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


CONCLUSIONS
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.
De Minicis
Samuele
S
Department of Medicine, University of California San Diego, School of Medicine, San Diego, CA 92093-0602, USA.
Seki
Ekihiro
E
Paik
Yong-Han
YH
Osterreicher
Christoph H
CH
Kodama
Yuzo
Y
Kluwe
Johannes
J
Torozzi
Luciano
L
Miyai
Katsumi
K
Benedetti
Antonio
A
Schwabe
Robert F
RF
Brenner
David A
DA
D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D016026:Bone Marrow Transplantation; D002252:Carbon Tetrachloride Poisoning / Q000150:complications; D002796:Choline Deficiency / Q000503:physiopathology; D055166:Hepatic Stellate Cells / Q000201:enzymology; D007728:Kupffer Cells / Q000201:enzymology; D008026:Ligation; D015227:Lipid Peroxidation; D008099:Liver / Q000166:cytology* / Q000201:enzymology; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018183:Transplantation Chimera
D017382:Reactive Oxygen Species; D008715:Methionine; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1