mammalian species. PMID:27102712

  2. Essential role for a novel population of binucleated mammary epithelial cells in lactation

    PubMed Central

    Rios, Anne C.; Fu, Nai Yang; Jamieson, Paul R.; Pal, Bhupinder; Whitehead, Lachlan; Nicholas, Kevin R.; Lindeman, Geoffrey J.; Visvader, Jane E.

    2016-01-01

    The mammary gland represents a unique tissue to study organogenesis as it predominantly develops in the post-natal animal and undergoes dramatic morphogenetic changes during puberty and the reproductive cycle. The physiological function of the mammary gland is to produce milk to sustain the newborn. Here we view the lactating gland through three-dimensional confocal imaging of intact tissue. We observed that the majority of secretory alveolar cells are binucleated. These cells first arise in very late pregnancy due to failure of cytokinesis and are larger than mononucleated cells. Augmented expression of Aurora kinase-A and Polo-like kinase-1 at the lactogenic switch likely mediates the formation of binucleated cells. Our findings demonstrate an important physiological role for polyploid mammary epithelial cells in lactation, and based on their presence in five different species, suggest that binucleated cells evolved to maximize milk production and promote the survival of offspring across all mammalian species. PMID:27102712

  3. NEUROENDOCRINE ACTIONS AND REGULATION OF HYPOTHALAMIC NEUROPEPTIDE Y DURING LACTATION

    PubMed Central

    Crowley, W,R.; Ramoz, G.; Torto, R.; Keefe, K.A.; Wang, J. J.; Kalra, S. P.

    2007-01-01

    The expression of neuropeptide Y (NPY) and its co-messenger, agouti-related peptide (AgRP), in arcuate neurons of the hypothalamus is increased during lactation in rats. Our research has been addressing the questions of the physiological actions of these peptides during lactation and the physiological signals associated with lactation that result in increased expression of their genes. Our studies indicate that NPY and AgRP exert pleiotropic actions during lactation that help integrate neuroendocrine regulation of energy balance with controls over anterior and posterior pituitary hormone secretion. Further, reciprocal signaling to the NPY/AgRP system by leptin and ghrelin is responsible for the changes in expression of these hypothalamic peptides in lactating animals, and thus, may contribute to regulation of food intake and the various neuroendocrine adaptations of lactation. PMID:17241697

  4. Bacterial contamination of commercially available ethacridine lactate (acrinol) products.

    PubMed

    Oie, S; Kamiya, A

    1996-09-01

    Bacterial contamination of commercially available ethacridine lactate (acrinol) solutions and cotton gauze soaked in ethacridine lactate solution was investigated. Of 56 samples from ethacridine lactate solutions (eight products, seven manufacturers), seven samples (12.5%) of two products (two manufacturers) were contaminated with 10(1)-10(4) colony forming units (cfu)/mL of Burkholderia pickettii. Of 67 samples obtained from gauze soaked in ethacridine lactate solution (seven products, seven manufacturers), 41 (61.2%) of six products (six manufacturers) were contaminated with 10(2)-10(6) cfu/mL of bacteria. The major bacteria detected were Burkholderia cepacia and Burkholderia pickettii. This relatively high incidence of bacterial contamination in commercially available cotton gauze soaked in ethacridine lactate solution may be due to the presence of gauze in ethacridine lactate solution. PMID:8880550

  5. Experimental nonalcoholic steatohepatitis compromises ureagenesis, an essential hepatic metabolic function.

    PubMed

    Thomsen, Karen Louise; Grønbæk, Henning; Glavind, Emilie; Hebbard, Lionel; Jessen, Niels; Clouston, Andrew; George, Jacob; Vilstrup, Hendrik

    2014-08-01

    Nonalcoholic steatohepatitis (NASH) is increasing in prevalence, yet its consequences for liver function are unknown. We studied ureagenesis, an essential metabolic liver function of importance for whole body nitrogen homeostasis, in a rodent model of diet-induced NASH. Rats were fed a high-fat, high-cholesterol diet for 4 and 16 wk, resulting in early and advanced experimental NASH, respectively. We examined the urea cycle enzyme mRNAs in liver tissue, the hepatocyte urea cycle enzyme proteins, and the in vivo capacity of urea-nitrogen synthesis (CUNS). Early NASH decreased all of the urea cycle mRNAs to an average of 60% and the ornithine transcarbamylase protein to 10%, whereas the CUNS remained unchanged. Advanced NASH further decreased the carbamoyl phosphate synthetase protein to 63% and, in addition, decreased the CUNS by 20% [from 5.65 ± 0.23 to 4.58 ± 0.30 μmol × (min × 100 g)(-1); P = 0.01]. Early NASH compromised the genes and enzyme proteins involved in ureagenesis, whereas advanced NASH resulted in a functional reduction in the capacity for ureagenesis. The pattern of urea cycle perturbations suggests a prevailing mitochondrial impairment by NASH. The decrease in CUNS has consequences for the ability of the body to adjust to changes in the requirements for nitrogen homeostasis e.g., at stressful events. NASH, thus, in terms of metabolic consequences, is not an innocuous lesion, and the manifestations of the damage seem to be a continuum with increasing disease severity. PMID:24924745

  6. 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

  7. 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

  8. 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

  9. Increased Susceptibility to Methotrexate-Induced Toxicity in Nonalcoholic Steatohepatitis

    PubMed Central

    Hardwick, Rhiannon N.; Clarke, John D.; Lake, April D.; Canet, Mark J.; Anumol, Tarun; Street, Stephanie M.; Merrell, Matthew D.; Goedken, Michael J.; Snyder, Shane A.; Cherrington, Nathan J.

    2014-01-01

    Hepatic drug metabolizing enzymes and transporters play a crucial role in determining the fate of drugs, and alterations in liver function can place individuals at greater risk for adverse drug reactions (ADRs). We have shown that nonalcoholic steatohepatitis (NASH) leads to changes in the expression and localization of enzymes and transporters responsible for the disposition of numerous drugs. The purpose of this study was to determine the effect of NASH on methotrexate (MTX) disposition and the resulting toxicity profile. Sprague Dawley rats were fed either a control or methionine-choline-deficient diet for 8 weeks to induce NASH, then administered a single ip vehicle, 10, 40, or 100 mg/kg MTX injection followed by blood, urine, and feces collection over 96 h with terminal tissue collection. At the onset of dosing, Abcc1–4, Abcb1, and Abcg2 were elevated in NASH livers, whereas Abcc2 and Abcb1 were not properly localized to the membrane, similar to that previously observed in human NASH. NASH rodents receiving 40–100 mg/kg MTX exhibited hepatocellular damage followed by initiation of repair, whereas damage was absent in controls. NASH rodents receiving 100 mg/kg MTX exhibited slightly greater renal toxicity, indicating multiple organ toxicity, despite the majority of the dose being excreted by 6 h. Intestinal toxicity in NASH however, was strikingly less severe than controls, and coincided with reduced fecal MTX excretion. Because MTX-induced gastrointestinal toxicity limits the dose escalation necessary for cancer remission, these data suggest a greater risk for life-threatening MTX-induced hepatic and renal toxicity in NASH in the absence of overt gastrointestinal toxicity. PMID:25080921

  10. 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

  11. 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

  12. 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

  13. Portable system for continuous ex vivo measurements of lactate.

    PubMed

    Håkanson, H; Kyröläinen, M; Mattiasson, B

    1993-01-01

    The lactate profile in serum was monitored continuously in volunteers under physical exercise on a test bicycle. The assay was operated ex vivo by means of continuous sampling through a coaxial catheter. After dialysis online, lactate was converted by means of lactate oxidase immobilized to porous glass, and the depletion of oxygen was registered by means of a Clark electrode. Good agreement between the continuous monitoring and off-line analyses was found. PMID:8357576

  14. Enhanced responsiveness to selective serotonin reuptake inhibitors during lactation.

    PubMed

    Jury, Nicholas J; McCormick, Betsy A; Horseman, Nelson D; Benoit, Stephen C; Gregerson, Karen A

    2015-01-01

    The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence

  15. Lactate dehydrogenase in sickle cell disease.

    PubMed

    Stankovic Stojanovic, Katia; Lionnet, François

    2016-07-01

    Lactate dehydrogenase (LDH) activity is elevated in many pathological states. Interest in LDH activity in sickle cell disease (SCD) has developed out of an increased comprehension of the pathophysiological process and the clinical course of the disease. Elevated LDH activity in SCD comes from various mechanisms, especially intravascular hemolysis, as well as ischemia-reperfusion damage and tissular necrosis. Intravascular hemolysis is associated with vasoconstriction, platelet activation, endothelial damage, and vascular complications. LDH has been used as a diagnostic and prognostic factor of acute and chronic complications. In this review we have evaluated the literature where LDH activity was examined during steady-state or acute conditions in SCD. PMID:27138446

  16. Bipolar Depression: Pregnancy, Postpartum, and Lactation.

    PubMed

    Wald, Marla F; Muzyk, Andrew J; Clark, Drue

    2016-03-01

    Medication management of bipolar depression in pregnancy and lactation is best done by assessing each patient's and family's needs in detail. Keeping pregnant patients as psychiatrically stable as possible is the most important principle for clinicians. Unfortunately, there is no risk-free situation for patients with psychiatric illness. This is often the most difficult and hard to accept reality for these patients, families, and clinicians. Clinicians serve these patients best by being as transparent as possible about the risk/benefit analysis of each patient's situation with the realization that ultimately the decisions are made by the patient and family. PMID:26876318

  17. Not only osmoprotectant: betaine increased lactate dehydrogenase activity and L-lactate production in lactobacilli.

    PubMed

    Zou, Huibin; Wu, Zaiqiang; Xian, Mo; Liu, Hui; Cheng, Tao; Cao, Yujin

    2013-11-01

    Lactobacilli are commonly used for industrial production of polymer-grade L-lactic acid. The present study tested the Tween 80 alternative betaine in L-lactate production by several industrial lactobacilli. In flask fermentation of Lactobacillus casei, Lactobacillus buchneri, Lactobacillus lactis and Lactobacillus rhamnosus, the betaine addition (2g/l) had similar osmoprotectant effect with Tween 80 but had increased the lactate dehydrogenase activities and L-lactate production than Tween 80 control. In fed-batch fermentation of L. casei, betaine supplementation improved the L-lactic acid titer to 190 g/l, the yield to 95.5% (g L-lactic acid/g glucose), the productivity to 2.6g/lh, and the optical purity to 97.0%. The results demonstrated that supplementation of Tween 80 alternative - betaine in the fermentation medium is feasible for industrial l-lactic acid fermentation by lactobacilli, which will improve the lactate production but will not increase the process costs and modify any process conditions. PMID:24035452

  18. Response of blood vessels in vitro to hyperbaric oxygen (HBO): modulation of VEGF and NO(x) release by external lactate or arginine.

    PubMed

    Yuan, J; Handy, R D; Moody, A J; Bryson, P

    2009-07-01

    Hyperbaric oxygen therapy (HBO) is suggested to promote angiogenesis during wound healing, but the mechanisms involved are not understood. This study used a novel isolated blood vessel preparation to explore the effects of air, normobaric oxygen or hyperbaric oxygen (2.2 ATA for 90 min) on the angiogenesis factor, vascular endothelial growth factor (VEGF), nitrite and nitrate (NO(x)), lactate dehydrogenase (LDH) and lactate release from the tissue in normal Krebs Ringer, and the Ringer supplemented with either l-arginine, or 15 mM lactate to mimic a wound environment, or both (l-arginine+lactate). The in vitro blood vessel preparation remained viable during all experiments. There were no effects of HBO treatment on any of the parameters measured in normal Krebs Ringer, but some treatment-dependent effects were observed in supplemented Krebs Ringer. In the lactate supplemented Krebs Ringer, medium LDH levels increased in response to either normobaric oxygen (NBO) or HBO, compared to air alone. There were also small, but statistically significant increases in total glutathione due to HBO treatment, compared to NBO or air in the lactate supplemented medium, and in the combined supplement. There were no effects of HBO on NO(x), changes in external medium lactate levels, or tissue VEGF in any of the Krebs Ringers tested. However, post treatment increases in VEGF were observed in the lactate supplemented medium, and for lactate release into the medium for the combined supplement. We conclude that HBO does not cause NO or VEGF production from the blood vessel in normal Krebs Ringer, but the data from supplemented medium show that the response of the tissue is subtly affected by the chemical environment around the blood vessel, and the tissue is more responsive to HBO when wound conditions are mimicked. PMID:19298791

  19. Lactate Stimulates IL-4 and IL-13 Production in Activated HuT-78 T Lymphocytes Through a Process That Involves Monocarboxylate Transporters and Protein Hyperacetylation.

