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25-Hydroxyvitamin D Inhibits Hepatitis C Virus Production in Hepatocellular Carcinoma Cell Line by a Vitamin D Receptor-Independent Mechanism

1
Endocrine Immunology Laboratory, Sackler School of Medicine, Tel-Aviv University, Beilinson Hospital, Petah Tikva 49100, Israel
2
Molecular Hepatology Research Laboratory, Sackler School of Medicine, Tel-Aviv University, Beilinson Hospital, Petah Tikva 49100, Israel
3
Liver Institute, Rabin Medical Center, Beilinson Hospital, 49100 Petah Tikva, Israel
4
Department of Nephrology and Hypertension, Rabin Medical Center, Beilinson Hospital, Petah Tikva 49100, Israel
5
Faculty of Medicine in the Galilee, Bar-Ilan University, 1311502 Safed, Israel
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(9), 2367; https://doi.org/10.3390/ijms20092367
Received: 20 March 2019 / Revised: 7 May 2019 / Accepted: 10 May 2019 / Published: 13 May 2019
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Abstract

Previously, we have reported that the active vitamin D metabolite, calcitriol and vitamin D3 (cholecalciferol), both remarkably inhibit hepatitis C virus production. The mechanism by which vitamin D3 exerts its effect is puzzling due to the low levels of calcitriol produced in vitamin D3-treated Huh7.5 cells. In this study, we aimed to explore the mechanism of vitamin D3 anti-hepatitis C virus effect. We show that vitamin D3 activity is not mediated by its metabolic conversion to calcitriol, but may be due to its primary metabolic product 25(OH)D3. This is inferred from the findings that 25(OH)D3 could inhibit hepatitis C virus production in our system, and that adequate concentrations needed to exert this effect are produced in Huh7.5 cells treated with vitamin D3. Using the CRISPR-Cas9 editing technology to knockout the vitamin D receptor, we found that the antiviral activity of vitamin D3 and 25(OH)D3 was not impaired in the vitamin D receptor knockout cells. This result indicates that 25(OH)D3 anti-hepatitis C virus effect is exerted by a vitamin D receptor-independent mode of action. The possibility that vitamin D3 and 25(OH)D3, being 3β-hydroxysteroids, affect hepatitis C virus production by direct inhibition of the Hedgehog pathway in a vitamin D receptor-independent manner was ruled out. Taken together, this study proposes a novel mode of action for the anti-hepatitis C virus activity of vitamin D3 that is mediated by 25(OH)D3 in a vitamin D receptor-independent mechanism. View Full-Text
Keywords: vitamin D3; 25-hydroxyvitamin D3; vitamin D receptor; hepatitis C virus vitamin D3; 25-hydroxyvitamin D3; vitamin D receptor; hepatitis C virus
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Ravid, A.; Rapaport, N.; Issachar, A.; Erman, A.; Bachmetov, L.; Tur-Kaspa, R.; Zemel, R. 25-Hydroxyvitamin D Inhibits Hepatitis C Virus Production in Hepatocellular Carcinoma Cell Line by a Vitamin D Receptor-Independent Mechanism. Int. J. Mol. Sci. 2019, 20, 2367.

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