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Oxidative stress and regulation of anti-oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non-alcoholic fatty liver.
J Gastroenterol Hepatol. 2010 Jun; 25(6):1136-43.JG

Abstract

BACKGROUND AND AIM

Reactive oxygen species produced by cytochrome P4502E1 (CYP2E1) are believed to play a role in pathophysiology of non-alcoholic fatty liver disease (NAFLD). However, little is known about the expression, protein content and activity of anti-oxidant enzymes and the role of inducible nitric oxide synthase (iNOS), a source of reactive nitrogen species, in NAFLD. In the present study, we evaluate gene expression, protein content and activity of anti-oxidant enzymes, and iNOS, in a CYP2E1 overexpressing model of non-alcoholic fatty liver (NAFL).

METHODS

Non-transgenic (nTg) and CYP2E1 transgenic (Tg) mice were fed rodent chow for 8 months. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver triglycerides, malondialdehyde and protein carbonyls were measured. Gene expression of NF-E2-related factor (Nrf2), superoxide dismutase-1, -2 (SOD-1,2), catalase (CAT), glutathione peroxidase (GPx), heme oxygenase-1 (HO-1) and iNOS were determined. Protein content, activity and nitrosylation of the enzymes were also measured.

RESULTS

Tg mice had greater CYP2E1 activity and histological liver injury. MDA and protein carbonyls were increased, indicating insufficient anti-oxidant response. Gene expression of Nrf2, CAT, GPx, HO-1 and iNOS were significantly increased. Protein content and enzyme activities of most anti-oxidant enzymes were not correspondingly increased. iNOS activity and nitrosylation of CAT and SOD was greater in Tg mice liver.

CONCLUSION

Hepatocyte-specific CYP2E1 overexpression results in increased oxidative stress and nitrosative stress. Several anti-oxidant enzymes are upregulated. Failure of corresponding increase in total protein and activity of anti-oxidant enzymes suggests modification/degradation, possibly by nitrosylation, due to increased iNOS activity in a CYP2E1 overexpressing NAFL mouse model.

Authors+Show Affiliations

Research Service, VA Long Beach Healthcare System, Long Beach, California 90822, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20594230

Citation

Kathirvel, Elango, et al. "Oxidative Stress and Regulation of Anti-oxidant Enzymes in Cytochrome P4502E1 Transgenic Mouse Model of Non-alcoholic Fatty Liver." Journal of Gastroenterology and Hepatology, vol. 25, no. 6, 2010, pp. 1136-43.
Kathirvel E, Chen P, Morgan K, et al. Oxidative stress and regulation of anti-oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non-alcoholic fatty liver. J Gastroenterol Hepatol. 2010;25(6):1136-43.
Kathirvel, E., Chen, P., Morgan, K., French, S. W., & Morgan, T. R. (2010). Oxidative stress and regulation of anti-oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non-alcoholic fatty liver. Journal of Gastroenterology and Hepatology, 25(6), 1136-43. https://doi.org/10.1111/j.1440-1746.2009.06196.x
Kathirvel E, et al. Oxidative Stress and Regulation of Anti-oxidant Enzymes in Cytochrome P4502E1 Transgenic Mouse Model of Non-alcoholic Fatty Liver. J Gastroenterol Hepatol. 2010;25(6):1136-43. PubMed PMID: 20594230.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxidative stress and regulation of anti-oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non-alcoholic fatty liver. AU - Kathirvel,Elango, AU - Chen,Philip, AU - Morgan,Kengathevy, AU - French,Samuel W, AU - Morgan,Timothy R, PY - 2010/7/3/entrez PY - 2010/7/3/pubmed PY - 2010/10/20/medline SP - 1136 EP - 43 JF - Journal of gastroenterology and hepatology JO - J Gastroenterol Hepatol VL - 25 IS - 6 N2 - BACKGROUND AND AIM: Reactive oxygen species produced by cytochrome P4502E1 (CYP2E1) are believed to play a role in pathophysiology of non-alcoholic fatty liver disease (NAFLD). However, little is known about the expression, protein content and activity of anti-oxidant enzymes and the role of inducible nitric oxide synthase (iNOS), a source of reactive nitrogen species, in NAFLD. In the present study, we evaluate gene expression, protein content and activity of anti-oxidant enzymes, and iNOS, in a CYP2E1 overexpressing model of non-alcoholic fatty liver (NAFL). METHODS: Non-transgenic (nTg) and CYP2E1 transgenic (Tg) mice were fed rodent chow for 8 months. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver triglycerides, malondialdehyde and protein carbonyls were measured. Gene expression of NF-E2-related factor (Nrf2), superoxide dismutase-1, -2 (SOD-1,2), catalase (CAT), glutathione peroxidase (GPx), heme oxygenase-1 (HO-1) and iNOS were determined. Protein content, activity and nitrosylation of the enzymes were also measured. RESULTS: Tg mice had greater CYP2E1 activity and histological liver injury. MDA and protein carbonyls were increased, indicating insufficient anti-oxidant response. Gene expression of Nrf2, CAT, GPx, HO-1 and iNOS were significantly increased. Protein content and enzyme activities of most anti-oxidant enzymes were not correspondingly increased. iNOS activity and nitrosylation of CAT and SOD was greater in Tg mice liver. CONCLUSION: Hepatocyte-specific CYP2E1 overexpression results in increased oxidative stress and nitrosative stress. Several anti-oxidant enzymes are upregulated. Failure of corresponding increase in total protein and activity of anti-oxidant enzymes suggests modification/degradation, possibly by nitrosylation, due to increased iNOS activity in a CYP2E1 overexpressing NAFL mouse model. SN - 1440-1746 UR - https://www.unboundmedicine.com/medline/citation/20594230/Oxidative_stress_and_regulation_of_anti_oxidant_enzymes_in_cytochrome_P4502E1_transgenic_mouse_model_of_non_alcoholic_fatty_liver_ L2 - https://doi.org/10.1111/j.1440-1746.2009.06196.x DB - PRIME DP - Unbound Medicine ER -