    PubMed

    Wagner, Waldemar; Ciszewski, Wojciech; Kania, Katarzyna; Dastych, Jarosław

    2016-05-01

    Mucosal cells of the gastrointestinal and female reproductive tract are constantly exposed to l- and d-lactate of bacterial origin. These compounds not only protect the host from pathogen colonization but also modulate the activity of mucosal immune cells, thereby playing an important role in inflammatory host responses. In this study, we demonstrated that exposure of anti-CD3/CD28 or phorbol 12-myristate 13-acetate (PMA)/ionomycin-activated HuT-78 T lymphocyte cells to 10-20 mM d-lactate significantly increased IL-4 and IL-13 production. Interestingly, the d-lactate isomer, exclusively produced locally by gut or cervicovaginal microbiota, was found to be more potent than the l-isomer. Interestingly, neither of the strong histone deacetylase inhibitors [structurally similar butyrate and suberoylanilide hydroxamic acid (SAHA)] was as effective in the stimulation of IL-13 production as d-lactate. Lactate transport through monocarboxylate transporters was required for lactate-enhanced IL-13 production in a manner that was not hydroxycarboxylic acid receptor 1-dependent. Furthermore, lactate treatment increased the acetylation of GATA-3, a critical regulator of Th1/Th2 differentiation and resulted in H3 and H4 histone hyperacetylation state, which is a characteristic feature of transcriptionally active chromatin. Both lactate isomers also enhanced IL4 and IL13 promoter-driven activity of reporter constructs in murine and human cells. Together, these findings demonstrate that a local millimolar concentration of l- or d-lactate may play an important role in the modulation of inflammation-mediated processes. PMID:27119568

  20. N-acetylcysteine attenuates progression of liver pathology in a rat model of nonalcoholic steatohepatitis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A "two-hit" model for non-alcoholic steatohepatitis (NASH) has been proposed in which steatosis constitutes the "first hit" and sensitizes the liver to potential "second hits" resulting in NASH. Oxidative stress is considered a candidate for the second hit. N-acetylcysteine (NAC), an antioxidant, ...

  1. [Hepatic steato-fibrosis and non-alcoholic liver disease in elderly].

    PubMed

    Mancinella, Angelo; Mancinella, Mirta; Marigliano, Benedetta; Marigliano, Vincenzo

    2012-05-01

    The critical role of the hepatic stellate cells in pathogenesis and evolution of hepatic fibrosis is stressed. The authors, also, illustrate the most recent acquisitions about morphological and bioumoral aspects of complex sinusoidal-Disse space-stellate cells and their importance for the risk of evolution towards non-alcoholic liver disease. PMID:22677947

  2. 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

  3. Nonalcoholic steatohepatitis is associated with increased hepatocyte apoptosis, JNK activation and Bax protein

    Technology Transfer Automated Retrieval System (TEKTRAN)

    High-fat diet enriched in omega-6 polyunsaturated fatty acids (PUFA) induces non-alcoholic steatohepatitis (NASH). The potential mechanisms involved in this process have not been defined. Male Sprague-Dawley rats were fed ad libitum Lieber-DeCarli diet at either 35% energy from fat (control) or 71% ...

  4. 78 FR 46351 - Trial Designs and Endpoints for Liver Disease Secondary to Nonalcoholic Steatohepatitis; Public...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-31

    ...The Food and Drug Administration's (FDA's) Center for Drug Evaluation and Research in cosponsorship with the American Association for the Study of Liver Diseases (AASLD) is announcing a 2-day public workshop entitled ``Trial Designs and Endpoints for Liver Disease Secondary to Nonalcoholic fatty liver disease (NAFLD).'' There are no approved treatments for NAFLD and its complications of......

  5. 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...

  6. Attributional Style, Depressive Features, and Self-Esteem: Adult Children of Alcoholic and Nonalcoholic Parents.

    ERIC Educational Resources Information Center

    Bush, Stephanie I.; And Others

    1995-01-01

    Undergraduate adult children of alcoholics (ACOAs) (n=57) were compared with children of nonalcoholic parents (n=100) on depression, self-esteem, and attributional style. ACOAs were found to have higher depression scores and lower self-esteem and were more likely to have a depressive attributional style. (SLD)

  7. Comparison of Alcoholic and Non-Alcoholic Students in a Community College Addictions Program.

    ERIC Educational Resources Information Center

    Hohman, Melinda M.

    1998-01-01

    One hundred eighty community college students enrolled in an alcohol and drug counseling certification program were surveyed to determine differences between recovering alcoholic/addicts and nonalcoholics. Alcoholic students had less education and income, were more likely to be enrolled for personal growth, or to obtain a job in the addictions…

  8. Relationship between season, lactation number and incidence of clinical mastitis in different stages of lactation in a Holstein dairy farm

    PubMed Central

    Moosavi, Maede; Mirzaei, Abdolah; Ghavami, Mohsen; Tamadon, Amin

    2014-01-01

    The aim of the present study was to compare the occurrence and duration of clinical mastitis in different seasons, stages of lactation period and parities in a Holstein dairy farm in Iran. A retrospective epidemiological survey from April 2005 to March 2008 was conducted on 884 clinical mastitis cases of 7437 lactations. Data of each case including calendar-date of mastitis onset, days in milk (DIM) of mastitis onset (early: 0-74 DIM; middle: 75-150 DIM, and late ≥ 150 DIM), duration of mastitis, and parity (1, 2, and ≥ 3) were recorded. Based on date of mastitis onset, cases were classified into stages of lactation. Moreover, beginning of mastitis was seasonally categorized. Duration of clinical mastitis after treatment in early lactation was less than late lactation in the first-parity cows (p = 0.005). In early lactation period, the first-parity cows suffered clinical mastitis in days earlier than two other parity groups (p < 0.001). Moreover, in late lactation period, the first-parity cows had clinical mastitis in days later than cows in the third and more parities (p = 0.002). Occurrence of clinical mastitis in summer increased in late lactation period but in winter increased in early lactation period (p = 0.001). In addition, occurrence time of clinical mastitis in summer were in days later than in spring (p = 0.02) and winter (p = 0.03) in early lactation period. In conclusion, occurrence of mastitis in winter and spring during early lactation and in summer during late lactation period were more prevalent especially in lower parities. PMID:25568687

  9. Somatosensory evoked potentials and blood lactate levels.

    PubMed

    Perciavalle, Valentina; Alagona, Giovanna; De Maria, Giulia; Rapisarda, Giuseppe; Costanzo, Erminio; Perciavalle, Vincenzo; Coco, Marinella

    2015-09-01

    We compared, in 20 subjects, the effects of high blood lactate levels on amplitude and latency of P1, N1, P2 and N2 components of lower limb somatosensory evoked potential (SEP), an useful, noninvasive tool for assessing the transmission of the afferent volley from periphery up to the cortex. SEPs were recorded from CPz located over the somatosensory vertex and referenced to FPz with a clavicle ground. Measurements were carried out before, at the end as well as 10 and 20 min after the conclusion of a maximal exercise carried out on a mechanically braked cycloergometer. After the exercise, P2-N2 amplitudes as well as latency of P1 and N1 components showed small but significant reductions. On the contrary, latency of N2 component exhibited a significant increase after the exercise's conclusion. These results suggest that blood lactate appears to have a protective effect against fatigue, at least at level of primary somatosensory cortex, although at the expense of efficiency of adjacent areas. PMID:25876852

  10. Blood lactate levels of decathletes during competition.

    PubMed Central

    Beaulieu, P; Ottoz, H; Grange, C; Thomas, J; Bensch, C

    1995-01-01

    There are many detailed physiological profiles of athletes who participate in a wide variety of sporting activities but few data have been obtained on decathletes. This study defines some physiological characteristics of these athletes and measures capillary lactate concentrations [La(b)] during a laboratory test of progressive maximal exhaustion and the different events during competition. The treadmill test is similar to the 100 m, 400 m and 1500 m in terms of [La(b)] accumulation but only similar to the 1500 m in terms of velocity. The 400 m is the most demanding event with the greatest blood lactate accumulation (mean(s.d.) 16.38(2.36) mmol l-1). The [La(b)] at the end of the 110 m hurdles is significantly lower than in any other racing events (mean(s.d.) 6.96(1.32) mmol l-1) compared with mean(s.d.) 12.14(2.87) and mean(s.d.) 11.44(2.16) for the 100 m and 1500 m respectively. The [La(b)] after the long jump, the high jump and the pole vault are not significantly different (mean(s.d.) 5.30(2.23), 4.64(1.39) and 5.36(1.34) mmol l-1) respectively). PMID:7551765

  11. Cellular cholesterol accumulation modulates high fat high sucrose (HFHS) diet-induced ER stress and hepatic inflammasome activation in the development of non-alcoholic steatohepatitis.

    PubMed

    Bashiri, Amir; Nesan, Dinushan; Tavallaee, Ghazaleh; Sue-Chue-Lam, Ian; Chien, Kevin; Maguire, Graham F; Naples, Mark; Zhang, Jing; Magomedova, Lilia; Adeli, Khosrow; Cummins, Carolyn L; Ng, Dominic S

    2016-07-01

    Non-alcoholic steatohepatitis (NASH), is the form of non-alcoholic fatty liver disease posing risk to progress into serious long term complications. Human and pre-clinical models implicate cellular cholesterol dysregulation playing important role in its development. Mouse model studies suggest synergism between dietary cholesterol and fat in contributing to NASH but the mechanisms remain poorly understood. Our laboratory previously reported the primary importance of hepatic endoplasmic reticulum cholesterol (ER-Chol) in regulating hepatic ER stress by comparing the responses of wild type, Ldlr-/-xLcat+/+ and Ldlr-/-xLcat-/- mice, to a 2% high cholesterol diet (HCD). Here we further investigated the roles of ER-Chol and ER stress in HFHS diet-induced NASH using the same strains. With HFHS diet feeding, both WT and Ldlr-/-xLcat+/+ accumulate ER-Chol in association with ER stress and inflammasome activation but the Ldlr-/-xLcat-/- mice are protected. By contrast, all three strains accumulate cholesterol crystal, in correlation with ER-Chol, albeit less so in Ldlr-/-xLcat-/- mice. By comparison, HCD feeding per se (i) is sufficient to promote steatosis and activate inflammasomes, and (ii) results in dramatic accumulation of cholesterol crystal which is linked to inflammasome activation in Ldlr-/-xLcat-/- mice, independent of ER-Chol. Our data suggest that both dietary fat and cholesterol each independently promote steatosis, cholesterol crystal accumulation and inflammasome activation through distinct but complementary pathways. In vitro studies using palmitate-induced hepatic steatosis in HepG2 cells confirm the key roles by cellular cholesterol in the induction of steatosis and inflammasome activations. These novel findings provide opportunities for exploring a cellular cholesterol-focused strategy for treatment of NASH. PMID:27090939

  12. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease.

    PubMed

    Tallino, Savannah; Duffy, Megan; Ralle, Martina; Cortés, María Paz; Latorre, Mauricio; Burkhead, Jason L

    2015-10-01

    Nonalcoholic fatty liver disease (NAFLD) prevalence is increasing worldwide, with the affected US population estimated near 30%. Diet is a recognized risk factor in the NAFLD spectrum, which includes nonalcoholic steatohepatitis (NASH) and fibrosis. Low hepatic copper (Cu) was recently linked to clinical NAFLD/NASH severity. Simple sugar consumption including sucrose and fructose is implicated in NAFLD, while consumption of these macronutrients also decreases liver Cu levels. Though dietary sugar and low Cu are implicated in NAFLD, transcript-level responses that connect diet and pathology are not established. We have developed a mature rat model of NAFLD induced by dietary Cu deficiency, human-relevant high sucrose intake (30% w/w) or both factors in combination. Compared to the control diet with adequate Cu and 10% (w/w) sucrose, rats fed either high-sucrose or low-Cu diet had increased hepatic expression of genes involved in inflammation and fibrogenesis, including hepatic stellate cell activation, while the combination of diet factors also increased ATP citrate lyase and fatty acid synthase gene transcription (fold change > 2, P < 0.02). Low dietary Cu decreased hepatic and serum Cu (P ≤ 0.05), promoted lipid peroxidation and induced NAFLD-like histopathology, while the combined factors also induced fasting hepatic insulin resistance and liver damage. Neither low Cu nor 30% sucrose in the diet led to enhanced weight gain. Taken together, transcript profiles, histological and biochemical data indicate that low Cu and high sucrose promote hepatic gene expression and physiological responses associated with NAFLD and NASH, even in the absence of obesity or severe steatosis. PMID:26033743

  13. Clinical significance of lactate in acute cardiac patients

    PubMed Central

    Lazzeri, Chiara; Valente, Serafina; Chiostri, Marco; Gensini, Gian Franco

    2015-01-01

    Lactate, as a metabolite of easy and quick assessment, has been studied over time in critically ill patients in order to evaluate its prognostic ability. The present review is focused on the prognostic role of lactate levels in acute cardiac patients (that is with acute coronary syndrome, cardiogenic shock, cardiac arrest, non including post cardiac surgery patients). In patients with ST-elevation myocardial infarction treated with mechanical revascularization, hyperlactatemia identified a subset of patients at higher risk for early death and in-hospital complications, being strictly related mainly to hemodynamic derangement. The prognostic impact of hyperlactatemia on mortality has been documented in patients with cardiogenic shock and in those with cardiac arrest even if there is no cut-off value of lactate to be associated with worse outcome or to guide resuscitation or hemodynamic management. Therapeutic hypothermia seems to affect per se lactate values which have been shown to progressively decrease during hypothermia. The mechanism(s) accounting for lactate levels during hypothemia seem to be multiple ranging from the metabolic effects of reduced temperatures to the hemodynamic effects of hypothermia (i.e., reduced need of vasopressor agents). Serial lactate measurements over time, or lactate clearance, have been reported to be clinically more reliable than lactate absolute value also in acute cardiac patients. Despite differences in study design, timing of lactate measurements and type of acute cardiac conditions (i.e., cardiogenic shock, cardiac arrest, refractory cardiac arrest), available evidence strongly suggests that higher lactate levels can be observed on admission in non-survivors and that higher lactate clearance is associated with better outcome. PMID:26322188

