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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory Grants (P20)
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Cleveland Clinic Lerner
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Barnes, Mark A; Roychowdhury, Sanjoy; Nagy, Laura E (2014) Innate immunity and cell death in alcoholic liver disease: role of cytochrome P4502E1. Redox Biol 2:929-35
Bakhautdin, Bakytzhan; Das, Dola; Mandal, Palash et al. (2014) Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice. J Hepatol 61:1029-37
Thapaliya, Samjhana; Runkana, Ashok; McMullen, Megan R et al. (2014) Alcohol-induced autophagy contributes to loss in skeletal muscle mass. Autophagy 10:677-90
Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M (2014) Chronic ethanol ingestion induces oxidative kidney injury through taurine-inhibitable inflammation. Free Radic Biol Med 69:403-16
Roychowdhury, Sanjoy; Chiang, Dian J; McMullen, Megan R et al. (2014) Moderate, chronic ethanol feeding exacerbates carbon-tetrachloride-induced hepatic fibrosis via hepatocyte-specific hypoxia inducible factor 1? Pharmacol Res Perspect 2:e00061
Cresci, Gail A; Bush, Katelyn; Nagy, Laura E (2014) Tributyrin supplementation protects mice from acute ethanol-induced gut injury. Alcohol Clin Exp Res 38:1489-501
Barnes, Mark A; McMullen, Megan R; Roychowdhury, Sanjoy et al. (2013) Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis, and steatosis. Hepatology 57:1980-91
Dixon, Laura J; Flask, Chris A; Papouchado, Bettina G et al. (2013) Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis. PLoS One 8:e56100
Dixon, Laura J; Barnes, Mark; Tang, Hui et al. (2013) Kupffer cells in the liver. Compr Physiol 3:785-97
Roychowdhury, Sanjoy; McMullen, Megan R; Pisano, Sorana G et al. (2013) Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57:1773-83

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