leptin and Liver-Diseases--Alcoholic

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The presentation was Nonalcoholic fatty liver disease: Implications for alcoholic liver disease pathogenesis, by Anna Mae Diehl.

Topics: Animals; Apoptosis; Endotoxins; Fatty Liver; Humans; Leptin; Liver; Liver Diseases, Alcoholic; Mice; Mice, Obese; Mitochondria, Liver; Necrosis; Obesity; Reactive Oxygen Species; Signal Transduction; Tumor Necrosis Factor-alpha

There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood.. Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks. The EtOH treatment also consisted of a weekly 2.5 g EtOH/kg body weight gavage. Markers for lipid regulation, oxidative stress, inflammation, and fibrosis were measured by RT-qPCR, RNA-seq, Western blot, and metabolomics.. Combined FFC-EtOH induced more body weight gain, glucose intolerance, steatosis, and hepatomegaly compared to Chow, EtOH, or FFC. Glucose intolerance by FFC-EtOH was associated with decreased hepatic protein kinase B (AKT) protein expression and increased gluconeogenic gene expression. FFC-EtOH increased hepatic triglyceride and ceramide levels, plasma leptin levels, hepatic Perilipin 2 protein expression, and decreased lipolytic gene expression. FFC and FFC-EtOH also increased AMP-activated protein kinase (AMPK) activation. Finally, FFC-EtOH enriched the hepatic transcriptome for genes involved in immune response and lipid metabolism.. In our model of early SMAFLD, we observed that the combination of an obesogenic diet and alcohol caused more weight gain, promoted glucose intolerance, and contributed to steatosis by dysregulating leptin/AMPK signaling. Our model demonstrates that the combination of an obesogenic diet with a chronic-binge pattern alcohol intake is worse than either insult alone.

Topics: AMP-Activated Protein Kinases; Animals; Diet, High-Fat; Diet, Western; Ethanol; Glucose Intolerance; Leptin; Lipid Metabolism; Liver; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity

Alcohol-associated liver disease (ALD) is caused by chronic use of alcohol and ranges from hepatic steatosis to fibrosis and cirrhosis. Bile acids are physiological detergents that also regulate hepatic glucose and lipid homeostasis by binding to several receptors. One such receptor, Takeda G protein-coupled receptor 5 (TGR5), may represent a therapeutic target for ALD. Here, we used a chronic 10-day + binge ethanol-feeding model in mice to study the role of TGR5 in alcohol-induced liver injury.. Female C57BL/6J wild-type mice and Tgr5-/- mice were pair-fed Lieber-DeCarli liquid diet with ethanol (5% v/v) or isocaloric control diet for 10 days followed by a gavage of 5% ethanol or isocaloric maltose control, respectively, to represent a binge-drinking episode. Tissues were harvested 9 hours following the binge, and metabolic phenotypes were characterized through examination of liver, adipose, and brain mechanistic pathways.. Tgr5-/- mice were protected from alcohol-induced accumulation of hepatic triglycerides. Interestingly, liver and serum levels of Fgf21 were significantly increased during ethanol feeding in Tgr5-/- mice, as was phosphorylation of Stat3. Parallel to Fgf21 levels, increased leptin gene expression in white adipose tissue and increased leptin receptor in liver were detected in Tgr5-/- mice fed ethanol diet. Adipocyte lipase gene expression was significantly increased in Tgr5-/- mice regardless of diet, whereas adipose browning markers were also increased in ethanol-fed Tgr5-/- mice, indicating potential for enhanced white adipose metabolism. Lastly, hypothalamic mRNA targets of leptin, involved in the regulation of food intake, were significantly increased in Tgr5-/- mice fed ethanol diet.. Tgr5-/- mice are protected from ethanol-induced liver damage and lipid accumulation. Alterations in lipid uptake and Fgf21 signaling, and enhanced metabolic activity of white adipose tissue, may mediate these effects.

Topics: Animals; Ethanol; Female; Leptin; Lipids; Liver Diseases, Alcoholic; Mice; Mice, Inbred C57BL; Obesity