  14. Increased metallothionein in mouse liver, kidneys, and duodenum during lactation.

    PubMed

    Solaiman, D; Jonah, M M; Miyazaki, W; Ho, G; Bhattacharyya, M H

    2001-03-01

    Lactation-induced increases in cadmium absorption and retention have been demonstrated in mid-lactating mice, but no systematic measurements of endogenous metal-binding protein concentrations during lactation have been reported. Using Cd/hemoglobin radioassay, this study detected significant increases in metallothionein (MT) concentrations in liver (4-fold), kidneys (2-fold), and duodenum (2-fold), but not jejunum, of mouse dams on days 13 and 20 of lactation. These increases occurred in the absence of cadmium exposure and were specific to the lactation period; dams 5 days after weaning showed MT levels that were similar to those of nonpregnant (NP) mice. Similarly, Northern blot analyses of livers from lactating mice demonstrated that MT mRNA concentrations in maternal liver during mid-lactation were 6-fold higher than those observed 5 days after pups were weaned. Gel filtration of final supernatants from the Cd/hemoglobin assay confirmed that the Cd-binding molecule induced during lactation was indeed metallothionein. In addition, chromatographic analyses of cytosols from tissues taken from dams administered small amounts of Cd (66 ng/mouse) showed that the trace amounts of Cd absorbed through the maternal gastrointestinal tract during mid-lactation were also bound to the MT. These results indicate MT induction in mouse dams occurs as a physiological consequence of lactation, requiring no external stimulus. This induced MT participates in binding low levels of dietary cadmium consumed by the dam. During lactation, elevated maternal MT may affect pathways for essential trace metals as well as sequester toxic metals harmful to the neonate. Multiparous humans may have increased risk of accumulating environmental Cd. PMID:11222885

  15. Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation.

    PubMed

    Wang, Xing-Chun; Gusdon, Aaron M; Liu, Huan; Qu, Shen

    2014-10-28

    Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials. PMID:25356042

  16. AMPKα1 overexpression alleviates the hepatocyte model of nonalcoholic fatty liver disease via inactivating p38MAPK pathway.

    PubMed

    Zhang, Hong-Ai; Yang, Xiao-Yan; Xiao, Yan-Feng

    2016-05-27

    Nonalcoholic fatty liver disease (NAFLD) has a wide spectrum of liver damage with a worldwide prevalence of almost 20%. AMP-activated protein kinase α1 (AMPKα1) is an energy sensor that plays a key role in regulating lipid metabolism of the liver. This study explores the role of AMPKα1 overexpression in a steatotic hepatocyte model. The results displayed that the AMPKα1 overexpression suppressed lipid accumulation in the cytoplasm, decreased triglyceride levels, maintained the survival of steatotic hepatocyte model with decreased cell apoptosis and increased survival rate. Besides, AMPKα1 overexpression promoted the expression of lipid catabolism-related genes, reduced the level of anabolism-related genes, alleviated the inflammatory response by reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. Moreover, AMPKα1 overexpression could inhibit the activation of p38 mitogen-activated protein kinase (p38MAPK). Finally, Anisomycin, a frequently-used activator of p38MAPK, reversed the inhibitory effect of pc-AMPKα1 on the expression of p-p38MAPK, suggesting that AMPKα1 overexpression alleviates inflammatory response through the inactivation of p38MAPK. These results indicated that AMPKα1 may serve as a novel target for treatment of NAFLD. PMID:27109475

  17. Kuppfer Cells Trigger Nonalcoholic Steatohepatitis Development in Diet-induced Mouse Model through Tumor Necrosis Factor-α Production*

    PubMed Central

    Tosello-Trampont, Annie-Carole; Landes, Susan G.; Nguyen, Virginia; Novobrantseva, Tatiana I.; Hahn, Young S.

    2012-01-01

    Nonalcoholic steatohepatitis (NASH), characterized by lipid deposits within hepatocytes (steatosis), is associated with hepatic injury and inflammation and leads to the development of fibrosis, cirrhosis, and hepatocarcinoma. However, the pathogenic mechanism of NASH is not well understood. To determine the role of distinct innate myeloid subsets in the development of NASH, we examined the contribution of liver resident macrophages (i.e. Kupffer cells) and blood-derived monocytes in triggering liver inflammation and hepatic damage. Employing a murine model of NASH, we discovered a previously unappreciated role for TNFα and Kupffer cells in the initiation and progression of NASH. Sequential depletion of Kupffer cells reduced the incidence of liver injury, steatosis, and proinflammatory monocyte infiltration. Furthermore, our data show a differential contribution of Kupffer cells and blood monocytes during the development of NASH; Kupffer cells increased their production of TNFα, followed by infiltration of CD11bintLy6Chi monocytes, 2 and 10 days, respectively, after starting the methionine/choline-deficient (MCD) diet. Importantly, targeted knockdown of TNFα expression in myeloid cells decreased the incidence of NASH development by decreasing steatosis, liver damage, monocyte infiltration, and the production of inflammatory chemokines. Our findings suggest that the increase of TNFα-producing Kupffer cells in the liver is crucial for the early phase of NASH development by promoting blood monocyte infiltration through the production of IP-10 and MCP-1. PMID:23066023

  18. 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

  19. Choline, Its Potential Role in Nonalcoholic Fatty Liver Disease, and the Case for Human and Bacterial Genes.

    PubMed

    Sherriff, Jill L; O'Sullivan, Therese A; Properzi, Catherine; Oddo, Josephine-Lee; Adams, Leon A

    2016-01-01

    Our understanding of the impact of poor hepatic choline/phosphatidylcholine availability in promoting the steatosis characteristic of human nonalcoholic fatty liver disease (NAFLD) has recently advanced and possibly relates to phosphatidylcholine/phosphatidylethanolamine concentrations in various, membranes as well as cholesterol dysregulation. A role for choline/phosphatidylcholine availability in the progression of NAFLD to liver injury and serious hepatic consequences in some individuals requires further elucidation. There are many reasons for poor choline/phosphatidylcholine availability in the liver, including low intake, estrogen status, and genetic polymorphisms affecting, in particular, the pathway for hepatic de novo phosphatidylcholine synthesis. In addition to free choline, phosphatidylcholine has been identified as a substrate for trimethylamine production by certain intestinal bacteria, thereby reducing host choline bioavailability and providing an additional link to the increased risk of cardiovascular disease faced by those with NAFLD. Thus human choline requirements are highly individualized and biomarkers of choline status derived from metabolomics studies are required to predict those at risk of NAFLD induced by choline deficiency and to provide a basis for human intervention trials. PMID:26773011

  20. The effects of pigs' feet consumption on lactation.

    PubMed

    Kim, Myo-Kyoung; Shin, Jung-Sook; Patel, Rajul A; Min, Young Sil; Song, Hyun Ju; Sohn, Uy Dong; Kim, Dong Kyue; Nam, Jean-Yong; Kim, Dong-Seok

    2013-01-01

    Pigs' feet are traditionally consumed by Korean women to increase milk production during lactation. In this study, we evaluated the perceived effectiveness and safety of consuming pigs' feet. Parous women were recruited to complete survey questionnaires in South Korea. Of the 516 respondents, 188 (36%) claimed they consumed pigs' feet. One-hundred twenty women (64%) who consumed pigs' feet reported experiencing an increase in breast milk production. Seventy-three (61%) women from this same group exclusively breastfed. In contrast, 16 (25%) of 65 respondents who did not embrace the same purported effect of pigs' feet indicated that they solely breastfed. Ninety-eight (82%) respondents who consumed pigs' feet and reported galactagoguic effects would recommend its use. Study findings reveal that the majority of women who consume pigs' feet believe in its milk-promoting effects. The results of this study suggest that further investigation of the galactagoguic effects of pigs' feet via conduction of an experimental study is warranted. PMID:23621487

  1. Protective role of macrophage migration inhibitory factor in nonalcoholic steatohepatitis.

    PubMed

    Heinrichs, Daniel; Berres, Marie-Luise; Coeuru, Melanie; Knauel, Meike; Nellen, Andreas; Fischer, Petra; Philippeit, Claudia; Bucala, Richard; Trautwein, Christian; Wasmuth, Hermann E; Bernhagen, Jürgen

    2014-12-01

    MIF is an inflammatory cytokine but is hepatoprotective in models of hepatotoxin-induced liver fibrosis. Hepatic fibrosis can also develop from metabolic liver disease, such as nonalcoholic fatty liver disease (NASH). We investigated the role of MIF in high-fat or methionine- and choline-deficient diet mouse models of NASH. Mif(-/-) mice showed elevated liver triglyceride levels (WT, 53±14 mg/g liver; Mif(-/-), 103±7 mg/g liver; P<0.05) and a 2-3-fold increased expression of lipogenic genes. Increased fatty degeneration in the livers of Mif(-/-) mice was associated with increased hepatic inflammatory cells (1.6-fold increase in F4/80(+) macrophages) and proinflammatory cytokines (e.g., 2.3-fold increase in Tnf-α and 2-fold increase in Il-6 expression). However, inflammatory cells and cytokines were decreased by 50-90% in white adipose tissue (WAT) of Mif(-/-) mice. Subset analysis showed that macrophage phenotypes in livers of Mif(-/-) mice were skewed toward M2 (e.g., 1.7-fold and 2.5-fold increase in Arg1 and Il-13, respectively, and 2.5-fold decrease in iNos), whereas macrophages were generally reduced in WAT of these mice (70% reduction in mRNA expression of F4/80(+) macrophages). The protective MIF effect was scrutinized in isolated hepatocytes. MIF reversed inflammation-induced triglyceride accumulation in Hepa1-6 cells and primary hepatocytes and also attenuated oleic acid-elicited triglyceride increase in 3T3-L1 adipocytes. Protection from fatty hepatocyte degeneration was paralleled by a 2- to 3-fold reduction by MIF of hepatocyte proinflammatory cytokine production. Blockade of MIF receptor cluster of differentiation 74 (CD74) but not of CXCR2 or CXCR4 fully reverted the protective effect of MIF, comparable to AMPK inhibition. In summary, we demonstrate that MIF mediates hepatoprotection through the CD74/AMPK pathway in hepatocytes in metabolic models of liver injury. PMID:25122558

  2. 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

  3. 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

  4. 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

  5. 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

  6. Lactate Racemization as a Rescue Pathway for Supplying d-Lactate to the Cell Wall Biosynthesis Machinery in Lactobacillus plantarum

    PubMed Central

    Goffin, Philippe; Deghorain, Marie; Mainardi, Jean-Luc; Tytgat, Isabelle; Champomier-Vergès, Marie-Christine; Kleerebezem, Michiel; Hols, Pascal

    2005-01-01

    Lactobacillus plantarum is a lactic acid bacterium that produces d- and l-lactate using stereospecific NAD-dependent lactate dehydrogenases (LdhD and LdhL, respectively). However, reduction of glycolytic pyruvate by LdhD is not the only pathway for d-lactate production since a mutant defective in this activity still produces both lactate isomers (T. Ferain, J. N. Hobbs, Jr., J. Richardson, N. Bernard, D. Garmyn, P. Hols, N. E. Allen, and J. Delcour, J. Bacteriol. 178:5431-5437, 1996). Production of d-lactate in this species has been shown to be connected to cell wall biosynthesis through its incorporation as the last residue of the muramoyl-pentadepsipeptide peptidoglycan precursor. This particular feature leads to natural resistance to high concentrations of vancomycin. In the present study, we show that L. plantarum possesses two pathways for d-lactate production: the LdhD enzyme and a lactate racemase, whose expression requires l-lactate. We report the cloning of a six-gene operon, which is involved in lactate racemization activity and is positively regulated by l-lactate. Deletion of this operon in an L. plantarum strain that is devoid of LdhD activity leads to the exclusive production of l-lactate. As a consequence, peptidoglycan biosynthesis is affected, and growth of this mutant is d-lactate dependent. We also show that the growth defect can be partially restored by expression of the d-alanyl-d-alanine-forming Ddl ligase from Lactococcus lactis, or by supplementation with various d-2-hydroxy acids but not d-2-amino acids, leading to variable vancomycin resistance levels. This suggests that L. plantarum is unable to efficiently synthesize peptidoglycan precursors ending in d-alanine and that the cell wall biosynthesis machinery in this species is specifically dedicated to the production of peptidoglycan precursors ending in d-lactate. In this context, the lactate racemase could thus provide the bacterium with a rescue pathway for d-lactate production upon

  7. METABOLIC ADAPTATION TO FEEDING AND FASTING DURING LACTATION IN HUMANS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of these studies was to determine the metabolic adaptation to fasting and feeding during lactation. Normal lactating (L) and nonlactating (NL) women (n = 6 each) were studied using infusions of [U-13C]glucose and [2-13C]glycerol during: 1) a 24-h fast, and 2) ingestion of Sustacal (protocol ...

