Hepatic stellate cells ( HSC) are liver perisinusoidal cells that store vitamin A and triglycerides and play a role in maintaining vascular tone. They localize beneath the endothelial cells and produce some of the extracellular matrix components found in the Space of Disse. When the liver is injured HSC undergo a phenotypic change referred to as transdifferentiation or activation. During this process they transform into myofibroblasts-like cells, they develop a rich contractile cytoskeleton, lose their vitamin A stores and upregulate the expression of type I collagen, the main collagen found in scar tissue. A similar transdifferentiation of HSC is observed in culture. Our studies pertaining to the molecular mechanisms whereby acetaldehyde (ACH), the first metabolite of ethanol, upregulates type I collagen gene expression by cultured HSC have revealed that this alcohol metabolite also induces the expression and nuclear translocation of beta-catenin, a key component of the Wnt pathway known to play a role in embryonic development and tissue determination. Based on these findings we propose to investigate molecular mechanisms underlying this ACH exerted effect. In addition, we plan to determine whether activation of beta-catenin by ACH plays a role in HSC transdifferentiation and upregulation of type I collagen gene expression. A better understanding of key regulatory steps leading to ethanol-elicited enhanced production of Type I collagen in HSC could lead to the development of new therapeutic modalities for alcohol-induced liver fibrosis and cirrhosis. Public Health Relevance: As alcohol-induced liver cirrhosis is among the leading causes of death in the U.S. and worldwide, there is urgent need of therapies for this devastating disease. The goal of these studies is to better understand the mechanisms whereby acetaldehyde, the first and main metabolite of alcohol, induces the deposit of scar tissue in the liver. These studies have the potential to yield novel therapeutic modalities to treat or ameliorate this disease.
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