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Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis

 Samuele De Minicis  ;  Ekihiro Seki  ;  Yong-Han Paik  ;  Christoph H. Österreicher  ;  Yuzo Kodama  ;  Johannes Kluwe  ;  Luciano Torozzi  ;  Katsumi Miyai  ;  Antonio Benedetti  ;  Robert F. Schwabe  ;  David A. Brenner 
 HEPATOLOGY, Vol.52(4) : 1420-1430, 2010 
Journal Title
Issue Date
Animals ; Bile Ducts/surgery ; Bone Marrow Transplantation ; Carbon Tetrachloride Poisoning/complications ; Choline Deficiency/physiopathology ; Hepatic Stellate Cells/enzymology ; Kupffer Cells/enzymology ; Ligation ; Lipid Peroxidation ; Liver/cytology* ; Liver/enzymology ; Liver Cirrhosis/enzymology* ; Liver Cirrhosis/etiology ; Liver Cirrhosis/physiopathology ; Male ; Methionine/deficiency ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NADPH Oxidases/metabolism* ; NADPH Oxidases/physiology ; Reactive Oxygen Species/metabolism ; Transplantation Chimera
Reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate oxidase (NOX) is required for liver fibrosis. This study investigates the role of NOX in ROS production and the differential contribution of NOX from bone marrow (BM)-derived and non-BM-derived liver cells. Hepatic fibrosis was induced by bile duct ligation (BDL) for 21 days or by methionine-choline-deficient (MCD) diet for 10 weeks in wild-type (WT) mice and mice deficient in p47phox (p47phox knockout [KO]), a component of NOX. The p47phox KO chimeric mice were generated by the combination of liposomal clodronate injection, irradiation, and BM transplantation of p47phox KO BM into WT recipients and vice versa. Upon BDL, chimeric mice with p47phox KO BM-derived cells, including Kupffer cells, and WT endogenous liver cells showed a ∼25% reduction of fibrosis, whereas chimeric mice with WT BM-derived cells and p47phox KO endogenous liver cells, including hepatic stellate cells, showed a ∼60% reduction of fibrosis. In addition, p47phox KO compared to WT mice treated with an MCD diet showed no significant changes in steatosis and hepatocellular injury, but a ∼50% reduction in fibrosis. Cultured WT and p47phox KO hepatocytes treated with free fatty acids had a similar increase in lipid accumulation. Free fatty acids promoted a 1.5-fold increase in ROS production both in p47phox KO and in WT hepatocytes. CONCLUSION: NOX in both BM-derived and non-BM-derived cells contributes to liver fibrosis. NOX does not play a role in experimental steatosis and the generation of ROS in hepatocytes, but exerts a key role in fibrosis.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Paik, Yong Han(백용한)
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