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Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase
Kouichi Miura1, Kojiro Taura, Yuzo Kodama
1Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Insights
Hepatitis C virus (HCV) infection lowers hepcidin levels by increasing oxidative stress and histone deacetylase (HDAC) activity, impairing iron regulation.
Area of Science:
- Hepatology
- Molecular Biology
- Virology
Background:
- Chronic hepatitis C (HCV) involves liver iron accumulation, which is hepatotoxic.
- The precise mechanisms of HCV's regulation of iron metabolism remain unclear.
- Hepcidin is a key regulator of iron absorption, and its dysregulation is implicated in liver disease.
Purpose of the Study:
- To investigate how HCV influences hepcidin expression.
- To elucidate the role of oxidative stress and histone deacetylase (HDAC) activity in HCV-mediated hepcidin suppression.
Main Methods:
- Utilized Huh 7 and Huh7.5 cells, HCV replicon cells, and adenoviruses expressing HCV proteins.
- Assessed hepcidin expression, reactive oxygen species (ROS) production, and HDAC activity.
- Investigated the impact of antioxidants and HDAC inhibitors on hepcidin regulation and transcription factor binding.
Main Results:
- HCV infection and core protein expression significantly reduced hepcidin levels, correlating inversely with ROS production.
- Antioxidants restored hepcidin expression and reduced elevated HDAC activity in HCV-infected cells.
- HCV-induced ROS stabilized HIF1alpha/HIF2alpha, inhibited C/EBPalpha and STAT3 binding to the hepcidin promoter via hypoacetylation, effects reversed by antioxidants or HDAC inhibitors.
Conclusions:
- HCV-induced oxidative stress suppresses hepcidin expression.
- Increased HDAC activity is a key mechanism by which HCV suppresses hepcidin.
- Restoring HDAC activity and reducing oxidative stress can normalize hepcidin expression and iron metabolism in HCV infection.
Unlabelled:
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.
Conclusion:
HCV-induced oxidative stress suppresses hepcidin expression through increased HDAC activity.
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