  8. Regional differences in adipocyte lactate production from glucose

    SciTech Connect

    Newby, F.D.; Sykes, M.N.; DiGirolamo, M. )

    1988-11-01

    Having shown that lactate is an important product of glucose metabolism by rat epididymal adipocytes, the authors investigated possible regional differences in adipocyte lactate production and the role of the animals' nutritional state and stage of development. (U-{sup 14}C)glucose metabolism, lactate production, and response to insulin were measured in fat cells isolated from four adipose regions from young lean and older fatter rats, killed either in the fed state or after fasting for 48 h. In the absence of insulin, mesenteric fat cells from either age group metabolized significantly more glucose per cell and converted more glucose to lactate than cells from other depots, regardless of nutritional state. Adipocytes from fasted lean rats showed a significant increase in the relative glucose conversion to lactate in all depots when compared with cells from fed lean rats. Fasting of older fatter rats, however, had limited effects on the relative adipocyte glucose conversion to lactate since lactate production was already high. Mesenteric fat cells had the lowest relative response to insulin, possibly due to the high basal rate of glucose metabolism. These findings indicate that differences exist among adipose regions in the rates of glucose metabolism, lactate production and response to insulin. The anatomical location of the mesenteric adipose depot, coupled with a high metabolic rate and blood perfusion, suggests that mesenteric adipocytes may provide a unique and more direct contribution of metabolic substrates for hepatic metabolism than adipocytes from other depots.

  9. 21 CFR 862.1445 - Lactate dehydrogenase isoenzymes test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Lactate dehydrogenase isoenzymes test system. 862.1445 Section 862.1445 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1445 Lactate...

  10. 21 CFR 862.1445 - Lactate dehydrogenase isoenzymes test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Lactate dehydrogenase isoenzymes test system. 862.1445 Section 862.1445 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1445 Lactate...

  11. 21 CFR 862.1440 - Lactate dehydrogenase test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Lactate dehydrogenase test system. 862.1440 Section 862.1440 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1440 Lactate dehydrogenase...

  12. 21 CFR 862.1445 - Lactate dehydrogenase isoenzymes test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Lactate dehydrogenase isoenzymes test system. 862.1445 Section 862.1445 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1445 Lactate...

  13. Zoledronate prevents lactation induced bone loss and results in additional post-lactation bone mass in mice.

    PubMed

    Wendelboe, Mette Høegh; Thomsen, Jesper Skovhus; Henriksen, Kim; Vegger, Jens Bay; Brüel, Annemarie

    2016-06-01

    In rodents, lactation is associated with a considerable and very rapid bone loss, which almost completely recovers after weaning. The aim of the present study was to investigate whether the bisphosphonate Zoledronate (Zln) can inhibit lactation induced bone loss, and if Zln interferes with recovery of bone mass after lactation has ceased. Seventy-six 10-weeks-old NMRI mice were divided into the following groups: Baseline, Pregnant, Lactation, Lactation+Zln, Recovery, Recovery+Zln, and Virgin Control (age-matched). The lactation period was 12days, then the pups were removed, and thereafter recovery took place for 28days. Zln, 100μg/kg, was given s.c. on the day of delivery, and again 4 and 8days later. Mechanical testing, μCT, and dynamic histomorphometry were performed. At L4, lactation resulted in a substantial loss of bone strength (-55% vs. Pregnant, p<0.01), BV/TV (-40% vs. Pregnant, p<0.01), and trabecular thickness (Tb.Th) (-29% vs. Pregnant, p<0.001). Treatment with Zln completely prevented lactation induced loss of bone strength, BV/TV, and Tb.Th at L4. Full recovery of micro-architectural and mechanical properties was found 28days after weaning in vehicle-treated mice. Interestingly, the recovery group treated with Zln during the lactation period had higher BV/TV (+45%, p<0.01) and Tb.Th (+16%, p<0.05) compared with virgin controls. Similar results were found at the proximal tibia and femur. This indicates that Zln did not interfere with the bone formation taking place after weaning. On this background, we conclude that post-lactation bone formation is not dependent on a preceding lactation induced bone loss. PMID:27021151

  14. l-Lactate mediates neuroprotection against ischaemia by increasing TREK1 channel expression in rat hippocampal astrocytes in vitro.

    PubMed

    Banerjee, Aditi; Ghatak, Swagata; Sikdar, Sujit Kumar

    2016-07-01

    Brain ischaemia is a highly debilitating condition where shortage of oxygen and glucose leads to profuse cell death. Lactate is a neuroprotective metabolite whose concentrations increase up to 15-30 mmol/L during ischaemia and TREK1 is a neuroprotective potassium channel which is upregulated during ischaemia. The aim of this study was to investigate the effect of l-lactate on TREK1 expression and to evaluate the role of l-lactate-TREK1 interaction in conferring neuroprotection in ischaemia-prone hippocampus. We show that 15-30 mmol/L l-lactate increases functional TREK1 protein expression by 1.5-3-fold in hippocampal astrocytes using immunostaining and electrophysiology. Studies with transcription blocker actinomycin-D and quantitative PCR indicate that the increase in TREK1 expression is due to enhanced TREK1 mRNA transcription. We further report that l-lactate-mediated increase in TREK1 expression is via protein kinase A (PKA)-dependent pathway. This is the first report of an ischaemic metabolite affecting functional expression of an ion channel. Our studies in an in vitro model of ischaemia using oxygen glucose deprivation show that 30 mmol/L l-lactate fails to reduce cell death in rat hippocampal slices treated with TREK1 blockers, PKA inhibitors and gliotoxin. The above effects were specific to l-lactate as pyruvate failed to increase TREK1 expression and reduce cell death. l-Lactate-induced TREK1 upregulation is a novel finding of physiological significance as TREK1 channels contribute to neuroprotection by enhancing potassium buffering and glutamate clearance capacity of astrocytes. We propose that l-lactate promotes neuronal survival in hippocampus by increasing TREK1 channel expression via PKA pathway in astrocytes during ischaemia. Insufficient blood supply to the brain leads to cerebral ischaemia and increase in extracellular lactate concentrations. We incubated hippocampal astrocytes in lactate and observed increase in TREK1 channel expression via

  15. Exercise mitigates mitochondrial permeability transition pore and quality control mechanisms alterations in nonalcoholic steatohepatitis.

    PubMed

    Gonçalves, Inês O; Passos, Emanuel; Diogo, Cátia V; Rocha-Rodrigues, Sílvia; Santos-Alves, Estela; Oliveira, Paulo J; Ascensão, António; Magalhães, José

    2016-03-01

    Mitochondrial quality control and apoptosis have been described as key components in the pathogenesis of nonalcoholic steatohepatitis (NASH); exercise is recognized as a nonpharmacological strategy to counteract NASH-associated consequences. We aimed to analyze the effect of voluntary physical activity (VPA) and endurance training (ET) against NASH-induced mitochondrial permeability transition pore (mPTP) opening and mitochondrial and cellular quality control deleterious alterations. Forty-eight male Sprague-Dawley rats were divided into standard-diet sedentary (SS, n = 16), standard-diet VPA (n = 8), high-fat diet sedentary (HS, n = 16), and high-fat diet VPA (n = 8). After 9 weeks of diet treatment, half of the SS and HS groups were engaged in an ET program for 8 weeks, 5 days/week, 1 h/day. Liver mPTP susceptibility through osmotic swelling, mPTP-related proteins (cyclophilin D, Sirtuin3, Cofilin-1), markers of mitochondrial biogenesis ((mitochondrial transcription factor A (Tfam) and peroxisome proliferator-activated receptor gamma co-activator protein (PGC-1α)), dynamics (Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2), Dynamin related protein 1, and Optic atrophy 1)), auto/mitophagy (Beclin-1, microtubule-associated protein 1 light chain 3, p62, PINK1, and Parkin), and apoptotic signaling (Bax, Bcl-2) and caspases-like activities were assessed. HS animals showed an increased susceptibility to mPTP, compromised expression of Tfam, Mfn1, PINK1, and Parkin and an increase in Bax content (HS vs. SS). ET and VPA improved biogenesis-related proteins (PGC-1α) and autophagy signaling (Beclin-1 and Beclin-1/Bcl-2 ratio) and decreased apoptotic signaling (caspases 8 activity, Bax content, and Bax/Bcl-2 ratio). However, only ET decreased mPTP susceptibility and positively modulated Bcl-2, Tfam, Mfn1, Mfn2, PINK1, and Parkin content. In conclusion, exercise reduces the increased susceptibility to mPTP induced by NASH and promotes the increase of auto/mitophagy and mitochondrial

  16. 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

  17. Effect of Oxygen on Glucose Metabolism: Utilization of Lactate in Staphylococcus Aureus as Revealed by In Vivo NMR Studies

    PubMed Central

    Gaspar, Paula; Pinho, Mariana G.; Neves, Ana Rute

    2013-01-01

    The ability to successfully adapt to changing host conditions is crucial for full virulence of bacterial pathogens. Staphylococcus aureus has to cope with fluctuating oxygen concentrations during the course of infection. Hence, we studied the effect of oxygen on glucose metabolism in non-growing S. aureus COL-S cells by in vivo 13C-NMR. Glucose catabolism was probed at different oxygen concentrations in suspensions of cells grown aerobically (direct effects on metabolism) or anaerobically (transcriptional adjustment to oxygen deprivation). In aerobically-grown cells, the rate of glucose consumption diminished progressively with decreasing oxygen concentrations. Additionally, oxygen deprivation resulted in biphasic glucose consumption, with the second phase presenting a higher rate. The fructose-1,6-bisphosphate pool peaked while glucose was still abundant, but the transient maximum varied with the oxygen concentration. As oxygen became limiting mannitol/mannitol-1-phosphate were detected as products of glucose catabolism. Under anoxic conditions, accumulation of mannitol-1-phosphate ceased with the switch to higher glucose consumption rates, which implies the activation of a more efficient means by which NAD+ can be regenerated. The distribution of end-products deriving from glucose catabolism was dramatically affected by oxygen: acetate increased and lactate decreased with the oxygen concentration; ethanol was formed only anaerobically. Moreover, oxygen promoted the energetically favourable conversion of lactate into acetate, which was particularly noticeable under fully oxygenated conditions. Interestingly, under aerobiosis growing S. aureus cells also converted lactate to acetate, used simultaneously glucose and lactate as substrates for growth, and grew considerably well on lactate-medium. We propose that the efficient lactate catabolism may endow S. aureus with a metabolic advantage in its ecological niche. PMID:23472168

  18. Catecholamine regulation of lactate dehydrogenase in rat brain cell culture

    SciTech Connect

    Kumar, S.; McGinnis, J.F.; de Vellis, J.

    1980-03-25

    The mechanism of catecholamine induction of the soluble cytoplasmic enzyme lactate dehydrogenase (EC 1.1.1.27) was studied in the rat glial tumor cell line, C6. Lactate dehydrogenase was partially purified from extracts of (/sup 3/H)leucine-labeled cells by affinity gel chromatography and quantitatively immunoprecipitated with anti-lactate dehydrogenase-5 IgG and with antilactate dehydrogenase-1 IgG. The immunoprecipitates were dissociated and electrophoresed on sodium dodecyl sulfate polyacrylamide gels. Using this methodology, the increased enzyme activity of lactate dehydrogenase in norepinephrine-treated C6 cells was observed to be concomitant with the increased synthesis of enzyme molecules. Despite the continued presence of norepinephrine, the specific increase in the rate of synthesis of lactate dehydrogenase was transient. It was first detected at 4 h, was maximum at 9 h, and returned to basal levels by 24 h. The half-life of lactate dehydrogenase enzyme activity was 36 h during the induction and 40 h during deinduction. The half-life for decay of /sup 3/H-labeled lactate dehydrogenase was 41 h. These observations suggest that the increase in lactate dehydrogenase activity in norepinephrine-treated cells does not involve any change in the rate of degradation. Norepinephrine increased the specific rate of synthesis of both lactate dehydrogenase-5 (a tetramer of four M subunits) and lactate dehydrogenase-1 (a tetramer of four H subunits), although to different extents. Since these subunits are coded for by two separate genes on separate chromosomes, it suggests that the regulatory mechanism involves at least two separate sites of action.

  19. L-lactate transport in Ehrlich ascites-tumour cells.

    PubMed

    Spencer, T L; Lehninger, A L

    1976-02-15

    Ehrlich ascites-tumour cells were investigated with regard to their stability to transport L-lactate by measuring either the distribution of [14C]lactate or concomitant H+ ion movements. The movement of lactate was dependent on the pH difference across the cell membrane and was electroneutral, as evidenced by an observed 1:1 antiport for OH- ions or 1:1 symport with H+ ions. 2. Kinetic experiments showed that lactate transport was saturable, with an apparent Km of approx. 4.68 mM and a Vmax. as high as 680 nmol/min per mg of protein at pH 6.2 and 37 degrees C. 3. Lactate transport exhibited a high temperature dependence (activation energy = 139 kJ/mol). 4. Lactate transport was inhibited competitively by (a) a variety of other substituted monocarboxylic acids (e.g. pyruvate, Ki = 6.3 mM), which were themselves transported, (b) the non-transportable analogues alpha-cyano-4-hydroxycinnamate (Ki = 0.5 mM), alpha-cyano-3-hydroxycinnamate (Ki = 2mM) and DL-p-hydroxyphenyl-lactate (Ki = 3.6 mM) and (c) the thiol-group reagent mersalyl (Ki = 125 muM). 5. Transport of simple monocarboxylic acids, including acetate and propionate, was insensitive to these inhibitors; they presumably cross the membrane by means of a different mechanism. 6. Experiments using saturating amounts of mersalyl as an "inhibitor stop" allowed measurements of the initial rates of net influx and of net efflux of [14C]lactate. Influx and efflux of lactate were judged to be symmetrical reactions in that they exhibited similar concentration dependence. 7. It is concluded that lactate transport in Ehrlich ascites-tumour cells is mediated by a carrier capable of transporting a number of other substituted monocarboxylic acids, but not unsubstituted short-chain aliphatic acids. PMID:7237

  20. Cobalamins in human pregnancy and lactation

    PubMed Central

    Craft, I. L.; Matthews, D. M.; Linnell, J. C.

