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Open AccessArticle

A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin

1
Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea
2
Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea
3
Department of Radiology, National Cancer Center, Gyeonggi-do 10408, Korea
4
Department of Endocrinology and Metabolism, School of Medicine, Kyung Hee University, Seoul 02447, Korea
5
Department of Physiology, School of Medicine, Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea
6
Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive, Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 02447, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(15), 5516; https://doi.org/10.3390/ijms21155516
Received: 17 July 2020 / Revised: 30 July 2020 / Accepted: 30 July 2020 / Published: 1 August 2020
(This article belongs to the Section Molecular Biology)
Hepatic hepcidin is a well-known major iron regulator and has been reported to be closely related to hepatitis C virus (HCV) replication. However, pharmacological targeting of the hepcidin in HCV replication has not been reported. A short-chain fatty acid, 4-Phenyl butyrate (4-PBA), is an acid chemical chaperone that acts as a histone deacetylase inhibitor (HDACi) to promote chromosomal histone acetylation. Here, we investigated the therapeutic effect of 4-PBA on hepcidin expression and HCV replication. We used HCV genotype 1b Huh 7.5-Con1 replicon cells and engraftment of NOD/SCID mice as in vitro and in vivo models to test the effect of 4-PBA. It was found that 4-PBA inhibited HCV replication in Huh7.5-Con1 replicon cells in a concentration- and time-dependent manner through the induction of hepcidin expression by epigenetic modification and subsequent upregulation of interferon-α signaling. HCV formed a membranous web composed of double-membrane vesicles and was utilized for RNA replication. Moreover, 4-PBA also disrupted the integrity of the membranous web and interfered with the molecular interactions critical for the assembly of the HCV replication complex. These findings suggest that 4-PBA is a key epigenetic inducer of anti-HCV hepatic hepcidin and might at least in part play a role in targeting host factors related to HCV infection as an attractive complement to current HCV therapies. View Full-Text
Keywords: 4-phenylbutyric acid; hepatitis C virus; membranous web; histone deacetylase inhibitor; small molecule 4-phenylbutyric acid; hepatitis C virus; membranous web; histone deacetylase inhibitor; small molecule
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Kim, K.; Lee, Y.-S.; Jeong, S.; Kim, D.; Chon, S.; Pak, Y.K.; Kim, S.; Ha, J.; Kang, I.; Choe, W. A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin. Int. J. Mol. Sci. 2020, 21, 5516.

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