Heme Oxygenase-1 Protects Against Steatohepatitis in Both Cultured Hepatocytes and Mice

Date

2010

Authors

Yu, Jun
Chu, Eagle S. H.
Wang, Ruizhi
Wang, Shiyan
Wu, Chung W.
Wong, Vincent
Chan, Henry L. Y.
Farrell, Geoffrey
Sung, Joseph J. Y.

Journal Title

Journal ISSN

Volume Title

Publisher

W B Saunders Co

Abstract

Background & Aims: Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced tissue injury. We investigated the role of HO-1 in nutritional steatohepatitis in vitro and in vivo. Methods: AML-12 hepatocytes were cultured in methionine- and choline-deficient (MCD) medium. Cells were transfected with an adenovirus vector that expressed HO-1 (Ad-HO-1) or incubated with the HO-1 inducer hemin or the HO-1 inhibitor stannic mesoporphyrin for 24 hours. C57BL6 mice and db/db mice were fed MCD or control diets, with or without hemin, for up to 4 weeks. Results: AML-12 cells exposed to MCD medium developed significant steatosis, increased release of alanine aminotransferase, and showed signs of oxidative injury. Incubation with hemin induced HO-1 protein, suppressed steatosis, and reduced levels of alanine aminotransferase and lipid peroxidation. A comparable effect was observed in cells transfected with Ad-HO-1, whereas incubation of these cells with stannic mesoporphyrin completely abolished the Ad-HO-1- or hemin-mediated protection of hepatocytes. Mice injected with hemin significantly attenuated MCD-induced steatohepatitis and increased HO-1 protein and activity. This effect was associated with up-regulation of antioxidant chaperones and enzymes, down-regulation of proinflammatory cytokines, and up-regulation of the anti-inflammatory interleukin-22. Moreover, the reduction in steatosis caused by hemin was affected by up-regulation of peroxisome proliferator-activated receptor-α and by down-regulation of sterol regulatory element binding protein-1c. Conclusions: HO-1 can interrupt progression of nutritional steatohepatitis by inducing an antioxidant pathway, suppressing production of cytokines, and modifying fatty acid turnover. Induction of HO-1 might provide a new approach for treatment of steatohepatitis.

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Keywords

Keywords: adenovirus vector; alanine aminotransferase; chaperone; choline; cytokine; heme oxygenase 1; hemin; interleukin 22; mesoporphyrin; methionine; peroxisome proliferator activated receptor agonist; stannic mesoporphyrin; sterol regulatory element binding pro

Citation

Source

Gastroenterology

Type

Journal article

Book Title

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DOI

10.1053/j.gastro.2009.09.058

Restricted until

2037-12-31