The mechanisms of alcohol-mediated advanced liver injury in HIV-infected individuals are poorly understood. Thus, this study was aimed to investigate the effect of binge alcohol on the inflammatory liver disease in HIV transgenic rats as a model for simulating human conditions. Female wild-type (WT) or HIV transgenic rats were treated with three consecutive doses of binge ethanol (EtOH) (3.5 g/kg/dose oral gavages at 12-h intervals) or dextrose (Control). Blood and liver tissues were collected at 1 or 6-h following the last dose of ethanol or dextrose for the measurements of serum endotoxin and liver pathology, respectively. Compared to the WT, the HIV rats showed increased sensitivity to alcohol-mediated gut leakiness, hepatic steatosis and inflammation, as evidenced with the significantly elevated levels of serum endotoxin, hepatic triglycerides, histological fat accumulation and F4/80 staining. Real-time PCR analysis revealed that hepatic levels of toll-like receptor-4 (TLR4), leptin and the downstream target monocyte chemoattractant protein-1 (MCP-1) were significantly up-regulated in the HIV-EtOH rats, compared to all other groups. Subsequent experiments with primary cultured cells showed that both hepatocytes and hepatic Kupffer cells were the sources of the elevated MCP-1 in HIV-EtOH rats. Further, TLR4 and MCP-1 were found to be upregulated by leptin. Collectively, these results show that HIV rats, similar to HIV-infected people being treated with the highly active anti-retroviral therapy (HAART), are more susceptible to binge alcohol-induced gut leakiness and inflammatory liver disease than the corresponding WT, possibly due to additive or synergistic interaction between binge alcohol exposure and HIV infection. Based on these results, HIV transgenic rats can be used as a surrogate model to study the molecular mechanisms of many disease states caused by heavy alcohol intake in HIV-infected people on HAART.

Topics: Animals; Cells, Cultured; Central Nervous System Depressants; Chemokine CCL2; Dose-Response Relationship, Drug; Ethanol; Female; Gene Expression; Hepatocytes; HIV; HIV Infections; Humans; Intestinal Diseases; Intestinal Mucosa; Intestines; Leptin; Liver Diseases, Alcoholic; Permeability; Rats, Inbred F344; Rats, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; Toll-Like Receptor 4

Clinical studies have demonstrated that alcoholics have a lower dietary zinc intake compared to health controls. The present study was undertaken to determine the interaction between dietary zinc deficiency and ethanol consumption in the pathogenesis of alcoholic liver disease. C57BL/6N mice were subjected to 8-week feeding of 4 experimental liquid diets: (1) zinc adequate diet, (2) zinc adequate diet plus ethanol, (3) zinc deficient diet, and (4) zinc deficient diet plus ethanol. Ethanol exposure with adequate dietary zinc resulted in liver damage as indicated by elevated plasma alanine aminotransferase level and increased hepatic lipid accumulation and inflammatory cell infiltration. Dietary zinc deficiency alone increased hepatic lipid contents, but did not induce hepatic inflammation. Dietary zinc deficiency showed synergistic effects on ethanol-induced liver damage. Dietary zinc deficiency exaggerated ethanol effects on hepatic genes related to lipid metabolism and inflammatory response. Dietary zinc deficiency worsened ethanol-induced imbalance between hepatic pro-oxidant and antioxidant enzymes and hepatic expression of cell death receptors. Dietary zinc deficiency exaggerated ethanol-induced reduction of plasma leptin, although it did not affect ethanol-induced reduction of white adipose tissue mass. Dietary zinc deficiency also deteriorated ethanol-induced gut permeability increase and plasma endotoxin elevation. These results demonstrate, for the first time, that dietary zinc deficiency is a risk factor in alcoholic liver disease, and multiple intrahepatic and extrahepatic factors may mediate the detrimental effects of zinc deficiency.

Topics: Adipose Tissue, White; Animals; Biomarkers; Body Weight; Cytokines; Diet; Endotoxemia; Ethanol; Fatty Liver; Gene Expression Regulation; Inflammation Mediators; Intestinal Mucosa; Intestines; Leptin; Lipid Metabolism; Lipid Peroxidation; Lipids; Liver; Liver Diseases, Alcoholic; Male; Mice; Neutrophil Infiltration; Organ Size; Oxidative Stress; Permeability; Receptors, Death Domain; Zinc

There is growing evidence that white adipose tissue is an important contributor in the pathogenesis of alcoholic liver disease (ALD). We investigated serum concentrations of total adiponectin (Acrp30), leptin, and resistin in patients with chronic alcohol abuse and different grades of liver dysfunction, as well as ALD complications.. One hundred forty-seven consecutive inpatients with ALD were prospectively recruited. The evaluation of plasma adipokine levels was performed using immunoenzymatic ELISA tests. Multivariable logistic regression was applied in order to select independent predictors of advanced liver dysfunction and the disease complications.. Acrp30 and resistin levels were significantly higher in patients with ALD than in controls. Lower leptin levels in females with ALD compared to controls, but no significant differences in leptin concentrations in males, were found. High serum Acrp30 level revealed an independent association with advanced liver dysfunction, as well as the development of ALD complications, that is, ascites and hepatic encephalopathy.. Gender-related differences in serum leptin concentrations may influence the ALD course, different in females compared with males. Serum Acrp30 level may serve as a potential prognostic indicator for patients with ALD.

