Alcoholic liver disease (ALD) continues to be an important health problem in the United States. Abnormal hepatic methionine metabolism is an acquired metabolic abnormality in ALD and the effects of chronic alcohol intake on hepatic methionine metabolism are initially seemingly paradoxic. Whereas alcohol consumption causes hepatic deficiency of S-adenosylmethionie (SAMe), it elevates hepatic homocysteine levels, a product of SAMe metabolism. ? ? Decreased SAMe levels and elevated homocysteine levels may contribute to alcohol induced liver injury. The effect of alcohol on S-adenosylhomocysteine (SAH) levels, another metabolite in the methionine metabolism pathway, has received little investigative attention. It is our working hypothesis that tumor necrosis factor (TNF) in conjunction with certain metabolic abnormalities observed in ALD, such as altered intracellular methylation status due to abnormal methionine/SAMe/SAH metabolism play an etiologic role in the development of liver injury in ALD. We postulate that chronic alcohol abuse causes increased gut permeability and endotoxemia, generation of reactive oxygen intermediates, activation of Kupffer cell NFkB with increased TNF production, decreased hepatocyte MAT activity with subsequent SAMe deficiency, increased S-adenosylhomocysteine (SAH) concentrations, inhibition of transmethylation reactions, decreased hepatic methylation status, elevated expression/ activation/activity of proteins sensitive to intracellular methylation status such as caspase-8, mitochondrial dysfunction, increased susceptibility to hepatic TNF cytotoxicity, and subsequent liver injury. In this proposal, we will evaluate inhibition of hepatic transmethylation reactions by chronic alcohol exposure as a mechanism for hepatic sensitization to TNF-induced cytotoxicity in a relevant model of ALD. The specific objectives of this project are as follows: 1. Evaluate the effects of inhibition of hepatic transmethylation reactions on """"""""sensitization"""""""" to TNF hepatotoxicity; 2. Investigate possible mechanisms by which inhibition of transmethylation reactions sensitizes hepatocytes to TNF hepatotoxicity; and 3. Evaluate the effects of chronic alcohol consumption (+/- SAMe supplementation) on hepatic methylation status and sensitization to TNF-hepatotoxicity in rats intragastrically fed alcohol. ? ? This research will be performed with structured mentoring support and a detailed training program designed to maximize my opportunity to become an independent NIH-funded investigator. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AA015344-03
Application #
7279907
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Radaeva, Svetlana
Project Start
2005-09-15
Project End
2008-08-16
Budget Start
2007-09-01
Budget End
2008-08-16
Support Year
3
Fiscal Year
2007
Total Cost
$105,003
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Wang, Zhigang; Dou, Xiaobing; Gu, Dongfang et al. (2012) 4-Hydroxynonenal differentially regulates adiponectin gene expression and secretion via activating PPAR? and accelerating ubiquitin-proteasome degradation. Mol Cell Endocrinol 349:222-31
Wang, Zhigang; Dou, Xiaobing; Yao, Tong et al. (2011) Homocysteine inhibits adipogenesis in 3T3-L1 preadipocytes. Exp Biol Med (Maywood) 236:1379-88
Wang, Zhigang; Pini, Maria; Yao, Tong et al. (2011) Homocysteine suppresses lipolysis in adipocytes by activating the AMPK pathway. Am J Physiol Endocrinol Metab 301:E703-12
Watson, Walter H; Song, Zhenyuan; Kirpich, Irina A et al. (2011) Ethanol exposure modulates hepatic S-adenosylmethionine and S-adenosylhomocysteine levels in the isolated perfused rat liver through changes in the redox state of the NADH/NAD(+) system. Biochim Biophys Acta 1812:613-8
Dou, Xiaobing; Wang, Zhigang; Yao, Tong et al. (2011) Cysteine aggravates palmitate-induced cell death in hepatocytes. Life Sci 89:878-85
Wang, Zhigang; Yao, Tong; Song, Zhenyuan (2010) Involvement and mechanism of DGAT2 upregulation in the pathogenesis of alcoholic fatty liver disease. J Lipid Res 51:3158-65
Wang, Zhigang; Yao, Tong; Pini, Maria et al. (2010) Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 298:G634-42
Wang, Zhigang; Yao, Tong; Song, Zhenyuan (2010) Extracellular signal-regulated kinases 1/2 suppression aggravates transforming growth factor-beta1 hepatotoxicity: a potential mechanism for liver injury in methionine-choline deficient-diet-fed mice. Exp Biol Med (Maywood) 235:1347-55
Wang, Zhigang; Yao, Tong; Song, Zhenyuan (2010) Chronic alcohol consumption disrupted cholesterol homeostasis in rats: down-regulation of low-density lipoprotein receptor and enhancement of cholesterol biosynthesis pathway in the liver. Alcohol Clin Exp Res 34:471-8
Song, Zhenyuan; Zhou, Zhanxiang; Song, Ming et al. (2007) Alcohol-induced S-adenosylhomocysteine accumulation in the liver sensitizes to TNF hepatotoxicity: possible involvement of mitochondrial S-adenosylmethionine transport. Biochem Pharmacol 74:521-31

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