The objectives of the proposed studies are two-fold: 1) To investigate the mechanisms of the effects of cytokines and hormones on the regulation of rat class I alcohol dehydrogenase (ADH). These studies include characterization of trans-acting factors that regulate expression of the gene, and determination of mechanisms whereby cytokines and hormones affect transcription. 2) To study the mechanisms whereby acetaldehyde, the product of ethanol oxidation by ADH, 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. The two objectives are related in that changes in ADH and ethanol oxidation lead to acetaldehyde formation which is an important factor in the pathogenesis of alcoholic liver disease and fibrosis. Lipopolysaccharide (LPS) administration in vivo increased ADH. Since LPS stimulates release of cytokines, it will now be determined whether the effect of LPS on ADH is mediated by cytokines. Furthermore, the effects of cytokines on ADH will be determined in hepatocyte culture, and the signaling and transcription mechanisms whereby cytokines may affect ADH will be investigated. Transforming growth factor beta (TGFbeta) is a principal stimulator of fibrogenesis. The plan is to identify the trans-acting factor or factors that mediate the effect of TGFbeta in stimulating the human alpha1 (I) collagen promoter, the identity and role of the TGFbeta binding elements and the trans-acting factor or factors binding the promoter in mediating the activating effect of acetaldehyde on the promoter. Furthermore, the role of oxidant stress and nitric oxide as mediators of the activating effect of TGFalpha and acetaldehyde on the human alpha1 (I) collagen promoter will be investigated.
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