    1971-01-01

    Samples of maternal and foetal blood and of human milk, cow's milk, and dried cow's milk have been analysed for cobalamins by chromatography and bioautography. Plasma cobalamins in late pregnancy and after delivery differed quantitatively from those in healthy non-pregnant women. Differences in the proportions of plasma cobalamins were also observed between mothers and their newborn infants. The findings suggest that methylcobalamin may be a more labile plasma form of the vitamin than 5-deoxyadenosyl cobalamin. Breast milk from healthy mothers contained more deoxyadenosylcobalamin and proportionately less methylcobalamin than their plasma. Cyanocobalamin given parenterally to lactating women was detected in the plasma, and high concentrations appeared unchanged in the milk. The B12 in fresh cow's milk was found to be largely 5-deoxyadenosyl cobalamin whereas dried milk contained only hydroxocobalamin and a little cyanocobalamin. The nutritional implications of the findings, and their bearing on problems of cobalamin transport, are discussed. Images PMID:5109777

  1. Managing Migraine During Pregnancy and Lactation.

    PubMed

    Wells, Rebecca Erwin; Turner, Dana P; Lee, Michelle; Bishop, Laura; Strauss, Lauren

    2016-04-01

    While over half of women with migraine report improvement during pregnancy, having a history of migraine may increase the chance of negative health outcomes. The state of pregnancy increases the risk of several dangerous secondary headache disorders, especially those associated with hypertensive disorders of pregnancy, and providers need to know the red flags to diagnose and treat emergently. Non-pharmacological migraine treatments can be instituted in advance of pregnancy as many are considered the safest options during pregnancy, but understanding the safety of medications and dietary supplements ensures appropriate care for the refractory migraine patient. New controversy exists over the safety of several historically routine and safe migraine treatment options in pregnancy, such as magnesium, acetaminophen, ondansetron, and butalbital. While it is not clear if breastfeeding decreases the postpartum recurrence of migraine, understanding safe treatment options during lactation can allow women to continue breastfeeding while achieving migraine relief. PMID:27002079

  2. Lactation-induced cadmium-binding proteins

    SciTech Connect

    Bhattacharyya, M.H.; Solaiman, D.; Garvey, J.S.; Miyazaki, W.Y.

    1987-01-01

    Previously we have demonstrated an increase during midlactation in /sup 109/Cd adsorption and increased retention by the duodenum, kidney, and mammary tissue of mouse dams receiving environmental levels of cadmium//sup 109/Cd via drinking water, with little change in /sup 109/Cd retention in liver and jejunum compared to nonpregnant controls. Results are reported here of a study of cadmium deposition during midlactation as associated with induction of metallothionein (MT). A cadmium/hemoglobin (Cd/Hb) assay and radioimmunoassay for MT which measures heat-stable cadmium binding capacity in tissues was used to determine MT concentrations in fractions of kidney, liver, duodenum, and jejunum from female mice. Both assays demonstrated clear lactation-induced increases in MT concentrations in liver, kidney, and duodenum, with MT concentrations falling rapidly to control levels after weaning. 4 refs., 1 tab.

  3. Homofermentative Lactate Production Cannot Sustain Anaerobic Growth of Engineered Saccharomyces cerevisiae: Possible Consequence of Energy-Dependent Lactate Export

    PubMed Central

    van Maris, Antonius J. A.; Winkler, Aaron A.; Porro, Danilo; van Dijken, Johannes P.; Pronk, Jack T.

    2004-01-01

    Due to a growing market for the biodegradable and renewable polymer polylactic acid, the world demand for lactic acid is rapidly increasing. The tolerance of yeasts to low pH can benefit the process economy of lactic acid production by minimizing the need for neutralizing agents. Saccharomyces cerevisiae (CEN.PK background) was engineered to a homofermentative lactate-producing yeast via deletion of the three genes encoding pyruvate decarboxylase and the introduction of a heterologous lactate dehydrogenase (EC 1.1.1.27). Like all pyruvate decarboxylase-negative S. cerevisiae strains, the engineered strain required small amounts of acetate for the synthesis of cytosolic acetyl-coenzyme A. Exposure of aerobic glucose-limited chemostat cultures to excess glucose resulted in the immediate appearance of lactate as the major fermentation product. Ethanol formation was absent. However, the engineered strain could not grow anaerobically, and lactate production was strongly stimulated by oxygen. In addition, under all conditions examined, lactate production by the engineered strain was slower than alcoholic fermentation by the wild type. Despite the equivalence of alcoholic fermentation and lactate fermentation with respect to redox balance and ATP generation, studies on oxygen-limited chemostat cultures showed that lactate production does not contribute to the ATP economy of the engineered yeast. This absence of net ATP production is probably due to a metabolic energy requirement (directly or indirectly in the form of ATP) for lactate export. PMID:15128549

  4. Pharmacokinetics of metoprolol during pregnancy and lactation.

    PubMed

    Ryu, Rachel J; Eyal, Sara; Easterling, Thomas R; Caritis, Steve N; Venkataraman, Raman; Hankins, Gary; Rytting, Erik; Thummel, Kenneth; Kelly, Edward J; Risler, Linda; Phillips, Brian; Honaker, Matthew T; Shen, Danny D; Hebert, Mary F

    2016-05-01

    The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25-750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight-adjusted dose (n = 3). Because of the large, pregnancy-induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker. PMID:26461463

  5. ASAS centennial paper: Lactation biology for the twenty-first century.

    PubMed

    Loor, J J; Cohick, W S

    2009-02-01

    Knowledge of general aspects of mammary gland function, including metabolic pathways and hormonal regulation of mammary gland development and lactation, in livestock species was obtained several decades ago. As basic biological information of growth factor action, apoptotic mechanisms, and signal transduction events has exploded, the mouse became the model of choice for studying fundamental mechanisms regulating mammary function. A complete sequenced genome also has made the mouse amenable for studies of mammary gene network expression. Advances in molecular biology techniques currently allow researchers to genetically modify mice to either overexpress or completely lack specific genes, thereby studying their function in an in vivo setting. Furthermore, the use of mammary-specific promoters has allowed genes related to mammary gland function to be eliminated from the mammary gland in a developmental and tissue-specific manner. These studies have demonstrated the complexity that underlies mammary gland development and function in rodents and may provide insight into the mechanisms that ultimately allow the ruminant or swine mammary gland to function in a coordinated fashion throughout puberty, pregnancy, lactation, and involution. The challenge facing animal scientists is how to obtain similar information in much larger and expensive livestock. One possible approach is to manipulate gene expression in vitro using mammary cell culture models derived from domestic animals (e.g., genes can be "knocked down" using small interfering RNA approaches). Ultimately, major advances in understanding lactation biology may come from coupling basic mechanistic information with functional genomics, proteomics, and metabolomics approaches. A strong foundation in bioinformatics will also be required to optimize use of these new technologies. Stem cell biology also represents an exciting area in the next decade that holds promise for improving lactation efficiency. Strong training of

  6. The effect of inspiratory muscle training upon maximum lactate steady-state and blood lactate concentration.

    PubMed

    McConnell, Alison K; Sharpe, Graham R

    2005-06-01

    Several studies have reported that improvements in endurance performance following respiratory muscle training (RMT) are associated with a decrease in blood lactate concentration ([Lac](B)). The present study examined whether pressure threshold inspiratory muscle training (IMT) elicits an increase in the cycling power output corresponding to the maximum lactate steady state (MLSS). Using a double-blind, placebo-controlled design, 12 healthy, non-endurance-trained male participants were assigned in equal numbers to an experimental (IMT) or sham training control (placebo) group. Cycling power output at MLSS was initially identified using a lactate minimum protocol followed by a series of constant power output rides (2.5% increments) of 29.5 min duration; MLSS was reassessed following six weeks of IMT or sham IMT. Maximum inspiratory mouth pressure increased significantly (26%) in the IMT group, but remained unchanged in the placebo group. The cycling power output corresponding to MLSS remained unchanged in both groups after the intervention. After IMT, [Lac](B) decreased significantly at MLSS power in the IMT group [-1.17 (1.01) mmol l(-1) after 29.5 min of cycling; mean (SD)], but remained unchanged in the placebo group [+0.37 (1.66) mmol l(-1)]. These data support previous observations that IMT results in a decrease in [Lac](B )at a given intensity of exercise. That such a decrease in [Lac](B) was not associated with a substantial (>2.5%) increase in MLSS power is a new finding suggesting that RMT-induced increases in exercise tolerance and reductions in [Lac](B) are not ascribable to a substantial increase in the 'lactate threshold'. PMID:15765241

  7. Lactate Up-Regulates the Expression of Lactate Oxidation Complex-Related Genes in Left Ventricular Cardiac Tissue of Rats

    PubMed Central

    Gabriel-Costa, Daniele; da Cunha, Telma Fatima; Bechara, Luiz Roberto Grassmann; Fortunato, Rodrigo Soares; Bozi, Luiz Henrique Marchesi; Coelho, Marcele de Almeida; Barreto-Chaves, Maria Luiza; Brum, Patricia Chakur

    2015-01-01

    Background Besides its role as a fuel source in intermediary metabolism, lactate has been considered a signaling molecule modulating lactate-sensitive genes involved in the regulation of skeletal muscle metabolism. Even though the flux of lactate is significantly high in the heart, its role on regulation of cardiac genes regulating lactate oxidation has not been clarified yet. We tested the hypothesis that lactate would increase cardiac levels of reactive oxygen species and up-regulate the expression of genes related to lactate oxidation complex. Methods/Principal Findings Isolated hearts from male adult Wistar rats were perfused with control, lactate or acetate (20mM) added Krebs-Henseleit solution during 120 min in modified Langendorff apparatus. Reactive oxygen species (O2●-/H2O2) levels, and NADH and NADPH oxidase activities (in enriched microsomal or plasmatic membranes, respectively) were evaluated by fluorimetry while SOD and catalase activities were evaluated by spectrophotometry. mRNA levels of lactate oxidation complex and energetic enzymes MCT1, MCT4, HK, LDH, PDH, CS, PGC1α and COXIV were quantified by real time RT-PCR. Mitochondrial DNA levels were also evaluated. Hemodynamic parameters were acquired during the experiment. The key findings of this work were that lactate elevated cardiac NADH oxidase activity but not NADPH activity. This response was associated with increased cardiac O2●-/H2O2 levels and up-regulation of MCT1, MCT4, LDH and PGC1α with no changes in HK, PDH, CS, COXIV mRNA levels and mitochondrial DNA levels. Lactate increased NRF-2 nuclear expression and SOD activity probably as counter-regulatory responses to increased O2●-/H2O2. Conclusions Our results provide evidence for lactate-induced up-regulation of lactate oxidation complex associated with increased NADH oxidase activity and cardiac O2●-/H2O2 driving to an anti-oxidant response. These results unveil lactate as an important signaling molecule regulating components of

  8. Determination of the lactate threshold and maximal blood lactate steady state intensity in aged rats.

    PubMed

    Cunha, Rafael Rodrigues; Cunha, Verusca Najara de Carvalho; Segundo, Paulo Russo; Moreira, Sérgio Rodrigues; Kokubun, Eduardo; Campbell, Carmen Sílvia Grubert; de Oliveira, Ricardo Jacó; Simões, Herbert Gustavo

    2009-08-01

    The reliability of the lactate threshold (LT) determined in aged rats and its validity to identify an exercise intensity corresponding to the maximal blood lactate steady state (MLSS) were analyzed. Eighteen male aged Wistar rats (approximately 365 days) were submitted to two incremental swimming tests until exhaustion, consisting of an initial load corresponding to 1% of body mass (BM) and increments of 1% BM at each 3-min with blood lactate ([lac]) measurements. The LT was determined by visual inspection (LT(V)) as well by applying a polynomial function on the [lac]/workload ratio (LT(P)) by considering the vertices of the curve. For the MLSS, twelve animals were submitted, on different days, to 3-4 exercise sessions of 30-min with workload corresponding to 4, 5 or 6% BM. The MLSS was considered the highest exercise intensity at which the [lac] variation was not higher than 0.07 mM.min(-1) during the last 20-min. No differences were observed for the test-retest results (4.9 +/- 0.7 and 5.0 +/- 0.8 %BM for LTv; and 6.0 +/- 0.6 and 5.8 +/- 0.6 %BM for LTp) that did not differ from the MLSS (5.4 +/- 0.5 %BM). The LT identified for aged rats in swimming, both by visual inspection and polynomial function, was reliable and did not differ from the MLSS. PMID:19585487

  9. Aerobic training effects on maximum oxygen consumption, lactate threshold and lactate disappearance during exercise recovery of dogs.

