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

  • Authors:
    • Nghi Phung
    • Natasha Pera
    • Geoffrey Farrell
    • Isabelle Leclercq
    • Jing Yun Hou
    • Jacob George
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  • Published online on: August 1, 2009     https://doi.org/10.3892/ijmm_00000220
  • Pages: 171-180
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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 thiobarbituric 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 α1(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.

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August 2009
Volume 24 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Phung N, Pera N, Farrell G, Leclercq I, Hou JY and George J: Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis. Int J Mol Med 24: 171-180, 2009.
APA
Phung, N., Pera, N., Farrell, G., Leclercq, I., Hou, J.Y., & George, J. (2009). Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis. International Journal of Molecular Medicine, 24, 171-180. https://doi.org/10.3892/ijmm_00000220
MLA
Phung, N., Pera, N., Farrell, G., Leclercq, I., Hou, J. Y., George, J."Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis". International Journal of Molecular Medicine 24.2 (2009): 171-180.
Chicago
Phung, N., Pera, N., Farrell, G., Leclercq, I., Hou, J. Y., George, J."Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis". International Journal of Molecular Medicine 24, no. 2 (2009): 171-180. https://doi.org/10.3892/ijmm_00000220