The vitamin D receptor agonist, calcipotriol, modulates fibrogenic pathways mitigating liver fibrosis in-vivo: An experimental study

Wahsh, E; Abu-Elsaad, Nashwa; El-Karef, Amr; Ibrahim, Tarek M.

doi:10.1016/j.ejphar.2016.07.052

Cited by 32 publications

(10 citation statements)

References 38 publications

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“…Bile duct ligation surgeries were performed as previous described (Qu et al, 2019) and sham operation group underwent the same procedure except for BDL and served as healthy controls. The low dose (LD; 80 µg/kg) of calcipotriol were referenced from a previous study and proved to be most effective in anti-fibrosis and liver protection in that in vivo experiment (Wahsh et al, 2016). We take an unstudied dose as the high dose (HD; 160 µg/kg) to explore it therapeutic efficacy in BDL-induced cholestasis.…”

Section: Bile Duct Ligation (Bdl)-induced Cholestasismentioning

confidence: 99%

Calcipotriol Inhibits NLRP3 Signal Through YAP1 Activation to Alleviate Cholestatic Liver Injury and Fibrosis

Wang

et al. 2020

Front. Pharmacol.

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Cholestasis is common in multiple clinical circumstances. The NOD-like receptor protein 3 (NLRP3) inflammasome pathway has been demonstrated to play an important role in liver injury and fibrosis induced by cholestasis. We previously proved that MCC950, a selective NLRP3 inhibitor, alleviates liver fibrosis and injury in experimental liver cholestasis induced by bile-duct ligation (BDL) in mice. Herein, we investigate the role of calcipotriol, a potent vitamin D receptor agonist, in experimental liver cholestasis, test its therapeutic efficacy, and explore its potential protective mechanism. C57BL/6 mice were made to undergo BDL or fed the 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to establish two classic cholestatic models. Calcipotriol was administered intraperitoneally to these mice daily. Serum makers of liver damage and integrity, liver histological changes, levels of liver pro-fibrotic markers, bile acid synthetases and transporters were measured in vivo. The underlying mechanism by which calcipotriol alleviates cholestatic liver injury and fibrosis was further investigated. The results of the current study demonstrated that calcipotriol supplement significantly alleviate cholestatic liver injury and fibrosis. Moreover, calcipotriol supplement markedly inhibited NLRP3 inflammasome pathway activation to alleviate liver injury and fibrosis in vivo and inhibit hepatic stellate cell (HSC) activation in vitro. In addition, VDR agonist calcipotriol exert inhibitory effect on NLRP3 inflammasome activation through activating yes-associated protein 1 (YAP1). In conclusion, our findings proved that calcipotriol suppressed the NLRP3 signal by activating YAP1 to alleviate liver injury and retard fibrogenesis in cholestasis.

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Section: Bile Duct Ligation (Bdl)-induced Cholestasismentioning

confidence: 99%

Calcipotriol Inhibits NLRP3 Signal Through YAP1 Activation to Alleviate Cholestatic Liver Injury and Fibrosis

Wang

et al. 2020

Front. Pharmacol.

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“…VDR knockout mice spontaneously develop cirrhosis 13 , and VDR and DHCR7 gene polymorphisms are associated with more severe liver fibrosis in CHC patients 14 , 15 . Furthermore, a non-calcemic VD derivative, calcipotriol, was shown to prevent liver fibrosis in a mouse model of cirrhosis 13 , 16 .…”

Section: Introductionmentioning

confidence: 99%

Vitamin D supplementation improves serum markers associated with hepatic fibrogenesis in chronic hepatitis C patients: A randomized, double-blind, placebo-controlled study

