Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity.
Chronic hepatitis C is characterized by iron accumulation in the liver, and excessive iron is hepatotoxic. However, the mechanism by which hepatitis C virus (HCV) regulates iron metabolism is poorly understood. Hepcidin plays a pivotal role as a negative regulator of iron absorption. The aim of the current study was to elucidate the mechanisms that govern hepcidin expression by HCV. Huh 7 cells, Huh7.5 cells, full-length HCV replicon cells established from Huh7.5 cells, and adenoviruses expressing HCV-core or HCV nonstructural proteins 3 through 5 (NS3-5) were used. Hepcidin expression was significantly lower in HCV replicon cells and in HCV core-expressing Huh7 cells. The expression was inversely correlated with the amount of reactive oxygen species (ROS) production. Anti-oxidants restored hepcidin expression in HCV replicon cells and Huh7 cells expressing HCV core. In HCV replicon cells, histone deacetylase (HDAC) activity was elevated at baseline and after exposure to hydrogen peroxide. Anti-oxidants reduced HDAC activity in a dose-dependent manner. HDAC inhibition increased hepcidin expression without affecting ROS production in HCV replicon cells. HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter. In addition, an HDAC inhibitor restored their binding to the hepcidin promoter via acetylation of histones.


CONCLUSIONS
HCV-induced oxidative stress suppresses hepcidin expression through increased HDAC activity.
Miura
Kouichi
K
Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Taura
Kojiro
K
Kodama
Yuzo
Y
Schnabl
Bernd
B
Brenner
David A
DA
D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D016174:Hepacivirus / Q000235:genetics* / Q000502:physiology; D064451:Hepcidins; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000235:genetics*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014158:Transcription, Genetic; D014779:Virus Replication
D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D034741:RNA, Small Interfering; D006655:Histone Deacetylases