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Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis.
J Hepatol. 2012 Oct; 57(4):860-6.JH

Abstract

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.

Authors+Show Affiliations

Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

22668639

Citation

Abdelmegeed, Mohamed A., et al. "Critical Role of Cytochrome P450 2E1 (CYP2E1) in the Development of High Fat-induced Non-alcoholic Steatohepatitis." Journal of Hepatology, vol. 57, no. 4, 2012, pp. 860-6.
Abdelmegeed MA, Banerjee A, Yoo SH, et al. Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. J Hepatol. 2012;57(4):860-6.
Abdelmegeed, M. A., Banerjee, A., Yoo, S. H., Jang, S., Gonzalez, F. J., & Song, B. J. (2012). Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. Journal of Hepatology, 57(4), 860-6. https://doi.org/10.1016/j.jhep.2012.05.019
Abdelmegeed MA, et al. Critical Role of Cytochrome P450 2E1 (CYP2E1) in the Development of High Fat-induced Non-alcoholic Steatohepatitis. J Hepatol. 2012;57(4):860-6. PubMed PMID: 22668639.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. AU - Abdelmegeed,Mohamed A, AU - Banerjee,Atrayee, AU - Yoo,Seong-Ho, AU - Jang,Sehwan, AU - Gonzalez,Frank J, AU - Song,Byoung-Joon, Y1 - 2012/06/02/ PY - 2012/02/24/received PY - 2012/05/22/revised PY - 2012/05/25/accepted PY - 2012/6/7/entrez PY - 2012/6/7/pubmed PY - 2013/4/3/medline SP - 860 EP - 6 JF - Journal of hepatology JO - J Hepatol VL - 57 IS - 4 N2 - 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. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/22668639/Critical_role_of_cytochrome_P450_2E1__CYP2E1__in_the_development_of_high_fat_induced_non_alcoholic_steatohepatitis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(12)00419-9 DB - PRIME DP - Unbound Medicine ER -