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Int. J. Mol. Sci. 2018, 19(2), 108;

Peretinoin, an Acyclic Retinoid, Inhibits Hepatitis B Virus Replication by Suppressing Sphingosine Metabolic Pathway In Vitro

Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8641, Japan
Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa 920-0942, Japan
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 11 December 2017 / Revised: 10 January 2018 / Accepted: 17 January 2018 / Published: 23 January 2018
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Hepatocellular carcinoma (HCC) frequently develops from hepatitis C virus (HCV) and hepatitis B virus (HBV) infection. We previously reported that peretinoin, an acyclic retinoid, inhibits HCV replication. This study aimed to examine the influence of peretinoin on the HBV lifecycle. HBV-DNA and covalently closed circular DNA (cccDNA) were evaluated by a qPCR method in HepG2.2.15 cells. Peretinoin significantly reduced the levels of intracellular HBV-DNA, nuclear cccDNA, and HBV transcript at a concentration that did not induce cytotoxicity. Conversely, other retinoids, such as 9-cis, 13-cis retinoic acid (RA), and all-trans-retinoic acid (ATRA), had no effect or rather increased HBV replication. Mechanistically, although peretinoin increased the expression of HBV-related transcription factors, as observed for other retinoids, peretinoin enhanced the binding of histone deacetylase 1 (HDAC1) to cccDNA in the nucleus and negatively regulated HBV transcription. Moreover, peretinoin significantly inhibited the expression of SPHK1, a potential inhibitor of HDAC activity, and might be involved in hepatic inflammation, fibrosis, and HCC. SPHK1 overexpression in cells cancelled the inhibition of HBV replication induced by peretinoin. This indicates that peretinoin activates HDAC1 and thereby suppresses HBV replication by inhibiting the sphingosine metabolic pathway. Therefore, peretinoin may be a novel therapeutic agent for HBV replication and chemoprevention against HCC. View Full-Text
Keywords: hepatitis B virus; acyclic retinoid; SPHK1; HDAC1 hepatitis B virus; acyclic retinoid; SPHK1; HDAC1

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Murai, K.; Shirasaki, T.; Honda, M.; Shimizu, R.; Shimakami, T.; Nakasho, S.; Shirasaki, N.; Okada, H.; Sakai, Y.; Yamashita, T.; Kaneko, S. Peretinoin, an Acyclic Retinoid, Inhibits Hepatitis B Virus Replication by Suppressing Sphingosine Metabolic Pathway In Vitro. Int. J. Mol. Sci. 2018, 19, 108.

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