During the last grant period, we discovered that chronic ethanol feeding causes the development and maintenance of fatty liver in mice by affecting several important liver transcription factors and co-factors;namely, sterol regulatory element binding protein 1 (SREBP-1), peroxisome proliferator-activated receptor alpha (PPAR-alpha) and PPAR-gamma co-activator-alpha (PGC-1-alpha.) We demonstrated that the effects of ethanol on these transcriptional regulators are mediated partially by inhibition of hepatic AMP-activated kinase (AMPK), a key "metabolic switch" that controls pathways of hepatic lipid metabolism. It is intriguing that ethanol metabolism is required for each of these effects to occur, as ethanol metabolism has also been unequivocally associated with the development of alcoholic fatty liver disease. However, the identity of a potential bridging molecule that might link ethanol metabolism with downstream effects (including activation of said transcriptional regulators and the expression of genes that ultimately promote lipid accumulation) is still unknown. Sirtuin 1 (SIRT1), a class III NAD+-dependent protein deacetylase, is emerging as a master lipid regulator. The requirement of NAD+ for SIRT1 enzymatic activity implies a potential link between ethanol metabolism and SIRT1. Therefore, the objective of the current proposal is to test the hypothesis that ethanol metabolism significantly down regulates SIRT1 in the liver. Such inhibition of SIRT1 may lead to impairment of hepatic fat metabolism through modulation of the above-described signaling molecules, thereby contributing to increased hepatic lipid synthesis and reduced oxidation and export of fatty acids. This hypothesis will be tested in both animal and cell culture models of chronic ethanol exposure. In the mouse liver, we will examine the effects of chronic ethanol feeding on SIRT1--in terms of its mRNA and protein levels, enzymatic activity, and responsiveness to a potent SIRT1 agonist (resveratrol). The effects of ethanol will be correlated with hepatic lipid content and histology. In primary cultured hepatocytes and in hepatoma cells, the molecular mechanisms by which ethanol metabolism inhibits SIRT1 and alters signaling events will be investigated. Since SIRT1 can be manipulated by both pharmacological agents and dietary polyphenols, testing this hypothesis could possibly lead to novel therapies for human alcoholic fatty liver disease and steatohepatitis.

Public Health Relevance

This project investigates the effect of chronic ethanol exposure of animal liver or liver cells on the function of Sirtuin 1 (SIRT1) and its signaling that are associated with the development of alcoholic fatty liver disease.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Gao, Peter
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University of South Florida
Schools of Medicine
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Yin, Huquan; Hu, Ming; Liang, Xiaomei et al. (2014) Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver. Gastroenterology 146:801-11
Everitt, Hannah; Hu, Ming; Ajmo, Joanne M et al. (2013) Ethanol administration exacerbates the abnormalities in hepatic lipid oxidation in genetically obese mice. Am J Physiol Gastrointest Liver Physiol 304:G38-47
Yin, Huquan; Hu, Ming; Zhang, Ray et al. (2012) MicroRNA-217 promotes ethanol-induced fat accumulation in hepatocytes by down-regulating SIRT1. J Biol Chem 287:9817-26
Hu, Ming; Wang, Fengming; Li, Xin et al. (2012) Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice. Hepatology 55:437-46
Liang, Xiaomei; Hu, Ming; Rogers, Christopher Q et al. (2011) Role of SIRT1-FoxO1 signaling in dietary saturated fat-dependent upregulation of liver adiponectin receptor 2 in ethanol-administered mice. Antioxid Redox Signal 15:425-35
Shen, Zheng; Liang, Xiaomei; Rogers, Christopher Q et al. (2010) Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 298:G364-74
Peng, Yanhua; Rideout, Drew A; Rakita, Steven S et al. (2010) Does LKB1 mediate activation of hepatic AMP-protein kinase (AMPK) and sirtuin1 (SIRT1) after Roux-en-Y gastric bypass in obese rats? J Gastrointest Surg 14:221-8
Esfandiari, Farah; Medici, Valentina; Wong, Donna H et al. (2010) Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse. Hepatology 51:932-41
Peng, Yanhua; Rideout, Drew; Rakita, Steven et al. (2009) Downregulation of adiponectin/AdipoR2 is associated with steatohepatitis in obese mice. J Gastrointest Surg 13:2043-9
You, Min; Rogers, Christopher Q (2009) Adiponectin: a key adipokine in alcoholic fatty liver. Exp Biol Med (Maywood) 234:850-9

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