Alcoholic fatty liver disease (AFLD) is a major risk factor for advanced liver injuries such as steatohepatitis, fibrosis, and cirrhosis. Adiponectin is one of the adipocyte-derived adipokines with potent lipid-lowering properties. During the last grant period, we and several other groups have discovered that the development of AFLD in several rodent models is associated with reduced circulating adiponectin levels, decreased hepatic adiponectin receptor expression, and impaired hepatic adiponectin signaling. While the role of adiponectin and its hepatic signaling has been firmly established in the development of AFLD, the cellular and molecular mechanisms whereby ethanol inhibits the expression and production of adiponectin in adipose tissue and impairs adiponectin-mediated signaling in liver remain largely unknown. Therefore, this current competitive renewal proposal focuses specifically and exclusively on the molecular mechanisms of ethanol-induced inhibition of adipose adiponectin expression and impairment of hepatic adiponectin signaling by examining novel and exciting hypotheses that two important adipose transcriptional regulators, FoxO1 and Lipin-1, may be involved in ethanol-dependent regulation of adiponectin, and that the inhibitory effect of ethanol on adiponectin via these two molecules may result partially from ethanol inhibition of SIRT1, an NAD(+)-dependent class III protein deacetylase, and more generally, SIRT1 may represent a central target for the action of adiponectin and ethanol both in the adipose tissue and in the liver.
The Specific Aims of the proposal are to: 1) Investigate the roles of FoxO1, Lipin-1 and SIRT1 in ethanol-mediated down regulation of adiponectin in mouse adipose tissue;2) Identify underlying mechanisms by which ethanol impairs the SIRT1-adiponectin axis via FoxO1 or Lipin-1 in cultured adipocytes;3) Investigate the mechanisms through which ethanol impairs hepatic adiponectin-SIRT1 signaling. We will utilize state-of-the-art molecular, cellular and biochemical approaches with cell culture and animal models to dissect the signaling events mediating the action of ethanol on adiponectin and its hepatic signaling. Since effects of ethanol on SIRT1 and adiponectin are highly regulated by dietary factors and pharmacological agents, these studies may lead to novel therapeutic strategies for the treatment of human AFLD and possibly steatohepatitis.

Public Health Relevance

Adiponectin plays a vital role in the development of alcoholic fatty liver disease. This renewal application will study the molecular mechanisms by which ethanol inhibits adipose-derived adiponectin expression and impairs its hepatic signaling. This study will increase our knowledge of the pathogenesis and therapeutics for treatment of human alcoholic fatty liver disease and possibly steatohepatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA015951-10
Application #
8702032
Study Section
Special Emphasis Panel (ZRG1-DKUS-L (03))
Program Officer
Gao, Peter
Project Start
2014-03-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
$323,514
Indirect Cost
$110,114
Name
Northeast Ohio Medical University
Department
Type
DUNS #
077779882
City
Rootstown
State
OH
Country
United States
Zip Code
44272
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
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
Shen, Zheng; Ajmo, Joanne M; Rogers, Christopher Q et al. (2009) Role of SIRT1 in regulation of LPS- or two ethanol metabolites-induced TNF-alpha production in cultured macrophage cell lines. Am J Physiol Gastrointest Liver Physiol 296:G1047-53

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