Topics: Adiponectin; Adipose Tissue; Adult; Aged; Alcoholism; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Leptin; Liver; Liver Diseases; Liver Diseases, Alcoholic; Male; Middle Aged; Multivariate Analysis; Prognosis; Prospective Studies; Resistin; Sex Factors

Ethanol metabolism is accompanied by generation of free radicals, which stimulate lipid peroxidation. Previous studies have proposed a possible link between leptin and non-alcoholic fatty liver disease; however, the effect of leptin on ethanol-induced liver diseases remains unclear. The aim of the present study was to explore the effect of leptin on ethanol-induced liver injury in mice. Administering ethanol (6.32 g/kg body weight p.o.) to 4-week-old healthy mice for 45 days resulted in significantly elevated levels of plasma leptin, total bilirubin, gamma-glutamyl transpeptidase (GGT), tissue lipid hydroperoxides (LOOH), and lowered levels of tissue vitamins C and E when compared with those of the control mice. Subsequent to the experimental induction of hepatotoxicity (i.e. after the initial period of 30 days) exogenous leptin was administered (230 microg/kg body weight i.p.) every alternate day for 15 days along with the daily dose of ethanol. Leptin administration to control and ethanol-treated mice significantly reduced the weight gain, elevated the plasma levels of leptin, bilirubin, GGT and tissue LOOH, and significantly lowered the levels of tissue vitamins C and E when compared with the untreated control and ethanol-supplemented mice. It is postulated that the increase in systemic leptin levels enhances oxidative stress, and lowers antioxidant defence, leading to the augmented hepatic inflammation observed in alcoholic liver disease.

Topics: Animals; Ethanol; Hepatitis, Alcoholic; Kidney; Leptin; Lipid Peroxidation; Liver Diseases, Alcoholic; Liver Function Tests; Male; Mice

Hepatic injury elicits intracellular stress that leads to peroxidation of membrane lipids accompanied by alteration of structural and functional characteristics of the membrane, which affects the activity of membrane-bound ATPases. We have explored the effect of leptin on hepatic marker enzyme and membrane-bound adenosine triphosphatases in ethanol-induced liver toxicity in mice. The experimental groups were control, leptin (230 microg kg(-1), i.p. every alternate day for last 15 days), alcohol (6.32 g kg(-1), by intragastric intubation for 45 days), and alcohol plus leptin. Ethanol feeding to mice significantly (P < 0.05) elevated the plasma leptin, alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and hepatic lipid hydroperoxides (LOOH), and plasma and hepatic total ATPases, Na(+), K(+)-ATPase and Mg(2+)-ATPase. There was a significant decrease in Ca(2+)-ATPase and reduced glutathione (GSH). Leptin injections to ethanol-fed animals further elevated the levels of hepatic LOOH, plasma and hepatic total ATPases, Na(+), K(+)-ATPase and Mg(2+)-ATPase, while the Ca(2)-ATPase and GSH were decreased significantly. In addition, leptin administration was found to increase the plasma levels of leptin, ALT, ALP, GGT, Na(+) and inorganic phosphorous, and decrease the levels of K(+) and Ca(2+) in ethanol-fed mice. These findings were consistent with our histological observations, confirming that leptin enhanced liver ailments in ethanol-supplemented mice.

Topics: Adenosine Triphosphatases; Animals; Biological Transport, Active; Ca(2+) Mg(2+)-ATPase; Calcium-Transporting ATPases; Cations; Cell Membrane; Central Nervous System Depressants; Chemical and Drug Induced Liver Injury; Electrolytes; Ethanol; Glutathione; Indicators and Reagents; Leptin; Lipid Peroxidation; Liver; Liver Diseases, Alcoholic; Liver Function Tests; Male; Mice; Phosphates; Sodium-Potassium-Exchanging ATPase

The mechanisms by which overweight makes the liver more susceptible to alcoholic liver injury remain to be determined. Therefore, we conducted the following studies to further elucidate the role of leptin in the pathogenesis of steatosis and cirrhosis caused by chronic alcohol consumption in human beings.. Two-hundred nine consecutive patients with alcoholic liver disease were studied. Serum leptin concentrations were measured by using radioimmunoassay, and the relationships between serum leptin level and liver lesions were studied. Statistical analysis used logistic regressions.. When serum leptin, serum cholesterol, and body mass index (BMI) were considered together in the multiple logistic regression analysis, compared with patients with severe steatosis, serum leptin remains significantly lower in patients without steatosis (p<0.05) and in patients with mild or moderate steatosis (p<0.05). When age, serum leptin, serum cholesterol, and steatosis grade were considered together in the logistic regression analysis, serum leptin (p<0.01) and age (p<0.02) were positively and independently correlated with the presence of cirrhosis. After BMI introduction in the statistical model, serum leptin was no more correlated with the presence of cirrhosis.. In patients with alcoholic liver disease, serum leptin is independently correlated with steatosis grade and might play an important role in severity of fibrosis as fatty liver is more vulnerable than normal liver to factors that lead to fibrosis.

