STIMULATION OF COLLAGEN ALPHA(1)(I) GENE-EXPRESSION IS ASSOCIATED WITH LIPID-PEROXIDATION IN HEPATOCELLULAR INJURY - A LINK TO TISSUE FIBROSIS

We have shown that lipid peroxidation stimulates collagen alpha(1)(I) gene transcription in cultured cells. Because increased lipid peroxidation and collagen production coexist in many hepatic disorders, including experimental carbon tetrachloride intoxication, we investigated whether lipid peroxidation modulates collagen gene expression in rats treated with carbon tetrachloride. In this animal model, we show colocalization of increased collagen alpha(1)(I) mRNA with lipid peroxidation by means of in situ hybridization and immunohistochemical study for malondialdehyde and 4-hydroxynonenal protein adducts, respectively. However, allyl alcohol treatment, which induced a similar degree of hepatocellular injury but without aldehyde-protein adducts, did not increase collagen alpha(1)(I) gene expression, suggesting that hepatocyte necrosis is not sufficient to induce the expression of collagen type I. Furthermore, in the absence of an inflammatory response, coculture experiments of hepatocytes and Ito cells treated with carbon tetrachloride indicate that hepatocytes exert a ''paracrine'' stimulation of both lipid peroxidation and collagen gene expression in Ito cells. These experiments suggest that hepatocyte lipid peroxidation plays a major role in the regulation of collagen alpha(1)(I) gene expression by Ito cells and that it maybe a link between hepatocyte injury and hepatic fibrosis.