Critical Role of Cytochrome P450 2E1 (CYP2E1) in the Development of High Fat-induced Non-alcoholic Steatohepatitis
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 Cyp2e1-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 Cyp2e1-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, TNFα 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. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
M. A. Abdelmegeed et al., "Critical Role of Cytochrome P450 2E1 (CYP2E1) in the Development of High Fat-induced Non-alcoholic Steatohepatitis," Journal of Hepatology, Elsevier, Jan 2012.
The definitive version is available at http://dx.doi.org/10.1016/j.jhep.2012.05.019
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© 2012 Elsevier, All rights reserved.