Ghrelin regulates adipose tissue metabolism: Role in hepatic steatosis.

Fatty liver is the earliest and most common response of the liver to consumption of excessive alcohol. Steatosis can predispose the fatty liver to develop progressive liver damage. Chief among the many mechanisms involved in development of hepatic steatosis is dysregulation of insulin-mediated adipose tissue metabolism. Particularly, it is the enhanced adipose lipolysis-derived free fatty acids and their delivery to the liver that ultimately results in hepatic steatosis. The adipose-liver axis is modulated by hormones, particularly insulin and adiponectin. In recent studies, we demonstrated that an alcohol-induced increase in serum ghrelin levels impairs insulin secretion from pancreatic ß-cells. The consequent reduction in circulating insulin levels promotes adipose lipolysis and mobilization of fatty acids to the liver to ultimately contribute to hepatic steatosis. Because many tissues, including adipose tissue, express ghrelin receptor we hypothesized that ghrelin may directly affect energy metabolism in adipocytes. We have exciting new preliminary data which shows that treatment of premature 3T3-L1 adipocytes with ghrelin impairs adipocyte differentiation and inhibits lipid accumulation in the tissue designed to store energy in the form of fat. We further observed that ghrelin treatment of differentiated adipocytes significantly inhibited secretion of adiponectin, a hepatoprotective hormone that reduces lipid synthesis and promotes lipid oxidation. These results were corroborated by our observations of a significant increase in serum adiponectin levels in ethanol-fed rats treated with a ghrelin receptor antagonist verses the un-treated ethanol-fed rats. Interestingly, in adipocytes, ghrelin also increases secretion of interleukin-6 (IL-6) and CCL2 (chemokine [C-C motif] ligand 2), cytokines which promote hepatic inflammation and progression of liver disease. To summarize, the alcohol-induced increase in serum ghrelin levels dysregulates adipose-liver interaction and promotes hepatic steatosis by increasing the free fatty acid released from adipose for hepatic uptake, and by altering adiponectin and cytokine secretion. Taken together, our data indicates that targeting the activity of ghrelin may be a powerful treatment strategy.

Aldose reductase inhibitor protects mice from alcoholic steatosis by repressing saturated fatty acid biosynthesis.

Alcoholic liver injury results in morbidity and mortality worldwide, but there are currently no effective and safe therapeutics. Previously we demonstrated that aldose reductase (AR) inhibitor ameliorated alcoholic hepatic steatosis. To clarify the mechanism whereby AR inhibitor improves alcoholic hepatic steatosis, herein we investigated the effect of AR inhibitor on hepatic metabolism in mice fed a Lieber-DeCarli liquid diet with 5% ethanol. Nontargeted metabolomics showed carbohydrates and lipids were characteristic categories in ethanol diet-fed mice with or without AR inhibitor treatment, whereas AR inhibitor mainly affected carbohydrates and peptides. Ethanol-induced galactose metabolism and fatty acid biosynthesis are important for the induction of hepatic steatosis, while AR inhibitor impaired galactose metabolism without perturbing fatty acid biosynthesis. In parallel with successful treatment of steatosis, AR inhibitor suppressed ethanol-activated galactose metabolism and saturated fatty acid biosynthesis. Sorbitol in galactose metabolism and stearic acid in saturated fatty acid biosynthesis were potential biomarkers responsible for ethanol or ethanol plus AR inhibitor treatment. In vitro analysis confirmed that exogenous addition of sorbitol augmented ethanol-induced steatosis and stearic acid. These findings not only reveal metabolic patterns associated with disease and treatment, but also shed light on functional biomarkers contribute to AR inhibition therapy.

Histological Analyses of Acute Alcoholic Liver Injury in Zebrafish.