    PubMed

    Proscurshim, P; Russo, A K; Silva, A C; Piçarro, I C; Freire, E; Tarasantchi, J

    1989-01-01

    1. Dogs were submitted to an aerobic training schedule and its maximum oxygen consumption, lactate threshold and lactate concentration during recovery were compared among the following conditions: not trained (UT), after 1 month of training (T1), after 2 months of training (T2) and after detraining (DT). 2. Maximum oxygen consumption increased significantly in relation to UT condition only at T2 condition. The detraining reversed this alteration. 3. Lactate threshold when expressed as Vo2 or absolute work load increased significantly after aerobic training (T2) but did not present any alteration when it was expressed as % of Vo2 max. 4. The lactate decreasing during recovery did not differ between the four experimental conditions (after 10 min). 5. The latency time for the lactate concentration to reach the top values was reduced by aerobic training (T2). PMID:2575959

  10. ZnT4 (SLC30A4)-null ("lethal milk") mice have defects in mammary gland secretion and hallmarks of precocious involution during lactation.

    PubMed

    McCormick, Nicholas H; Lee, Sooyeon; Hennigar, Stephen R; Kelleher, Shannon L

    2016-01-01

    During lactation, highly specialized secretory mammary epithelial cells (MECs) produce and secrete huge quantities of nutrients and nonnutritive factors into breast milk. The zinc (Zn) transporter ZnT4 (SLC30A4) transports Zn into the trans-Golgi apparatus for lactose synthesis, and across the apical cell membrane for efflux from MECs into milk. This is consistent with observations in "lethal milk" (lm/lm) mice, which have a truncation mutation in SLC30A4, and present with not only low milk Zn concentration, but also smaller mammary glands, decreased milk volume, and lactation failure by lactation day 2. However, the molecular underpinnings of these defects are not understood. Here, we used lactating C57BL/6J(lm/lm) (ZnT4-null) mice to explore the consequences of a ZnT4-null phenotype on mammary gland function during early lactation. Lactating C57BL/6J(lm/lm) mice had significantly fewer, smaller, and collapsed alveoli comprising swollen, lipid-filled MECs during early lactation. These defects were associated with decreased Akt expression and STAT5 activation, indicative of defects in MEC secretion. In addition, increased expression of ZnT2, TNF-α, and cleaved e-cadherin concomitant with increased activation of STAT3 implicated the loss of ZnT4 in precocious activation of involution. Collectively, our study indicates that the loss of ZnT4 has profound consequences on MEC secretion and may promote tissue remodeling in the mammary gland during early lactation. PMID:26538236

  11. Pregnancy and lactation differentially modify the transcriptional regulation of steroidogenic enzymes through DNA methylation mechanisms in the hippocampus of aged rats.

    PubMed

    Rossetti, María F; Varayoud, Jorgelina; Lazzarino, Gisela P; Luque, Enrique H; Ramos, Jorge G

    2016-07-01

    In the present study, we examined the mRNA expression and DNA methylation state of steroidogenic enzymes in the hippocampus of young adult (90-days-old) and middle-aged (450-days-old) nulliparous rats, and middle-aged multiparous rats subjected to three pregnancies with and without lactation. Aging decreased the mRNA levels of steroidogenic-related genes, while pregnancy and lactation significantly reduced the effect of aging, maintaining high expression levels of cytochrome P450 side-chain cleavage (P450scc), steroid 5α-reductase-1 (5αR-1), cytochrome P450arom (P450arom) and aldosterone synthase (P450(11β)-2). In addition, pregnancy and lactation diminished the methylation state of the 5αR-1 promoter and increased the transcription of brain-derived neurotrophic factor, synaptophysin and spinophilin. Pregnancy without lactation increased P450scc and 5αR-1 gene expression and decreased the methylation of their promoters. We concluded that the age-related decrease in the mRNA expression of steroidogenic enzymes is differentially attenuated by pregnancy and lactation in the rat hippocampus and that differential methylation mechanisms could be involved. PMID:27040308

  12. Lactate transport and receptor actions in cerebral malaria

    PubMed Central

    Mariga, Shelton T.; Kolko, Miriam; Gjedde, Albert; Bergersen, Linda H.

    2014-01-01

    Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolized mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate’s role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood–brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM. PMID:24904266

  13. Biochemical and structural characterization of Cryptosporidium parvum Lactate dehydrogenase.

    PubMed

    Cook, William J; Senkovich, Olga; Hernandez, Agustin; Speed, Haley; Chattopadhyay, Debasish

    2015-03-01

    The protozoan parasite Cryptosporidium parvum causes waterborne diseases worldwide. There is no effective therapy for C. parvum infection. The parasite depends mainly on glycolysis for energy production. Lactate dehydrogenase is a major regulator of glycolysis. This paper describes the biochemical characterization of C. parvum lactate dehydrogenase and high resolution crystal structures of the apo-enzyme and four ternary complexes. The ternary complexes capture the enzyme bound to NAD/NADH or its 3-acetylpyridine analog in the cofactor binding pocket, while the substrate binding site is occupied by one of the following ligands: lactate, pyruvate or oxamate. The results reveal distinctive features of the parasitic enzyme. For example, C. parvum lactate dehydrogenase prefers the acetylpyridine analog of NADH as a cofactor. Moreover, it is slightly less sensitive to gossypol inhibition compared with mammalian lactate dehydrogenases and not inhibited by excess pyruvate. The active site loop and the antigenic loop in C. parvum lactate dehydrogenase are considerably different from those in the human counterpart. Structural features and enzymatic properties of C. parvum lactate dehydrogenase are similar to enzymes from related parasites. Structural comparison with malate dehydrogenase supports a common ancestry for the two genes. PMID:25542170

  14. Gastrointestinal transport of calcium and glucose in lactating ewes.

    PubMed

    Klinger, Stefanie; Schröder, Bernd; Gemmer, Anja; Reimers, Julia; Breves, Gerhard; Herrmann, Jens; Wilkens, Mirja R

    2016-06-01

    During lactation, mineral and nutrient requirements increase dramatically, particularly those for Ca and glucose. In contrast to monogastric species, in ruminants, it is rather unclear to which extend this physiological change due to increased demand for milk production is accompanied by functional adaptations of the gastrointestinal tract (GIT). Therefore, we investigated potential modulations of Ca and glucose transport mechanisms in the GIT of lactating and dried-off sheep. Ussing-chamber technique was applied to determine the ruminal and jejunal Ca flux rates. In the jejunum, electrophysiological properties in response to glucose were recorded. Jejunal brush-border membrane vesicles (BBMV) served to characterize glucose uptake via sodium-linked glucose transporter 1 (SGLT1), and RNA and protein expression levels of Ca and glucose transporting systems were determined. Ruminal Ca flux rate data showed a trend for higher absorption in lactating sheep. In the jejunum, small Ca absorption could only be observed in lactating ewes. From the results, it may be assumed that lactating ewes compensate for the Ca loss by increasing bone mobilization rather than by increasing supply through absorption from the GIT Presence of SGLT1 in the jejunum of both groups was shown by RNA and protein identification, but glucose uptake into BBMV could only be detected in lactating sheep. This, however, could not be attributed to electrogenic glucose absorption in lactating sheep under Ussing-chamber conditions, providing evidence that changes in jejunal glucose uptake may include additional factors, that is, posttranslational modifications such as phosphorylation. PMID:27273883

  15. Blood lactate kinetics in normal and stress-susceptible pigs

    SciTech Connect

    Darrah, P.S.; Beitz, D.C.; Topel, D.G.; Christian, L.L.

    1981-10-01

    In vitro rates of lactate metabolism were determined in stress-susceptible (SS) and stress-resistant (SR) pigs. Three SR and three SS pigs were given 20 muCi of (U-/sup 14/C) L-lactate by a single injection method and resting blood lactate kinetics were measured. Seventeen blood samples were taken during the 60 min after injection. Lactate was separated from the deproteinized plasma by silicic acid column chromatography, and specific radioactivity was determined. Kinetic characteristics were calculated from plots of specific activity versus time. Pigs met steady-state requirements during the sampling period. There were no differences in kinetic characteristics of resting SS and SR pigs. Later, a second isotope injection was given after 5 min of electrical stress. Lactate pool sizes increased similarly in both types of pigs after stress; however, SS pigs had greater plasma lactate concentrations after stress. It is concluded that SS and SR pigs respond differently to stress but have similar capacities to metabolize lactate while resting.

  16. 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

  17. Complement Alternative Pathway Activation in Human Nonalcoholic Steatohepatitis

    PubMed Central

    Segers, Filip M.; Verdam, Froukje J.; de Jonge, Charlotte; Boonen, Bas; Driessen, Ann; Shiri-Sverdlov, Ronit; Bouvy, Nicole D.; Greve, Jan Willem M.; Buurman, Wim A.; Rensen, Sander S.

    2014-01-01

    The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associated with pathological complement activation leading to disease, was involved. Here, alternative pathway components were investigated in liver biopsies of obese subjects with healthy livers (n = 10) or with NASH (n = 12) using quantitative PCR, Western blotting, and immunofluorescence staining. Properdin accumulated in areas where neutrophils surrounded steatotic hepatocytes, and colocalized with the C3 activation product C3c. C3 activation status as expressed by the C3c/native C3 ratio was 2.6-fold higher (p<0.01) in subjects with NASH despite reduced native C3 concentrations (0.94±0.12 vs. 0.57±0.09; p<0.01). Hepatic properdin levels positively correlated with levels of C3c (rs = 0.69; p<0.05) and C3c/C3 activation ratio (rs = 0.59; p<0.05). C3c, C3 activation status (C3c/C3 ratio) and properdin levels increased with higher lobular inflammation scores as determined according to the Kleiner classification (C3c: p<0.01, C3c/C3 ratio: p<0.05, properdin: p<0.05). Hepatic mRNA expression of factor B and factor D did not differ between subjects with healthy livers and subjects with NASH (factor B: 1.00±0.19 vs. 0.71±0.07, p = 0.26; factor D: 1.00±0.21 vs. 0.66±0.14, p = 0.29;). Hepatic mRNA and protein levels of Decay Accelerating Factor tended to be increased in subjects with NASH (mRNA: 1.00±0.14 vs. 2.37±0.72; p = 0.22; protein: 0.51±0.11 vs. 1.97±0.67; p = 0.28). In contrast, factor H mRNA was downregulated in patients with NASH (1.00±0.09 vs. 0.71±0.06; p<0.05) and a similar trend was observed with hepatic protein levels (1.12±0.16 vs. 0.78±0.07; p = 0.08). Collectively, these data suggest a role for alternative pathway

  18. Cerebral lactate dynamics across sleep/wake cycles.

    PubMed

    Rempe, Michael J; Wisor, Jonathan P

    2014-01-01

    Cerebral metabolism varies dramatically as a function of sleep state. Brain concentration of lactate, the end product of glucose utilization via glycolysis, varies as a function of sleep state, and like slow wave activity (SWA) in the electroencephalogram (EEG), increases as a function of time spent awake or in rapid eye movement sleep and declines as a function of time spent in slow wave sleep (SWS). We sought to determine whether lactate concentration exhibits homeostatic dynamics akin to those of SWA in SWS. Lactate concentration in the cerebral cortex was measured by indwelling enzymatic biosensors. A set of equations based conceptually on Process S (previously used to quantify the homeostatic dynamics of SWA) was used to predict the sleep/wake state-dependent dynamics of lactate concentration in the cerebral cortex. Additionally, we applied an iterative parameter space-restricting algorithm (the Nelder-Mead method) to reduce computational time to find the optimal values of the free parameters. Compared to an exhaustive search, this algorithm reduced the computation time required by orders of magnitude. We show that state-dependent lactate concentration dynamics can be described by a homeostatic model, but that the optimal time constants for describing lactate dynamics are much smaller than those of SWA. This disconnect between lactate dynamics and SWA dynamics does not support the concept that lactate concentration is a biochemical mediator of sleep homeostasis. However, lactate synthesis in the cerebral cortex may nonetheless be informative with regard to sleep function, since the impact of glycolysis on sleep slow wave regulation is only just now being investigated. PMID:25642184

  19. Male 11β-HSD1 Knockout Mice Fed Trans-Fats and Fructose Are Not Protected From Metabolic Syndrome or Nonalcoholic Fatty Liver Disease.

