The objectives of the proposed studies are two-fold: 1) To investigate the mechanisms of the effects of hormones on the regulation of rat class I alcohol dehydrogenase. These studies include characterization of trans-acting factors that regulate expression of the gene, and determination of the mechanisms whereby hormones affect transcription of the gene. 2) To study mechanisms whereby acetaldehyde, the product of ethanol oxidation by alcohol dehydrogenase, stimulates fibrogenesis. These studies are focused on identifying trans-acting factors that regulate expression of the type I collagen genes, and determining whether the effect of acetaldehyde is mediated by modification of the amounts or binding affinity of these trans-acting factors to the collagen genes. Growth hormone (GH) increases alcohol dehydrogenase by increasing its synthesis at the level of transcription, while dihydrotestosterone decreases alcohol dehydrogenase by increasing its rate of degradation. It will now be determined whether the effect of GH in enhancing transcription (STAT) proteins. The pathway for degradation of alcohol dehydrogenase will be defined by determining if specific inhibitors of various pathways prevent the effect of dihydrotestosterone in increasing degradation of the enzyme. Mechanisms for the effects of acetaldehyde in enhancing collagen formation will be studied in cultured hepatic stellate cells. The role of retinoic acid (RA), retinoic acid receptors and their binding to RA-responsive elements (RARE) in the (1(I) collagen promoters will be assessed as mediators for the acetaldehyde. The role of C/EBP-beta for basal activity and for the activation of the alpha1 (I) collagen promoter by acetaldehyde will be determined in transfection experiments with the wild type and promoter mutated at the C/EBP-beta binding site and with co-transfection with a C/EBP-beta expression vector. The mechanism whereby acetaldehyde increases nuclear C/EBP-beta protein and binding to the collagen promoter will be determined.
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