Cytochrome P450 2E1 (
CYP2E1) plays an important role in alcohol and toxin metabolism by catalyzing the conversion of substrates into more polar metabolites and producing
reactive oxygen species.
Reactive oxygen species-induced oxidative stress promotes hepatocyte injury and death, which in turn induces
inflammation, activation of hepatic stellate cells, and
liver fibrosis. Here, we analyzed mice expressing only the human
CYP2E1 gene (hCYP2E1) to determine differences in hCYP2E1 versus endogenous mouse
Cyp2e1 function with different liver
injuries. After intragastric alcohol feeding,
CYP2E1 expression was induced in both hCYP2E1 and wild-type (Wt) mice. hCYP2E1 mice had greater
inflammation,
fibrosis, and lipid peroxidation but less hepatic steatosis. In addition, hCYP2E1 mice demonstrated increased expression of fibrogenic and proinflammatory genes but decreased expression of de novo lipogenic genes compared to Wt mice. Lipidomics of
free fatty acid,
triacylglycerol,
diacylglycerol, and
cholesterol ester species and proinflammatory
prostaglandins support these conclusions.
Carbon tetrachloride-induced injury suppressed expression of both mouse and human
CYP2E1, but again hCYP2E1 mice exhibited greater hepatic stellate cell activation and
fibrosis than Wt controls with comparable expression of proinflammatory genes. By contrast, 14-day bile duct
ligation induced comparable cholestatic injury and
fibrosis in both genotypes. Conclusion: Alcohol-induced
liver fibrosis but not hepatic steatosis is more severe in the hCYP2E1 mouse than in the Wt mouse, demonstrating the use of this model to provide insight into the pathogenesis of
alcoholic liver disease. (Hepatology Communications 2017;1:1043-1057).