Ethanol causes the development and maintenance of fatty liver by effects on two important liver nuclear transcription factors that are involved in hepatic fatty acid synthesis and oxidation pathways, activation of sterol regulatory element binding protein-1 (SREBP-1), and inhibition of peroxisome proliferators activated receptor alpha (PPARa). Moreover, ethanol effects on these transcription factors are resulted partially from ethanol inhibition of hepatic AMP-activated kinase (AMPK), a key """"""""metabolic switch"""""""" controlling pathways of hepatic cholesterol and triglyceride synthesis. Recently, studies have identified AMPK, PPARa and SREBP-1 as the major mediators of the metabolic effect of the newly discovered hormone adiponectin. Adiponectin, a hormone exclusively derived from adipocytes that circulates in plasma, plays a central role in the regulation of energy metabolism, lipid and carbohydrate metabolism. We hypothesize that development of alcoholic fatty liver may be in part caused by ethanol inhibition of adiponectin synthesis in adipose tissue or by ethanol-induced abnormalities of adiponectin receptor- mediated signaling in the liver. The net effect of these actions of ethanol is thus to impair fatty acid disposal and to increase the rate of fatty acid synthesis, and lead to liver steatosis. Our hypothesis will be tested in both animal and cell culture models of chronic ethanol exposure. In the animal adipose tissue, we will examine the effects of ethanol feeding on mRNA and protein levels of adiponectin, and responsiveness to known inducers of adiponectin, a PPARgamma agonist, thiazolidinedione (rosiglitazone). In the animal liver, we will examine the effects of ethanol administration on levels and function of adiponectin receptors and responsiveness to the PPARgamma agonist. The effects of ethanol in adipose and liver will be correlated with lipid content, measures of total body lipid metabolism and hepatic histology. The molecular mechanisms for the effects of ethanol on adiponectin synthesis will be tested in primary adipocytes and cultured rat 3T3-L1 adipocytes. Since effects of ethanol on adiponectin and its signaling are highly regulated by dietary fatty acids, our hypothesis may provide a promising novel therapeutic strategy, which is nutritional modulation of adiponectin synthesis and adiponectin mediated signaling, for the treatment of 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 #
5R01AA015951-05
Application #
7666214
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Radaeva, Svetlana
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
5
Fiscal Year
2009
Total Cost
$334,389
Indirect Cost
Name
University of South Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Xu, Jiesi; Xu, Yang; Li, Yuanyuan et al. (2016) Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4? and Protects Against Alcohol- and MCD diet-induced Liver Injury. Sci Rep 6:24277
Cai, Yan; Jogasuria, Alvin; Yin, Huquan et al. (2016) The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice. Am J Pathol 186:2417-28
Odena, Gemma; Chen, Jiegen; Lozano, Juan Jose et al. (2016) LPS-TLR4 Pathway Mediates Ductular Cell Expansion in Alcoholic Hepatitis. Sci Rep 6:35610
Wang, Jiayou; Kim, Chunki; Jogasuria, Alvin et al. (2016) Myeloid Cell-Specific Lipin-1 Deficiency Stimulates Endocrine Adiponectin-FGF15 Axis and Ameliorates Ethanol-Induced Liver Injury in Mice. Sci Rep 6:34117
Hu, Xudong; Jogasuria, Alvin; Wang, Jiayou et al. (2016) MitoNEET Deficiency Alleviates Experimental Alcoholic Steatohepatitis in Mice by Stimulating Endocrine Adiponectin-Fgf15 Axis. J Biol Chem 291:22482-22495
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Yin, Huquan; Liang, Xiaomei; Jogasuria, Alvin et al. (2015) miR-217 regulates ethanol-induced hepatic inflammation by disrupting sirtuin 1-lipin-1 signaling. Am J Pathol 185:1286-96

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