Although collagen overproduction is a critical step in the development of liver cirrhosis, the regulation of collagen gene expression, and its cell(s) of origin remain unclear. Lipid peroxidation is associated with the tissue injury and fibrogenesis of several hepatic disorders, including iron-overload, porphyria, and ethanol, and CC1-4-induced toxicity. We have recently shown that products of lipid peroxidation, such as reactive aldehydes, stimulate collagen gene expression in vitro (23), and we suggested that this could be the mechanism by which hepatic injuries are sometimes followed by fibrogenesis. To gain insight into the mechanisms underlying hepatic fibrosis, we will study the in vivo expression of collagen genes in hepatocytes and nonparenchymal cells in two animal models of lipid peroxidation and fibrogenesis: CC1-4-induced hepatic injury and chronic iron overload. Also we will assess the relationship between lipid peroxidation and collagen gene expression in cultured cells and in these animal models of hepatic fibrosis. Additional experiments will define the regulatory elements of the collagen alpha1(I) gene in cultured cells and in transgenic mice under control conditions and conditions of enhanced lipid peroxidation.
The specific aims of this proposal are to assess: 1) The cellular origin of hepatic collagen gene expression. 2) The regulation of collagen gene expression by lipid peroxidation in cultured fibroblasts. 3) The regulation of collagen gene expression by lipid peroxidation in primary rat hepatocyte and hepatic lipocyte cultures. The long range goal is to identify the factors responsible for fibrogenesis in hepatic lipid peroxidation and then test therapeutic interventions.
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