Alcoholic Liver Disease (ALD) refers to damage to the liver due to acute or chronic alcohol abuse. It is among the leading causes of alcohol-related morbidity and mortality and affects more than 2 million people in the United States. A better understanding of the cellular and molecular mechanisms underlying alcohol-induced liver injury is crucial for developing effective treatment for ALD. Zebrafish larvae exhibit hepatic steatosis and fibrogenesis after just 24 h of exposure to 2% ethanol, making them useful for the study of acute alcoholic liver injury. This work describes the procedure for acute ethanol treatment in zebrafish larvae and shows that it causes steatosis and swelling of the hepatic blood vessels. A detailed protocol for Hematoxylin and Eosin (H&E) staining that is optimized for the histological analysis of the zebrafish larval liver, is also described. H&E staining has several unique advantages over immunofluorescence, as it marks all liver cells and extracellular components simultaneously and can readily detect hepatic injury, such as steatosis and fibrosis. Given the increasing usage of zebrafish in modeling toxin and virus-induced liver injury, as well as inherited liver diseases, this protocol serves as a reference for the histological analyses performed in all these studies.

Chemical composition, characterization of anthocyanins and antioxidant potential of Euterpe edulis fruits: applicability on genetic dyslipidemia and hepatic steatosis in mice / Composición química y caracterización de antocianinas y potencial antioxidante de la fruta euterper edulis: aplicabilidad en la dislipidemia genética y la esteatosis hepática en ratones

The significance of polyphenol intake for the prevention of chronic diseases is controversial. Objective: this study investigated the chemical composition and antioxidant potential of an anthocyanin-rich extract from Euterpe edulis fruits (LPEF) and its effects on liver steatosis in dyslipidemic apoE-/- knockout mice. Materials and methods: mice were divided into G1 (C57BL/6) standard diet; G2 (apoE-/-) standard diet, G3 (apoE-/-) 2% LPEF, G4 (apoE-/-) 6% LPEF, G5 (apoE-/-) 10% LPEF, G6 (apoE-/-) 2% α-tocopherol acetate. After 75 days of treatment, the animals were euthanized. The LPEF contained a high level of monomeric anthocyanins (301.4 mg/100g) and marked antioxidant activity. Results: Catalase activity was reduced in G3, G4, G5 and G6 compared to G2. Superoxide dismutase was reduced only in G4. The animals in G4, G5, and G6 showed low HDL and triglycerides levels compared to G2. The proportion of lipid droplets in liver tissue was reduced in G4 and G5 compared to G2, G3, and G6. Conclusion: The results indicated that E. edulis pulp is rich in anthocyanins and the LPEF dietary consumption can reduce the severity of liver steatosis in apoE-/- mice, an effect that is potentially mediated by the antioxidant activity of this extract and modulation of triglyceride serum levels (AU)

El papel de los polifenoles en la prevención de enfermedades crónicas es controvertido. Objetivo: este estudio investigó la composición química y el potencial antioxidante de un extracto del fruto de Euterpe edulis rico en antocianinas (LPEF) y sus efectos en la esteatosis hepática en ratones apoE-/- knockout con dislipidemia. Material y métodos: los ratones fueron divididos en los siguientes grupos; G1 (C57BL/6) con una dieta estándar; G2 (apoE-/-) con dieta estándar; G3 G3 (apoE-/-) con 2% de LPEF; G4 (apoE-/-) con 6% de LPEF; G5 (apoE-/-) con 10% de LPEF y G6 (apoE-/-) con 2% acetato α-tocoferol (α-tocopherol acetate). Después de 75 días de tratamiento, los animales fueron eutanizados. El LPEF contenía un alto nivel de antocianinas monoméricas (301,4 mg/100 g) con notable actividad antioxidante. Resultados: la actividad catalasa fue reducida en los grupos G3, G4, G5 y G6 comparada con G2. La superoxidasa dismutasa solo se redujo en el grupo G4. Los animales de G4, G5 y G6 mostraron bajos niveles de HDL triglicéridos, comparados con G2. La proporción de lípidos en el tejido hepático fue reducida en G4 y G5, comparado con G2, G3 y G6. Conclusión: los resultados indicaron que la pulpa de E. edulis es rica en antocianinas, y que el consumo de LPEF en la dieta puede reducir la severidad de la esteatosis hepática en ratones apoE-/-, un efecto que es potencialmente mediado por la actividad antioxidante de este extracto y la modulación en los niveles séricos de triglicéridos (AU)