Komolmit

Kimtrakool

Suksawatamnuay

et al. 2017

Sci Rep

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Hepatic fibrosis is the net accumulation of matrix tissue components which controlled by pro-fibrolytic enzymes, matrix metalloproteinases (MMPs), and pro-fibrotic cytokine, TGF-β1, and enzymes, tissue inhibitors of MMPs (TIMPs). Vitamin D (VD) supplementation has been shown to reverse these processes in vitro and in vivo. This study sought to determine the effect of VD supplementation on serum fibrotic markers in chronic hepatitis C (CHC) patients. Fifty-four CHC patients with VD deficiency were randomized into two groups, a VD group (n = 29) and a placebo group (n = 29). The serum levels of 25-hydroxy VD, TGF-β1, TIMP-1, MMP2 and MMP9 were measured at baseline and at the end of the 6-week study period. Upon correction of VD levels, TGF-β1 and TIMP-1 levels were decreased, and the MMP2 and MMP9 levels were significantly increased in the VD group. A comparison of the mean changes (delta) in the markers between groups showed that TGF-β1 and TIMP-1 levels were significantly decreased and the MMP2 and MMP9 were significantly higher in the VD group than in the placebo group. By using CHC patients as a model, this study provides additional evidence that VD plays an important role in the reversal of hepatic fibrogenesis.

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“…Growing experimental and clinical evidence has revealed an anti-fibrogenic effect of VD (Baur et al 2012;Ding et al 2013;Wahsh et al 2016). Our previous study demonstrated a considerable improvement in serum fibrogenesis markers after VD restoration in patients with CHC before HCV treatment (Komolmit et al 2017).…”

Section: Introductionmentioning

confidence: 92%

Peer Review #1 of "Effect of vitamin D supplementation in patients with chronic hepatitis C after direct-acting antiviral treatment: a randomized, double-blind, placebo-controlled trial (v0.2)"

2021

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Background. Replacement of vitamin D (VD) among patients with chronic hepatitis C (CHC) before viral eradication has demonstrated a protective effect on serum markers associated with hepatic fibrogenesis. We therefore hypothesized that VD may facilitate further fibrosis amelioration following curative treatment with direct-acting antivirals (DAA).Methods. This study was a randomized, double-blind, placebo-controlled trial conducted between February 2018 and August 2018. Patients with CHC and VD deficiency were randomized in a 1:1 ratio to either receive ergicalciferol or placebo over 6 weeks. Biochemical analysis indicators, including 25hydroxyvitamin D (25(OH)D), fibrogenic markers [(transforming growth factor beta 1 (TGF-β1) and tissue inhibitors of matrix metalloproteinases 1 (TIMP-1)], and fibrolytic markers [matrix metalloproteinase 9 (MMP-9) and amino terminal type III procollagen peptide (P3NP)], were assessed at baseline and at 6 weeks. Serum 25(OH)D was analyzed by a chemiluminescence immunoassay. Serum hepatic fibrogenesis markers were measured using a quantitative sandwich enzyme-linked immunosorbent assay.Results. Seventy-five patients with CHC and VD deficiency were randomly assigned to VD (n=37) and placebo (n=38) groups. At the end of the study, the mean serum 25(OH)D level had risen to a normal level in the VD group, but was still deficient in the placebo group (41.8±9.1 vs. 18.1±4.6 ng/mL, p<0.001). Upon restoration of the VD level, there were no significant mean differences in the change from baseline for TGF-β1 (-0.6 ng/mL (95% confidence interval (95%CI) -2.8 -1.7), p=0.63), TIMP-1 3), p=0.60), MMP-9 (122.9 ng/mL (95%CI -69.0 -314.8), p=0.21), and P3NP (-0.1 ng/mL (95%CI -2.4 -2.2), p=0.92) between the VD and placebo groups. Conclusion.Short-term VD supplementation after DAA treatment in patients with CHC does not improve serum fibrogenesis markers and may not expedite the residual liver fibrosis healing process. Future studies are warranted to evaluate the long-term effect of VD supplementation on hepatic fibrosis regression.

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The vitamin D receptor agonist, calcipotriol, modulates fibrogenic pathways mitigating liver fibrosis in-vivo: An experimental study

Cited by 32 publications

References 38 publications

Calcipotriol Inhibits NLRP3 Signal Through YAP1 Activation to Alleviate Cholestatic Liver Injury and Fibrosis

Calcipotriol Inhibits NLRP3 Signal Through YAP1 Activation to Alleviate Cholestatic Liver Injury and Fibrosis

Vitamin D supplementation improves serum markers associated with hepatic fibrogenesis in chronic hepatitis C patients: A randomized, double-blind, placebo-controlled study

Peer Review #1 of "Effect of vitamin D supplementation in patients with chronic hepatitis C after direct-acting antiviral treatment: a randomized, double-blind, placebo-controlled trial (v0.2)"

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