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Article

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

by
Kiyoon Kim
1,
Young-seok Lee
2,
Suyun Jeong
2,
Daehong Kim
3,
Suk Chon
4,
Youngmi Kim Pak
1,2,5,
Sungsoo Kim
1,2,6,
Joohun Ha
1,2,6,
Insug Kang
1,2,6 and
Wonchae Choe
1,2,6,*
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
Submission received: 17 July 2020 / Revised: 30 July 2020 / Accepted: 30 July 2020 / Published: 1 August 2020
(This article belongs to the Section Molecular Biology)
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Abstract

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.
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

Share and Cite

MDPI and ACS Style

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. https://doi.org/10.3390/ijms21155516

AMA Style

Kim K, Lee Y-s, Jeong S, Kim D, Chon S, Pak YK, Kim S, Ha J, Kang I, Choe W. A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin. International Journal of Molecular Sciences. 2020; 21(15):5516. https://doi.org/10.3390/ijms21155516

Chicago/Turabian Style

Kim, Kiyoon, Young-seok Lee, Suyun Jeong, Daehong Kim, Suk Chon, Youngmi Kim Pak, Sungsoo Kim, Joohun Ha, Insug Kang, and Wonchae Choe. 2020. "A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin" International Journal of Molecular Sciences 21, no. 15: 5516. https://doi.org/10.3390/ijms21155516

APA Style

Kim, K., Lee, Y.-s., Jeong, S., Kim, D., Chon, S., Pak, Y. K., Kim, S., Ha, J., Kang, I., & Choe, W. (2020). A Small Molecule, 4-Phenylbutyric Acid, Suppresses HCV Replication via Epigenetically Induced Hepatic Hepcidin. International Journal of Molecular Sciences, 21(15), 5516. https://doi.org/10.3390/ijms21155516

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