Journal
JOURNAL OF HEPATOLOGY
Volume 57, Issue 4, Pages 860-866Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2012.05.019
Keywords
Liver; CYP2E1; Null mice; High-fat diet; NAFLD; NASH; Oxidative stress; Protein modifications; Inflammation; Insulin resistance
Categories
Funding
- NIH Institutes of Health
- Intramural Research Program of National Institute on Alcohol Abuse and Alcoholism
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available