    PubMed

    Larner, Dean P; Morgan, Stuart A; Gathercole, Laura L; Doig, Craig L; Guest, Phil; Weston, Christopher; Hazeldine, Jon; Tomlinson, Jeremy W; Stewart, Paul M; Lavery, Gareth G

    2016-09-01

    Nonalcoholic fatty liver disease (NAFLD) defines a spectrum of conditions from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis and is regarded as the hepatic manifestation of the metabolic syndrome. Glucocorticoids can promote steatosis by stimulating lipolysis within adipose tissue, free fatty acid delivery to liver and hepatic de novo lipogenesis. Glucocorticoids can be reactivated in liver through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme activity. Inhibition of 11β-HSD1 has been suggested as a potential treatment for NAFLD. To test this, male mice with global (11β-HSD1 knockout [KO]) and liver-specific (LKO) 11β-HSD1 loss of function were fed the American Lifestyle Induced Obesity Syndrome (ALIOS) diet, known to recapitulate the spectrum of NAFLD, and metabolic and liver phenotypes assessed. Body weight, muscle and adipose tissue masses, and parameters of glucose homeostasis showed that 11β-HSD1KO and LKO mice were not protected from systemic metabolic disease. Evaluation of hepatic histology, triglyceride content, and blinded NAFLD activity score assessment indicated that levels of steatosis were similar between 11β-HSD1KO, LKO, and control mice. Unexpectedly, histological analysis revealed significantly increased levels of immune foci present in livers of 11β-HSD1KO but not LKO or control mice, suggestive of a transition to NASH. This was endorsed by elevated hepatic expression of key immune cell and inflammatory markers. These data indicate that 11β-HSD1-deficient mice are not protected from metabolic disease or hepatosteatosis in the face of a NAFLD-inducing diet. However, global deficiency of 11β-HSD1 did increase markers of hepatic inflammation and suggests a critical role for 11β-HSD1 in restraining the transition to NASH. PMID:27384305

  20. LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease

    PubMed Central

    Mina, Marco; Gnani, Daniela; De Stefanis, Cristiano; Crudele, Annalisa; Rychlicki, Chiara; Petrini, Stefania; Bruscalupi, Giovannella; Agostinelli, Laura; Stronati, Laura; Cucchiara, Salvatore; Musso, Giovanni; Furlanello, Cesare; Svegliati-Baroni, Gianluca; Nobili, Valerio; Alisi, Anna

    2015-01-01

    Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH). We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-ĸB, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH. In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH. PMID:26573228

  1. Male 11β-HSD1 Knockout Mice Fed Trans-Fats and Fructose Are Not Protected From Metabolic Syndrome or Nonalcoholic Fatty Liver Disease

    PubMed Central

    Larner, Dean P.; Morgan, Stuart A.; Gathercole, Laura L.; Doig, Craig L.; Guest, Phil; Weston, Christopher; Hazeldine, Jon; Tomlinson, Jeremy W.; Stewart, Paul M.

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) defines a spectrum of conditions from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis and is regarded as the hepatic manifestation of the metabolic syndrome. Glucocorticoids can promote steatosis by stimulating lipolysis within adipose tissue, free fatty acid delivery to liver and hepatic de novo lipogenesis. Glucocorticoids can be reactivated in liver through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme activity. Inhibition of 11β-HSD1 has been suggested as a potential treatment for NAFLD. To test this, male mice with global (11β-HSD1 knockout [KO]) and liver-specific (LKO) 11β-HSD1 loss of function were fed the American Lifestyle Induced Obesity Syndrome (ALIOS) diet, known to recapitulate the spectrum of NAFLD, and metabolic and liver phenotypes assessed. Body weight, muscle and adipose tissue masses, and parameters of glucose homeostasis showed that 11β-HSD1KO and LKO mice were not protected from systemic metabolic disease. Evaluation of hepatic histology, triglyceride content, and blinded NAFLD activity score assessment indicated that levels of steatosis were similar between 11β-HSD1KO, LKO, and control mice. Unexpectedly, histological analysis revealed significantly increased levels of immune foci present in livers of 11β-HSD1KO but not LKO or control mice, suggestive of a transition to NASH. This was endorsed by elevated hepatic expression of key immune cell and inflammatory markers. These data indicate that 11β-HSD1-deficient mice are not protected from metabolic disease or hepatosteatosis in the face of a NAFLD-inducing diet. However, global deficiency of 11β-HSD1 did increase markers of hepatic inflammation and suggests a critical role for 11β-HSD1 in restraining the transition to NASH. PMID:27384305

  2. CD147 Required for Corneal Endothelial Lactate Transport

    PubMed Central

    Li, Shimin; Nguyen, Tracy T.; Bonanno, Joseph A.

    2014-01-01

    Purpose. CD147/basigin is a chaperone for lactate:H+ cotransporters (monocarboxylate transporters) MCT1 and MCT4. We tested the hypothesis that MCT1 and -4 in corneal endothelium contribute to lactate efflux from stroma to anterior chamber and that silencing CD147 expression would cause corneal edema. Methods. CD147 was silenced via small interfering ribonucleic acid (siRNA) transfection of rabbit corneas ex vivo and anterior chamber lenti-small hairpin RNA (shRNA) pseudovirus in vivo. CD147 and MCT expression was examined by Western blot, RT-PCR, and immunofluorescence. Functional effects were examined by measuring lactate-induced cell acidification, corneal lactate efflux, [lactate], central cornea thickness (CCT), and Azopt (a carbonic anhydrase inhibitor) sensitivity. Results. In ex vivo corneas, 100 nM CD147 siRNA reduced CD147, MCT1, and MCT4 expression by 85%, 79%, and 73%, respectively, while MCT2 expression was unaffected. CD147 siRNA decreased lactate efflux from 3.9 ± 0.81 to 1.5 ± 0.37 nmol/min, increased corneal [lactate] from 19.28 ± 7.15 to 56.73 ± 8.97 nmol/mg, acidified endothelial cells (pHi = 6.83 ± 0.07 vs. 7.19 ± 0.09 in control), and slowed basolateral lactate-induced acidification from 0.0034 ± 0.0005 to 0.0012 ± 0.0005 pH/s, whereas apical acidification was unchanged. In vivo, CD147 shRNA increased CCT by 28.1 ± 0.9 μm at 28 days; Azopt increased CCT to 24.4 ± 3.12 vs. 12.0 ± 0.48 μm in control, and corneal [lactate] was 47.63 ± 6.29 nmol/mg in shCD147 corneas and 17.82 ± 4.93 nmol/mg in paired controls. Conclusions. CD147 is required for the expression of MCT1 and MCT4 in the corneal endothelium. Silencing CD147 slows lactate efflux, resulting in stromal lactate accumulation and corneal edema, consistent with lactate efflux as a significant component of the corneal endothelial pump. PMID:24970254

  3. Mid-trimester pregnancy termination with ethacridine lactate.

    PubMed

    Shukla, S; Sapre, S; Olyai, P

    1984-12-01

    A study was conducted in Kamla Raja Hospital, G.R. Medical College, Gwalior, India to evaluate the efficacy of 1% ethacridine lactate and to compare the results with 20% hypertonic saline as abortifacients in midtrimester abortions. The abortions were performed using 1% ethacridine lactate in 65 patients with pregnancies between 12-20 weeks (group A). The patients were admitted to the hospital 1 day before the abortion. In a 2nd group of 65 patients (group B,), the abortion was done using 20% hypertonic saline. In this group oxytocin also was used as it had been with group A patients if the abortion did not occur with 24 hours. The mean induction abortion interval was lower with ethacridine lactate (37.82 hours) than with hypertonic saline (44.40 hours). This interval continued decreasing as the pregnancy advanced -- 12-14 weeks, 42.45 hours; 15-16 weeks, 36.05 hours; 17-20 weeks, 34.96 hours. In the hypertonic saline series, the induction abortion interval continued increasing as the pregnancy advanced -- 12-14 weeks, 44.30 hours; 15-16 weeks, 45.68 hours; and 17-20 weeks, 45.61 hours. With ethacridine lactate the abortion rate (24.62%) was significantly higher within the first 24 hours than with saline (9.23%), although the overall success rate was more with saline (96.92%) than with ethacridine lactate (90.77%). If reinstillation cases were included, the success rate with ethacridine lactate (95.39%) became almost similar to that of hypertonic saline. The complete expulsion rate with ethacridine lactate was only 35.38%, but it was 66.48% with hypertonic saline. The incidence of various side effects, such as headache, rigor, and vomiting, was more with hypertonic saline than with ethacridine lactate. Another advantage of ethacridine lactate was the fact that it can be used safely in patients with cardiovascular and renal diseases. The changes in the maternal coagulation system following intra-amniotic instillation of hyptonic saline, considered to be almost

  4. 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

  5. Host factors are dominant in the development of post-liver transplant non-alcoholic steatohepatitis

    PubMed Central

    Boga, Salih; Munoz-Abraham, Armando Salim; Rodriguez-Davalos, Manuel I; Emre, Sukru H; Jain, Dhanpat; Schilsky, Michael L

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a recognized problem in patients after orthotopic liver transplantation and may lead to recurrent graft injury. As the increased demand for liver allografts fail to match the available supply of donor organs, split liver transplantation (SLT) has emerged as an important technique to increase the supply of liver grafts. SLT allows two transplants to occur from one donor organ, and provides a unique model for observing the pathogenesis of NAFLD with respect to the role of recipient environmental and genetic factors. Here we report on two recipients of a SLT from the same deceased donor where only one developed non-alcoholic steatohepatitis (NASH), suggesting that host factors are critical for the development of NASH. PMID:27239259

  6. Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis

    PubMed Central

    Kessoku, Takaomi; Imajo, Kento; Honda, Yasushi; Kato, Takayuki; Ogawa, Yuji; Tomeno, Wataru; Kato, Shingo; Mawatari, Hironori; Fujita, Koji; Yoneda, Masato; Nagashima, Yoji; Saito, Satoru; Wada, Koichiro; Nakajima, Atsushi

    2016-01-01

    The natural polyphenol compound resveratrol (RSV) is considered to have a broad spectrum of beneficial biological activities upon human health. However, the exact effect of RSV on steatosis (a phenotype of non-alcoholic fatty liver [NAFL]) or fibrosis and inflammation (major phenotypes of non-alcoholic steatohepatitis [NASH]) is not known. Our data showed that administration of RSV (2 or 20 mg/kg/day) did not suppress steatosis in a high-fat diet-induced model of NAFL in mice. In contrast, identical concentrations of RSV dramatically inhibited inflammation and fibrosis in a low-dose lipopolysaccharide-induced model of NASH. These data suggested that RSV administration-mediated improvement of inflammation and fibrosis was due to the inhibition of LPS reactivity controlled by CD14 expression in Kupffer cells. These findings suggest that RSV could be a candidate agent for the treatment of NASH. PMID:26911834

  7. 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

  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. An Overview of Mouse Models of Nonalcoholic Steatohepatitis: From Past to Present.

    PubMed

    Jacobs, Ans; Warda, Anne-Sophie; Verbeek, Jef; Cassiman, David; Spincemaille, Pieter

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. It is associated with obesity and type 2 diabetes and represents a spectrum of histological abnormalities ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which can further progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver failure. To gain insight into the pathogenesis and evaluate treatment options, mouse models of NAFLD/NASH are of utmost importance. There is a high phenotypical variety in the available mouse models, however, models that truly display the full spectrum of histopathological and metabolic features associated with human NASH are rare. In this review, we summarize the most important NAFLD/NASH mouse models that have been developed over the years and briefly highlight the pros and cons. Also, we illustrate the preclinical research in which these models have been used. © 2016 by John Wiley & Sons, Inc. PMID:27248434

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. Targeting Cell Death and Sterile Inflammation Loop for the Treatment of Nonalcoholic Steatohepatitis

    PubMed Central

    Wree, Alexander; Mehal, Wajahat Z.; Feldstein, Ariel E.

    2016-01-01

    Nonalcoholic fatty liver disease represents a wide spectrum of conditions and is currently the most common form of chronic liver disease affecting both adults and children in the United States and many other parts of the world. Great effort has been focused on the development of novel therapies for those patients with the more advanced forms of the disease, in particular those with nonalcoholic steatohepatitis (NASH) and liver fibrosis that can be associated with significant morbidity and mortality. In this review, the authors focus on the role of cell death and sterile inflammatory pathways as well as the self-perpetuating deleterious cycle they may trigger as novel therapeutic targets for the treatment of fibrotic NASH. PMID:26870930

  19. 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

  20. 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

  1. Fulminant hepatitis in a patient with hepatocellular carcinoma related to nonalcoholic steatohepatitis treated with sorafenib.

