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Abstract

Cirrhosis is characterized by a marked increase in the deposition of type I collagen and in the expression of the type I collagen genes α1(I) and α2(I). Although α1(I) gene regulation has been extensively studied in cultured cells, these results may not be applicable to hepatic fibrogenesis in vivo. Therefore the regulation of the α1(I) endogenous gene and an α1(I) transgene was studied in a transgenic mouse model that has a single copy of a human α1(I) gene segment containing the structural gene and 1.6 Kb of 5′ DNA and 20 Kb of 3′ DNA. To initiate hepatic fibrogenesis, we treated mice with the hepatotoxin carbon tetrachloride, either in a single dose or in biweekly doses for a period of 3 to 8 wk. Subsequently, hepatic α1(I) messenger RNA levels were determined by a species-specific RNase protection assay. Carbon tetrachloride injections co-ordinately increased the messenger RNA levels of the α1(I) endogenous gene and the transgene, both immediately and after 8 wk. These experiments demonstrate that this α1(I) transgene fragment contains information sufficient for appropriate basal and carbon tetrachloride-stimulated hepatic expression. They further demonstrate that sufficient homology exists between the human and mouse regulatory elements for the recognition of human cis-acting elements by mouse trans-acting factors. Thus transgenic mice provide a unique model in which to characterize the collagen α1(I) regulatory elements that are required in vivo for pathophysiological responses. (HEPATOLOGY 1993;17:287–292.)