The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91phox mediate hepatic fibrosis in mice

Authors


  • Potential conflict of interest: Nothing to report.

  • Supported by grants from the Korea Research Foundation (KRF-2009 E00006) and the Good Health R&D Project, Ministry of Health, Welfare, and Family Affairs, Republic of Korea (A050021). Y. H. P. received a 2010 faculty research grant from Yonsei University College of Medicine (6-2010-0168). E. S. received a Liver Scholar Award from the American Association for the Study of Liver Diseases/American Liver Foundation and a research grant from ABMRF. D. A. B. received National Institutes of Health Grants NIH RO1 DK072237-06, NIH RO1 GM041804-23, and NIH P50 AA011999-11.

Abstract

Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a multicomponent enzyme that mediates electron transfer from nicotinamide adenine dinucleotide phosphate to molecular oxygen, which leads to the production of superoxide. NOX2/gp91phox is a catalytic subunit of NOX expressed in phagocytic cells. Several homologues of NOX2, including NOX1, have been identified in nonphagocytic cells. We investigated the contributory role of NOX1 and NOX2 in hepatic fibrosis. Hepatic fibrosis was induced in wild-type (WT) mice, NOX1 knockout (NOX1KO) mice, and NOX2 knockout (NOX2KO) mice by way of either carbon tetrachloride (CCl4) injection or bile duct ligation (BDL). The functional contribution of NOX1 and NOX2 in endogenous liver cells, including hepatic stellate cells (HSCs), and bone marrow (BM)-derived cells, including Kupffer cells (KCs), to hepatic reactive oxygen species (ROS) generation and hepatic fibrosis was assessed in vitro and in vivo using NOX1 or NOX2 BM chimeric mice. Hepatic NOX1 and NOX2 messenger RNA expression was increased in the two experimental mouse models of hepatic fibrosis. Whereas NOX1 was expressed in HSCs but not in KCs, NOX2 was expressed in both HSCs and KCs. Hepatic fibrosis and ROS generation were attenuated in both NOX1KO and NOX2KO mice after CCl4 or BDL. Liver fibrosis in chimeric mice indicated that NOX1 mediates the profibrogenic effects in endogenous liver cells, whereas NOX2 mediates the profibrogenic effects in both endogenous liver cells and BM-derived cells. Multiple NOX1 and NOX2 components were up-regulated in activated HSCs. Both NOX1- and NOX2-deficient HSCs had decreased ROS generation and failed to up-regulate collagen α1(I) and transforming growth factor β in response to angiotensin II. Conclusion: Both NOX1 and NOX2 have an important role in hepatic fibrosis in endogenous liver cells, including HSCs, whereas NOX2 has a lesser role in BM-derived cells. (HEPATOLOGY 2011;)

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