Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis.
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Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis. / Samuele, De Minicis; Seki, Ekihiro; Paik, Yong-Han; Osterreicher, Christoph H; Kodama, Yuzo; Kluwe, Johannes; Torozzi, Luciano; Miyai, Katsumi; Benedetti, Antonio; Schwabe, Robert F; Brenner, David A.
in: HEPATOLOGY, Jahrgang 52, Nr. 4, 4, 2010, S. 1420-1430.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis.
AU - Samuele, De Minicis
AU - Seki, Ekihiro
AU - Paik, Yong-Han
AU - Osterreicher, Christoph H
AU - Kodama, Yuzo
AU - Kluwe, Johannes
AU - Torozzi, Luciano
AU - Miyai, Katsumi
AU - Benedetti, Antonio
AU - Schwabe, Robert F
AU - Brenner, David A
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Hepatic Stellate Cells enzymology
KW - Mice
KW - Mice, Inbred C57BL
KW - Ligation
KW - Mice, Knockout
KW - Liver cytology
KW - Bile Ducts surgery
KW - Bone Marrow Transplantation
KW - Carbon Tetrachloride Poisoning complications
KW - Choline Deficiency physiopathology
KW - Kupffer Cells enzymology
KW - Lipid Peroxidation
KW - Liver Cirrhosis enzymology
KW - Methionine deficiency
KW - NADPH Oxidase metabolism
KW - Reactive Oxygen Species metabolism
KW - Transplantation Chimera
KW - Animals
KW - Male
KW - Hepatic Stellate Cells enzymology
KW - Mice
KW - Mice, Inbred C57BL
KW - Ligation
KW - Mice, Knockout
KW - Liver cytology
KW - Bile Ducts surgery
KW - Bone Marrow Transplantation
KW - Carbon Tetrachloride Poisoning complications
KW - Choline Deficiency physiopathology
KW - Kupffer Cells enzymology
KW - Lipid Peroxidation
KW - Liver Cirrhosis enzymology
KW - Methionine deficiency
KW - NADPH Oxidase metabolism
KW - Reactive Oxygen Species metabolism
KW - Transplantation Chimera
M3 - SCORING: Zeitschriftenaufsatz
VL - 52
SP - 1420
EP - 1430
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 4
M1 - 4
ER -
