M D Weltman1, G C Farrell, C Liddle. 1. Storr Liver Unit, Department of Gastroenterology and Hepatology, University of Sydney, Westmead Hospital, New South Wales, Australia.
Abstract
BACKGROUND & AIMS: Nonalcoholic steatohepatitis is morphologically identical to alcoholic hepatitis and has multiple etiologic associations and an unknown pathogenesis. The present study used a rat nutritional model of hepatic steatosis with inflammation to test the hypothesis that induction of the alcohol-inducible hepatic cytochrome P450 (CYP) 2E1 is associated with production of steatohepatitis. METHODS: Rats received a diet devoid of methionine-choline. CYP2E1 protein was detected in liver sections by immunohistochemistry and in hepatic microsomal fractions by immunoblotting; CYP2E1 activity was detected by N-demethylation of N,N-dimethylnltrosamine (NDMA). CYP2E1 messenger RNA was analyzed by Northern blotting and slot blot hybridization. RESULTS: After 4 weeks of methionine-choline devoid diet, macrovesicular steatosis and an inflammatory infiltrate were prominent in hepatic acinar zone 3. CYP2E1 immunostaining was increased and had a more extensive acinar distribution corresponding to that of the steatosis. Microsomal CYP2E1 protein, NDMA activity, and hepatic CYP2E1 messenger RNA levels were all correspondingly increased. CONCLUSIONS: CYP2E1 is induced, partly at a pretranslational level, in this experimental form of steatohepatitis. The finding of biochemical and histological similarities between this nutritional model of hepatic steatosis with inflammation and alcoholic hepatitis indicates possible clues to common pathogenetic mechanisms. The relevance of this finding to human nonalcoholic steatohepatitis remains uncertain and requires further investigation of human liver specimens.
BACKGROUND & AIMS:Nonalcoholic steatohepatitis is morphologically identical to alcoholic hepatitis and has multiple etiologic associations and an unknown pathogenesis. The present study used a rat nutritional model of hepatic steatosis with inflammation to test the hypothesis that induction of the alcohol-inducible hepatic cytochrome P450 (CYP) 2E1 is associated with production of steatohepatitis. METHODS:Rats received a diet devoid of methionine-choline. CYP2E1 protein was detected in liver sections by immunohistochemistry and in hepatic microsomal fractions by immunoblotting; CYP2E1 activity was detected by N-demethylation of N,N-dimethylnltrosamine (NDMA). CYP2E1 messenger RNA was analyzed by Northern blotting and slot blot hybridization. RESULTS: After 4 weeks of methionine-choline devoid diet, macrovesicular steatosis and an inflammatory infiltrate were prominent in hepatic acinar zone 3. CYP2E1 immunostaining was increased and had a more extensive acinar distribution corresponding to that of the steatosis. Microsomal CYP2E1 protein, NDMA activity, and hepatic CYP2E1 messenger RNA levels were all correspondingly increased. CONCLUSIONS:CYP2E1 is induced, partly at a pretranslational level, in this experimental form of steatohepatitis. The finding of biochemical and histological similarities between this nutritional model of hepatic steatosis with inflammation and alcoholic hepatitis indicates possible clues to common pathogenetic mechanisms. The relevance of this finding to humannonalcoholic steatohepatitis remains uncertain and requires further investigation of human liver specimens.