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Oxidative stress and regulation of anti-oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non-alcoholic fatty liver.

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.

journal_name

J Gastroenterol Hepatol

journal_title

Journal of gastroenterology and hepatology

authors

Kathirvel E,Chen P,Morgan K,French SW,Morgan TR

doi

10.1111/j.1440-1746.2009.06196.x

subject

Has Abstract

pub_date

2010-06-01 00:00:00

pages

1136-43

issue

eissn

0815-9319

issn

1440-1746

pii

JGH6196

journal_volume

pub_type

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Oxidative stress and regulation of anti-oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non-alcoholic fatty liver.