Calcitriol Inhibits HCV Infection via Blockade of Activation of PPAR and Interference with Endoplasmic Reticulum-Associated Degradation.

Yu-Min Lin,Yu-Chieh Chien,Hui-Chen Su,Wen-Tai Chiu,Hung-Chuen Chang,Chiung-Wen Tsao,Kung-Chia Young,Chyi-Huey Bai,Lee-Won Chong,Hung-Yu Sun

doi:10.3390/v10020057

Abstract

Vitamin D has been identified as an innate anti-hepatitis C virus (HCV) agent but the possible mechanisms for this issue remain unclear. Here, we clarified the mechanisms of calcitriol-mediated inhibition of HCV infection. Calcitriol partially inhibited HCV infection, nitric oxide (NO) release and lipid accumulation in Huh7.5 human hepatoma cells via the activation of vitamin D receptor (VDR). When cells were pretreated with the activators of peroxisome proliferator-activated receptor (PPAR)-α (Wy14643) and -γ (Ly171883), the calcitriol-mediated HCV suppression was reversed. Otherwise, three individual stimulators of PPAR-α/β/γ blocked the activation of VDR. PPAR-β (linoleic acid) reversed the inhibition of NO release, whereas PPAR-γ (Ly171883) reversed the inhibitions of NO release and lipid accumulation in the presence of calcitriol. The calcitriol-mediated viral suppression, inhibition of NO release and activation of VDR were partially blocked by an inhibitor of endoplasmic reticulum-associated degradation (ERAD), kifunensine. Furthermore, calcitriol blocked the HCV-induced expressions of apolipoprotein J and 78 kDa glucose-regulated protein, which was restored by pretreatment of kifunensine. These results indicated that the calcitriol-mediated HCV suppression was associated with the activation of VDR, interference with ERAD process, as well as blockades of PPAR, lipid accumulation and nitrative stress.

Highlights

Vitamin D is essential to regulation of calcium homeostasis, is involved in cell proliferation and differentiation and exerts an immunomodulatory and anti-inflammatory property
The Huh7.5-secreted alkaline phosphatase (SEAP) cells infected with hepatitis C virus (HCV) at multiplicity of infection (MOI) of 0.01 were treated with various concentrations of calcitriol for 6 days to examine whether calcitriol could directly affect HCV
The supernatant was subsequently collected for determining the SEAP activity and this activity was normalized with the number of cells as a reflection of the quantitative evaluation of HCV infection

Summary

Introduction

Vitamin D is essential to regulation of calcium homeostasis, is involved in cell proliferation and differentiation and exerts an immunomodulatory and anti-inflammatory property. Vitamin D is sourced from skin with ultraviolet B exposure and from dietary intake to be synthesized and partially stored in the adipocytes. It produces in part 25-hydroxyvitamin D via hepatic 25-hydroxylation, which is sent into circulation, attached to vitamin D binding protein and Viruses 2018, 10, 57; doi:10.3390/v10020057 www.mdpi.com/journal/viruses. Vitamin D deficiency participates in pathological mechanisms involved in diabetes mellitus, cardiovascular diseases, mood disorders, declining cognitive functions and increased risk of infections [1,2]. Several studies have recently focused on vitamin D deficiency to be associated with the development of chronic liver diseases, including non-alcoholic fatty liver disease and hepatitis C virus (HCV) infection with a lower probability of a sustained virological response (SVR) to interferon-α (IFN-α) regimen [3,4]. Whether the vitamin D deficiency acts as a consequence of disease or as a contributor to the dysfunction remains obscure [3,4,5]

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