Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis

Date

2009

Authors

Phung, Nghi
Pera, Natasha
Farrell, Geoffrey
Leclercq, Isabelle
Hou, Jung Yun
George, Jacob

Journal Title

Journal ISSN

Volume Title

Publisher

Spandidos Publications

Abstract

The mechanistic significance of oxidative stress to fibrogenesis in the methionine and choline-deficient (MCD) diet-induced model of steatohepatitis was evaluated by antioxidant intervention, using either vitamin E or L-2-oxothiazolidine-4-carboxylate (OTC), a cysteine precursor that promotes glutathione synthesis. Significant depletion of hepatic reduced glutathione (GSH) and elevation of thio-barbituric acid reactive substances (TBARS) occurred from week 3 in association with hepatic injury in mice fed the MCD diet. Hepatic stellate cell (HSC) activation and increased collagen α1(I) mRNA expression, together with morphologic fibrosis were evident from week 5. Vitamin E repleted GSH, reduced TBARS, steatosis, inflammation, HSC activation and collagen α1(I) mRNA expression, and ameliorated fibrosis. Vitamin E did not effect the expression of either profibrogenic cytokines (transforming growth factor-β 1, connective tissue growth factor) or matrix remodeling enzymes (tissue inhibitor of metalloproteinase-1 and -2, matrix metalloproteinase-2 and -13). Despite repletion of hepatic GSH in OTC-supplemented mice, the initial benefit in the reduction of hepatic TBARS and inhibition of collagen α 1(I) mRNA expression at week 5, failed to protect these mice from hepatic injury or fibrosis at later time points. Oxidative stress or products of lipid peroxidation mediate HSC activation and collagen gene expression directly in the MCD model of steatohepatitis. Vitamin E but not glutathione augmentation can interrupt this pathogenic process.

Description

Keywords

Keywords: 2 oxo 4 thiazolidinecarboxylic acid; alpha tocopherol; choline; collagen type 1; collagenase 3; connective tissue growth factor; gelatinase A; glutathione; messenger RNA; methionine; thiobarbituric acid reactive substance; tissue inhibitor of metalloprote Fibrosis; Lipid peroxidation; Oxidative stress; Steatohepatitis; Vitamin E

Citation

Source

International Journal of Molecular Medicine

Type

Journal article

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DOI

10.3892/ijmm_00000220

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