    PubMed

    Brandi, Giovanni; De Lorenzo, Stefania; Di Girolamo, Stefania; Bellentani, Stefano; Saccoccio, Gioconda; Biasco, Guido

    2015-01-01

    We describe a case of acute liver failure in a patient with advanced hepatocellular carcinoma related to nonalcoholic steatohepatitis during sorafenib treatment. A 74-year-old man with diabetes mellitus and hypertension was diagnosed with hepatocellular carcinoma associated with fatty liver. Three weeks after sorafenib therapy, at Eastern Cooperative Oncology Group performance status 3, he developed jaundice, general weakness, flapping tremor, nausea, and anorexia. Sorafenib was stopped: laboratory tests showed a relevant elevation of transaminases suggesting diagnosis of acute hepatitis. During hospital admission, the patient died of liver failure. Sorafenib is the first successful target therapy effective for advanced hepatocellular carcinoma. The most common adverse events are fatigue, hand-foot skin reaction, skin rash/desquamation, diarrhea, and hypertension, whereas liver dysfunction is uncommon. To our knowledge, this is the first patient reported in the literature with hepatocellular carcinoma related to nonalcoholic steatohepatitis who died of rapid worsening of liver function during sorafenib treatment. PMID:25702656

  2. 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

  3. Host factors are dominant in the development of post-liver transplant non-alcoholic steatohepatitis.

    PubMed

    Boga, Salih; Munoz-Abraham, Armando Salim; Rodriguez-Davalos, Manuel I; Emre, Sukru H; Jain, Dhanpat; Schilsky, Michael L

    2016-05-28

    Non-alcoholic fatty liver disease (NAFLD) is a recognized problem in patients after orthotopic liver transplantation and may lead to recurrent graft injury. As the increased demand for liver allografts fail to match the available supply of donor organs, split liver transplantation (SLT) has emerged as an important technique to increase the supply of liver grafts. SLT allows two transplants to occur from one donor organ, and provides a unique model for observing the pathogenesis of NAFLD with respect to the role of recipient environmental and genetic factors. Here we report on two recipients of a SLT from the same deceased donor where only one developed non-alcoholic steatohepatitis (NASH), suggesting that host factors are critical for the development of NASH. PMID:27239259

  4. 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

  5. The metabolic fate of lactate in renal cortical tubules

    PubMed Central

    Janssens, Peter; Hems, Reg; Ross, Brian

    1980-01-01

    1. Isolated kidney cortex tubules prepared from fed rats and incubated with near-physiological concentrations of [14C]lactate decrease the specific radioactivity of the added lactate. This effect may be attributable to at least two mechanisms; formation of lactate from endogenous precursors, or entry of unlabelled carbon into the lactate pool as a result of substrate cycling, via phosphoenolpyruvate, pyruvate and oxaloacetate, together with equilibration of the oxaloacetate pool with malate and fumarate. Such substrate cycling could occur within a single cell, or between two populations of different cells, one glycolytic and the other gluconeogenic. These possibilities have been investigated by using metabolic inhibitors or alternative metabolic substrates. 2. Tubules from fed rats produced a fall in specific radioactivity of 14.4% when incubated for 40min with 2mm-lactate alone. A mathematical treatment of this result is presented, which allows the rate of fall in specific radioactivity to be expressed as the addition of unlabelled lactate to the pool. This corresponds to a rate of formation of unlabelled lactate of 121±22μmol/h per g dry wt., a rate close to that of gluconeogenesis. In tubules from fasting rats, there was no reduction of the specific radioactivity of lactate, indicating that fasting for 24h suppresses production of unlabelled-lactate carbon. 3. Addition of 2mm-fumarate resulted in a significantly greater decrease in the specific radioactivity of lactate, but aspartate (2mm), malate (2mm) and glucose (5mm) were without effect. Total inhibition of gluconeogenesis with 3-mercaptopicolinate did not prevent the fall in specific radioactivity of lactate observed in tubules from fed-rat kidney, thereby excluding significant activity of the substrate cycle pyruvate→oxaloacetate→phosphoenolpyruvate→pyruvate. 4. The capacity of pyruvate kinase under the test conditions in tubules prepared from kidneys of fed or starved rats was at least ten times

  6. Comparative Transcriptome Analysis Reveals Different Molecular Mechanisms of Bacillus coagulans 2-6 Response to Sodium Lactate and Calcium Lactate during Lactic Acid Production

    PubMed Central

    Qin, Jiayang; Wang, Xiuwen; Wang, Landong; Zhu, Beibei; Zhang, Xiaohua; Yao, Qingshou; Xu, Ping

    2015-01-01

    Lactate production is enhanced by adding calcium carbonate or sodium hydroxide during fermentation. However, Bacillus coagulans 2-6 can produce more than 180 g/L L-lactic acid when calcium lactate is accumulated, but less than 120 g/L L-lactic acid when sodium lactate is formed. The molecular mechanisms by which B. coagulans responds to calcium lactate and sodium lactate remain unclear. In this study, comparative transcriptomic methods based on high-throughput RNA sequencing were applied to study gene expression changes in B. coagulans 2-6 cultured in non-stress, sodium lactate stress and calcium lactate stress conditions. Gene expression profiling identified 712 and 1213 significantly regulated genes in response to calcium lactate stress and sodium lactate stress, respectively. Gene ontology assignments of the differentially expressed genes were performed. KEGG pathway enrichment analysis revealed that ‘ATP-binding cassette transporters’ were significantly affected by calcium lactate stress, and ‘amino sugar and nucleotide sugar metabolism’ was significantly affected by sodium lactate stress. It was also found that lactate fermentation was less affected by calcium lactate stress than by sodium lactate stress. Sodium lactate stress had negative effect on the expression of ‘glycolysis/gluconeogenesis’ genes but positive effect on the expression of ‘citrate cycle (TCA cycle)’ genes. However, calcium lactate stress had positive influence on the expression of ‘glycolysis/gluconeogenesis’ genes and had minor influence on ‘citrate cycle (TCA cycle)’ genes. Thus, our findings offer new insights into the responses of B. coagulans to different lactate stresses. Notably, our RNA-seq dataset constitute a robust database for investigating the functions of genes induced by lactate stress in the future and identify potential targets for genetic engineering to further improve L-lactic acid production by B. coagulans. PMID:25875592

  7. 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

  8. 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

  9. Mitochondrial DNA from hepatocytes as a ligand for TLR9: Drivers of nonalcoholic steatohepatitis?

    PubMed

    Handa, Priya; Vemulakonda, Akhila; Kowdley, Kris V; Uribe, Misael; Méndez-Sánchez, Nahum

    2016-08-21

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, affecting approximately one third of the Western world. It consists of a wide spectrum of liver disorders, ranging from fatty liver to nonalcoholic steatohepatitis (NASH), which consists of steatosis, ballooning injury and inflammation. Despite an alarming growth in the statistics surrounding NAFLD, there are as yet no effective therapies for its treatment. Innate immune signaling has been thought to play a significant role in initiating and augmenting hepatic inflammation, contributing to the transition from nonalcoholic fatty liver to NASH. An immune response is triggered by countless signals called damage-associated molecular patterns (DAMPs) elicited by lipid-laden and damaged hepatocytes, which are recognized by pattern recognition receptors (PRRs) on hepatic immune cells to initiate inflammatory signaling. In this editorial, in addition to summarizing innate immune signaling in NAFLD and discussing potential therapies that target innate immune pathways, we have described a recent study that demonstrated that mitochondrial DNA serves as a DAMP activating a hepatic PRR, TLR9, in mice and in the plasma of NASH patients. In addition to identifying a new ligand for TLR9 during NASH progression, the study shows that blocking TLR9 reverses NASH, paving the way for the development of future NASH therapy. PMID:27610009

  10. A silybin-phospholipid complex prevents mitochondrial dysfunction in a rodent model of nonalcoholic steatohepatitis.

    PubMed

    Serviddio, Gaetano; Bellanti, Francesco; Giudetti, Anna Maria; Gnoni, Gabriele Vincenzo; Petrella, Antonio; Tamborra, Rosanna; Romano, Antonino Davide; Rollo, Tiziana; Vendemiale, Gianluigi; Altomare, Emanuele

    2010-03-01

    Mitochondrial dysfunction and oxidative stress are determinant events in the pathogenesis of nonalcoholic steatohepatitis. Silybin has shown antioxidant, anti-inflammatory, and antifibrotic effects in chronic liver disease. We aimed to study the effect of the silybin-phospholipid complex (SILIPHOS) on liver redox balance and mitochondrial function in a dietary model of nonalcoholic steatohepatitis. To accomplish this, glutathione oxidation, mitochondrial oxygen uptake, proton leak, ATP homeostasis, and H(2)O(2) production rate were evaluated in isolated liver mitochondria from rats fed a methionine- and choline-deficient (MCD) diet and the MCD diet plus SILIPHOS for 7 and 14 weeks. Oxidative proteins, hydroxynonenal (HNE)- and malondialdehyde (MDA)-protein adducts, and mitochondrial membrane lipid composition were also measured. Treatment with SILIPHOS limited glutathione depletion and mitochondrial H(2)O(2) production. Moreover, SILIPHOS preserved mitochondrial bioenergetics and prevented mitochondrial proton leak and ATP reduction. Finally, SILIPHOS limited the formation of HNE- and MDA-protein adducts. In conclusion, SILIPHOS is effective in preventing severe oxidative stress and preserving hepatic mitochondrial bioenergetics in nonalcoholic steatohepatitis induced by the MCD diet. The modifications of mitochondrial membrane fatty acid composition induced by the MCD diet are partially prevented by SILIPHOS, conferring anti-inflammatory and antifibrotic effects. The increased vulnerability of lipid membranes to oxidative damage is limited by SILIPHOS through preserved mitochondrial function. PMID:20008062

  11. Mitochondrial DNA from hepatocytes as a ligand for TLR9: Drivers of nonalcoholic steatohepatitis?

    PubMed Central

    Handa, Priya; Vemulakonda, Akhila; Kowdley, Kris V; Uribe, Misael; Méndez-Sánchez, Nahum

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, affecting approximately one third of the Western world. It consists of a wide spectrum of liver disorders, ranging from fatty liver to nonalcoholic steatohepatitis (NASH), which consists of steatosis, ballooning injury and inflammation. Despite an alarming growth in the statistics surrounding NAFLD, there are as yet no effective therapies for its treatment. Innate immune signaling has been thought to play a significant role in initiating and augmenting hepatic inflammation, contributing to the transition from nonalcoholic fatty liver to NASH. An immune response is triggered by countless signals called damage-associated molecular patterns (DAMPs) elicited by lipid-laden and damaged hepatocytes, which are recognized by pattern recognition receptors (PRRs) on hepatic immune cells to initiate inflammatory signaling. In this editorial, in addition to summarizing innate immune signaling in NAFLD and discussing potential therapies that target innate immune pathways, we have described a recent study that demonstrated that mitochondrial DNA serves as a DAMP activating a hepatic PRR, TLR9, in mice and in the plasma of NASH patients. In addition to identifying a new ligand for TLR9 during NASH progression, the study shows that blocking TLR9 reverses NASH, paving the way for the development of future NASH therapy. PMID:27610009

  12. 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

  13. 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

  14. 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

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

    PubMed Central

    Yki-Järvinen, Hannele

    2015-01-01

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

  16. 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

  17. Imperfect asymmetry of life: earth microbial communities prefer D-lactate but can use L-lactate also.

    PubMed

    Moazeni, Faegheh; Zhang, Gaosen; Sun, Henry J

    2010-05-01

    Asymmetrical utilization of chiral compounds has been sought on Mars as evidence for biological activity. This method was recently validated in glucose. Earth organisms utilize D-glucose, not L-glucose, a perfect asymmetry. In this study, we tested the method in lactate and found utilization of both enantiomers. Soil-, sediment-, and lake-borne microbial communities prefer D-lactate but can consume L-lactate if given extra time to acclimate. This situation is termed imperfect asymmetry. Future life-detection mission investigators need to be aware of imperfect asymmetry so as not to miss relatively subtle signs of life. PMID:20528194

  18. Mood stabilizers in pregnancy and lactation

    PubMed Central

    Grover, Sandeep; Avasthi, Ajit

    2015-01-01

    Management of bipolar during pregnancy and postpartum is very challenging. The treating clinicians have to take into account various factors like current mental state, longitudinal history of the patient, past history of relapse while off medication, response to medication, time of pregnancy at which patient presents to the clinician, etc. The choice of drug should depend on the balance between safety and efficacy profile. Whenever patient is on psychotropic medication, close and intensive monitoring should be done. Among the various mood stabilizers, use of lithium during the second and third trimester appears to be safe. Use of valproate during first trimester is associated with major malformation and long-term sequalae in the form of developmental delay, lower intelligence quotient, and higher risk of development of autism spectrum disorder. Similarly use of carbamazepine in first trimester is associated with higher risk of major congenital malformation and its use in first trimester is contraindicated. Data for lamotrigine (LTG) appears to be more favorable than other antiepileptics. During lactation, use of valproate and LTG is reported to be safe. Use of typical and/atypical antipsychotic is a good option during pregnancy in women with bipolar disorder. PMID:26330649

  19. Maximal lactate steady state in Judo

    PubMed Central

    de Azevedo, Paulo Henrique Silva Marques; Pithon-Curi, Tania; Zagatto, Alessandro Moura; Oliveira, João; Perez, Sérgio

    2014-01-01

    Summary Background: the purpose of this study was to verify the validity of respiratory compensation threshold (RCT) measured during a new single judo specific incremental test (JSIT) for aerobic demand evaluation. Methods: to test the validity of the new test, the JSIT was compared with Maximal Lactate Steady State (MLSS), which is the gold standard procedure for aerobic demand measuring. Eight well-trained male competitive judo players (24.3 ± 7.9 years; height of 169.3 ± 6.7cm; fat mass of 12.7 ± 3.9%) performed a maximal incremental specific test for judo to assess the RCT and performed on 30-minute MLSS test, where both tests were performed mimicking the UchiKomi drills. Results: the intensity at RCT measured on JSIT was not significantly different compared to MLSS (p=0.40). In addition, it was observed high and significant correlation between MLSS and RCT (r=0.90, p=0.002), as well as a high agreement. Conclusions: RCT measured during JSIT is a valid procedure to measure the aerobic demand, respecting the ecological validity of Judo. PMID:25332923

  20. Lack of Influence of the Menstrual Cycle on Blood Lactate.

    ERIC Educational Resources Information Center

    Lamont, Linda S.

    1986-01-01

    Nine healthy women were tested before, during, and after exercise during the follicular and luteal phases of their menstrual cycles to determine the effect of menstruation on blood lactate levels. Findings are discussed. (Author/MT)