Our laboratory has been actively studying the molecular mechanisms of alcoholic liver disease, focusing on the role of interleukin-6 (IL-6) and IL-10 and their downstream signal STAT3 in alcoholic fatty liver and liver inflammation Inflammation-associated IL-6/STAT3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in IL-10 deficient mice. Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, while inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin-10 (IL-10), a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic fatty liver disease models that were achieved via feeding mice with a liquid diet containing 5% ethanol for 4 weeks or a high fat diet for 12 weeks, respectively. IL-10 knockout (IL-10(-/-) ) mice and several other strains of genetically modified mice were generated and used. Compared to wild-type mice, IL-10(-/-) mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or high fat diet feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10(-/-) mice. In addition, the hepatic expression of SREBP1c and key downstream lipogenic proteins and enzymes in fatty acid synthesis were downregulated in IL-10(-/-) mice. Conversely, IL-10(-/-) mice displayed enhanced levels of phosphorylated AMPK and its downstream targets including phosphorylated ACC1 and CPT-1 in the liver. Such dysregulations were corrected in IL-10(-/-) IL-6(-/-) or IL-10(-/-) STAT3(Hep-/-) double knockout mice. In conclusion, IL-10(-/-) mice are prone to liver inflammatory response but resistant to steatosis and hepatocellular damage induced by ethanol or high fat diet feeding. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently downregulates lipogenic genes but upregulates fatty acid oxidation-associated genes in the liver In addition, we are also collaborating with Drs. George Kunos and Pal Pacher from NIAAA to investigate the role of the endocannabinoid system in alcoholic liver disease.

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National Institute on Alcohol Abuse and Alcoholism
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