RGD Reference Report - The role of human cytochrome P450 2E1 in liver inflammation and fibrosis. - Rat Genome Database

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The role of human cytochrome P450 2E1 in liver inflammation and fibrosis.

Authors: Xu, Jun  Ma, Hsiao-Yen  Liang, Shuang  Sun, Mengxi  Karin, Gabriel  Koyama, Yukinori  Hu, Ronglin  Quehenberger, Oswald  Davidson, Nicholas O  Dennis, Edward A  Kisseleva, Tatiana  Brenner, David A 
Citation: Xu J, etal., Hepatol Commun. 2017 Oct 30;1(10):1043-1057. doi: 10.1002/hep4.1115. eCollection 2017 Dec.
RGD ID: 14700873
Pubmed: PMID:29404441   (View Abstract at PubMed)
PMCID: PMC5721400   (View Article at PubMed Central)
DOI: DOI:10.1002/hep4.1115   (Journal Full-text)

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).

RGD Manual Disease Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
Cyp2e1  (cytochrome P450, family 2, subfamily e, polypeptide 1)

Genes (Mus musculus)
Cyp2e1  (cytochrome P450, family 2, subfamily e, polypeptide 1)

Genes (Homo sapiens)
CYP2E1  (cytochrome P450 family 2 subfamily E member 1)


Additional Information