Environmental/dietary models of steatosis Genetics can contribute to alcohol intake differences in mice(15; 16), however this grant will focus on the contribution of genetics to the development of steatosis. Both genetics and environmental factors can contribute to hepatic lipogenesis and steatosis. Several dietary models of steatosis have been used. These include the high fat high sucrose (HFHS) diet, the methionine-restricted choline-deficient (MCD) and the ethanol containing diet. The mouse strain, B6 is a well-accepted model of diet-induced obesity (17). The B6 mice fed a HFHS diet for 16 weeks increase their body weight by 15% and develop fatty liver. The MCD model is a diet-induced model that affects packaging of lipid for transport and fatty acid oxidation resulting in development of macrovesicular fat in the liver (18). Chronic ingestion of ethanol using the Lieber-DeCarli ethanol liquid diet or intragastric ethanol feeding cause hepatic steatosis and hepatic injury in a variety of animal models, modeling the pathogenesis of early stages of ALD in humans (19;20). The mechanism by which steatosis and hepatic injury develops from alcohol and diet-induced obesity is not fully understood. The purpose of this grant is to investigate the genetic susceptibility and the mechanisms for the development of steatosis and hepatic injury in novel genetic animal models, the CSS mice. We hypothesize that although the progression of steatosis to cirrhosis is similar from chronic alcohol consumption and from obesity, the genetic susceptibility to liver injury is different.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory Grants (P20)
Project #
5P20AA017837-05
Application #
8529405
Study Section
Special Emphasis Panel (ZAA1-BB)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$23,665
Indirect Cost
$8,590
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Zhou, Hao; Yu, Minjia; Zhao, Junjie et al. (2016) IRAKM-Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease. Hepatology 64:1978-1993
Chaudhry, Kamaljit K; Shukla, Pradeep K; Mir, Hina et al. (2016) Glutamine supplementation attenuates ethanol-induced disruption of apical junctional complexes in colonic epithelium and ameliorates gut barrier dysfunction and fatty liver in mice. J Nutr Biochem 27:16-26
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Smathers, Rebecca L; Chiang, Dian J; McMullen, Megan R et al. (2016) Soluble IgM links apoptosis to complement activation in early alcoholic liver disease in mice. Mol Immunol 72:9-18
McCullough, Rebecca L; McMullen, Megan R; Das, Dola et al. (2016) Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice. Mol Immunol 75:122-32
Roychowdhury, Sanjoy; McCullough, Rebecca L; Sanz-Garcia, Carlos et al. (2016) Receptor interacting protein 3 protects mice from high-fat diet-induced liver injury. Hepatology 64:1518-1533
Chaudhry, Kamaljit K; Samak, Geetha; Shukla, Pradeep K et al. (2015) ALDH2 Deficiency Promotes Ethanol-Induced Gut Barrier Dysfunction and Fatty Liver in Mice. Alcohol Clin Exp Res 39:1465-75
Berisha, Stela Z; Brubaker, Greg; Kasumov, Takhar et al. (2015) HDL from apoA1 transgenic mice expressing the 4WF isoform is resistant to oxidative loss of function. J Lipid Res 56:653-64
Golub, Haleigh M; Zhou, Qi-Gang; Zucker, Hannah et al. (2015) Chronic Alcohol Exposure is Associated with Decreased Neurogenesis, Aberrant Integration of Newborn Neurons, and Cognitive Dysfunction in Female Mice. Alcohol Clin Exp Res 39:1967-77
Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M (2015) Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption. Free Radic Biol Med 86:179-90

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