Lipid peroxidation is associated with the tissue injury and fibrogenesis of several hepatic disorders, including iron-overload, porphyria, and ethanol and CCl/4 induced toxicity. We have recently shown that products of lipid peroxidation, such as reactive aldehydes, stimulate collagen gene expression in cultured fibroblasts, and we suggested that this could be the mechanism by which tissue injuries are sometimes followed by fibrogenesis. To gain insight into the mechanisms underlying hepatic fibrosis, the PI will study the relationship between lipid peroxidation and collagen gene expression in cultured hepatic lipocytes and in hepatocyte-Ito cell co- cultures. The proposed research is aimed at characterizing the regulation of the collagen alpha-1(I)gene by oxidative stress.
The specific aims of this proposal are: 1) The characterization of the cis-regulatory region of the collagen alpha-1(I) gene responsive to lipid peroxidation. 2) The characterization of the cis-regulatory region of the collagen alpha-1(I) gene in lipocytes responsive to product(s) of CCl/4-treated hepatocytes in co-culture. 3) The identification of the gene encoding the factor(s) that transactivates the collagen alpha-1(I) gene in response to lipid peroxidation.
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| Houglum, K; Ramm, G A; Crawford, D H et al. (1997) Excess iron induces hepatic oxidative stress and transforming growth factor beta1 in genetic hemochromatosis. Hepatology 26:605-10 |
| Buck, M; Houglum, K; Chojkier, M (1996) Tumor necrosis factor-alpha inhibits collagen alpha1(I) gene expression and wound healing in a murine model of cachexia. Am J Pathol 149:195-204 |