Topics: Adult; Chi-Square Distribution; Female; Humans; Leptin; Liver Diseases, Alcoholic; Logistic Models; Male; Middle Aged; Overweight; Prospective Studies; Risk Factors

Previous studies suggest a possible link between leptin and hepatic inflammation; however, the role of leptin on liver disease remains unclear. The purpose of the present study was to evaluate the effect of leptin on tissue lipid peroxidation and the antioxidant status in experimental hepatotoxicity. Administering ethanol (6.32 g/kg body weight) to 4-week-old healthy mice for 45 days resulted in significantly elevated levels of tissue thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and lowered activities of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione related enzymes such as glutathione peroxidase (GPx) and glutathione S-transferase (GST) as compared with those of the control mice. subsequent to the experimental induction of hepatotoxicity (i.e. after the initial period of 30 days) exogenous leptin was simultaneously administered (230 microg/kg body weight) every alternate day for 15 days along with the daily dose of alcohol. Leptin administration to control and alcohol-treated mice significantly reduced the weight gain, significantly elevated the liver and kidney levels of TBARS and CD, and significantly lowered the levels of enzymic and non-enzymic antioxidants as compared with the untreated control and alcohol supplemented mice. It is postulated that the increase in systemic leptin levels enhance the oxidative stress, and lower the antioxidant defence, leading to augmented hepatic inflammation in alcoholic liver disease.

Topics: Analysis of Variance; Animals; Brain; Catalase; Ethanol; Glutathione; Kidney; Leptin; Lipid Peroxidation; Liver; Liver Diseases, Alcoholic; Male; Mice; Oxidative Stress; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Weight Gain

Previous studies suggest a possible link between leptin and hepatic inflammation; however the role of leptin in liver diseases remains unclear. The purpose of the present study was to evaluate the effect of leptin on plasma and tissue lipids in experimental hepatotoxicity. Administering ethanol (6.32 g/kg body weight) to 4-week-old healthy mice for 45 days resulted in significantly elevated levels of plasma and tissue phospholipids, triglycerides and free fatty acids as compared with those of the control animals. Subsequent to the experimental induction of hepatotoxicity (i.e., the initial period of 30 days) exogenous leptin was simultaneously administered (230 microg/kg body weight) every alternate day for 15 days along with the daily dose of alcohol. Leptin administration to control and alcohol-treated mice reduced the weight gain and significantly lowered the levels of plasma and tissue lipids as compared with the untreated control and alcohol supplemented mice. It is postulated that the increase in systemic leptin levels lower the plasma and tissue lipids of alcohol-treated mice, which operates independently of changes in food intake, body weight and the size of the fat stores.

Topics: Animals; Fatty Acids, Nonesterified; Hypolipidemic Agents; Leptin; Lipid Metabolism; Lipids; Liver Diseases, Alcoholic; Male; Mice; Phospholipids; Triglycerides; Weight Gain

Topics: Humans; Leptin; Liver Cirrhosis; Liver Diseases, Alcoholic; Male; Transforming Growth Factor beta; Transforming Growth Factor beta1

Increases in monocyte/macrophage production of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), parallel the evolution of liver injury in rats and humans with alcoholic liver disease. However, the possibility that TNF-alpha expression may be induced in other cell populations before serious liver disease develops has not been evaluated. To clarify this issue, mRNAs and/or protein levels of TNF-alpha and cytokines [interleukin (IL)-6, IL-10, transforming growth factor-beta (TGF)-beta, IL-12, and interferon-gamma] that regulate its biological activity were measured in sera, liver, and adipose tissues of rats that had developed hepatic steatosis after consuming ethanol-containing diets for 6 weeks. Cytokine expression in the ethanol-fed groups was compared with that of pair-fed controls rats that had received isocaloric amounts of a similar, ethanol-free diet for the same time period. Animals were studied both before and after a surgical stress (partial hepatectomy) that is known to provoke cytokine production. Chronic ethanol consumption led to increased serum concentrations of TNF and related cytokines, at least in part, by inducing the overproduction of these factors in the liver and peripheral adipose tissues. Despite the pair-feeding protocol that ensured similar calorie consumption in both groups, adipose tissues in ethanol-fed rats also expressed more leptin, a TNF-alpha-inducible mRNA that encodes an appetite-suppressing hormone. Thus, white adipose tissue can be an important source of cytokines in nonobese animals and may be a target for ethanol's actions. These data implicate TNF-alpha as a potential mediator of the nutritional-metabolic aberrations that often accompany chronic alcohol intake, even in the absence of advanced liver disease.

Topics: Adipose Tissue; Alcoholism; Animals; Cytokines; Ethanol; Fatty Liver, Alcoholic; Leptin; Liver; Liver Diseases, Alcoholic; Macrophages; Monocytes; Proteins; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha