Alcoholic liver disease in patients appears to progress from steatosis to alcoholic hepatitis, fibrosis, and finally cirrhosis. Recent studies in rodents have elucidated many of the pathways by which chronic alcoholic intake leads to steatosis and steatohepatitis. However, the progression to hepatic fibrosis and cirrhosis is largely unknown. The overall goal of this project is to define the mechanism by which steatohepatitis leads to fibrosis in alcoholic liver disease. We will perform studies using the intragastric lavage model in mice to take advantage of mouse genetics and using primary cultures of hepatic stellate cells. This proposal is based on several underlying hypotheses: 1. Activation of the hepatic stellate cell (HSC) is the key mediator of the progression of alcoholic liver disease from steatohepatitis to fibrosis. 2. Activation of HSCs in culture recapitulates critical components of activation and hepatic fibrosis in vivo. 3. Lipopolysaccharide (LPS) is a critical factor in alcohol-induced fibrosis. 4. Female mice are more susceptible to alcoholic fibrosis than male mice.
The specific aims to be addressed in this project are: 1. To determine if NF-rJ3 transcriptional activity is an early marker of HSC activation. 2. To determine if HSC activation and proliferation proceeds type 1 collagen expression in alcoholic liver disease. 3. To determine if fibrogenesis exceeds matrix degradation in activated HSCs in alcoholic liver disease. The experimental design will use three novel transgenic mice that were created in our laboratory. The trangenic lines express reporter genes driven by the collagen alpha1(I) promoter and enhancer, the smooth muscle a actin promoter, or an NF-kappaB responsive element. These mice will be treated chronically with ethanol by the intragastric ethanol feeding model. By combining in vivo and in culture studies using these transgenic mice, our goal is to discover new insights into the molecular pathogenesis of alcoholic liver fibrosis.
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