Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis

JOURNAL OF HEPATOLOGY

卷:57

Article

Abdelmegeed, Mohamed A.¹  Banerjee, Atrayee¹  Yoo, Seong-Ho^1,2  Jang, Sehwan¹  Gonzalez, Frank J.³  Song, Byoung-Joon¹ 

[1] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA

[2] Seoul Natl Univ, Coll Med, Dept Forens Med, Seoul, South Korea

[3] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

关键词: Liver;    CYP2E1;    Null mice;    High-fat diet;    NAFLD;    NASH;    Oxidative stress;    Protein modifications;    Inflammation;    Insulin resistance;   

DOI  :  10.1016/j.jhep.2012.05.019

来源: Elsevier

【 摘 要 】

Background & Aims: Ethanol-inducible cytochrome P450 2E1 (CYP2E1) activity contributes to oxidative stress. However, CYP2E1 may have an important role in the pathogenesis of high-fat mediated non-alcoholic steatohepatitis (NASH). Thus, the role of CYP2E1 in high-fat mediated NASH development was evaluated. Methods: Male wild type (WT) and Cyp2el-null mice were fed a low-fat diet (LFD, 10% energy-derived) or a high-fat diet (HFD, 60% energy-derived) for 10 weeks. Liver histology and tissue homogenates were examined for various parameters of oxidative stress and inflammation. Results: Liver histology showed that only WT mice fed a HFD developed NASH despite the presence of increased steatosis in both WT and Cyp2el-null mice fed HFD. Markers of oxidative stress such as elevated CYP2E1 activity and protein amounts, lipid peroxidation, protein carbonylation, nitration, and glycation with increased phospho-JNK were all markedly elevated only in the livers of HFD-fed WT mice. Furthermore, while the levels of inflammation markers osteopontin and F4/80 were higher in HFD-fed WT mice, TNF alpha and MCP-1 levels were lower compared to the corresponding LFD-fed WT. Finally, only HFD-fed WT mice exhibited increased insulin resistance and impaired glucose tolerance. Conclusions: These data suggest that CYP2E1 is critically important in NASH development by promoting oxidative/nitrosative stress, protein modifications, inflammation, and insulin resistance. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

【 授权许可】

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