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

Abstract

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.

Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway

“…However, as FXR expression is down-regulated in endotoxic mice, FXR synthetic ligands display a poor effect on cholestasis ( 136 ), thus advocating for the identification of an alternative therapeutic strategy such as promoting the increase of FXR expression. Finally, the VDR agonist calcipotriol is also able to alleviate cholestatic liver injury and fibrosis by inhibiting the NLRP3 inflammasome pathway involved in inflammation, and hepatic stellate cells activation likely responsible of fibrosis ( 166 ) ( Table 1 ).…”

VDR inhibits NLRP3 signal in lupus nephritis by competitively binding with importin 4 to suppress NF-κB nuclear translocation

“…According previous papers in other diseases, BRCC3-mediated deubiquitination of NLRP3 could be inhibited by VDR, and then NLRP3 activation is inhibited [18]. It has been proved that yes-associated protein 1 (YAP1) inhibit NLRP3 activation [36,37], and VDR agonist could negatively regulate NLRP3 in ammation activation through activating YAP1 [20]. NLRP3 in ammasome has a crosstalk with Aryl hydrocarbon receptor (AhR) and NF-κB [38], vitamin D3 can increase the activation of AhR signaling, AhR blocks NF-κB binding sites in the NLRP3 promoter region, which result to suppress NLRP3 in ammasome activation [39].…”

“…Untill now, the therapeutic effect of VDR agonist on LN has not been investigated, and the potential mechanisms are also unclear. Recently, it is reported that VDR inhibits NLRP3 activation which participated in LN development as described above in other diseases [18][19][20], at present the following issues need to clarify: 1) whether VDR agonist alleviates LN though inhibiting NLRP3 signal; 2) the molecular mechanism through which VDR inhibits NLRP3 signal.…”

Gout‐induced endothelial impairment: The role of SREBP2 transactivation of YAP

“…For example, NOX4 and NLRP3 are regulated by YAP/transcriptional coactivator with PDZ-binding motif (TAZ). 41,42 Therefore, the identified SREBP2 transactivation of YAP adds a new mechanism underlying EC inflammation and dysfunction. In line with this notion, atheroprone flow induces YAP, resulting in EC inflammation, proliferation, and migration.…”

“…Besides affecting the molecules detected in this study (eg, BIRC5, MCM6, AREG, CTGF, VCAM1, ICAM1, CYR61, CCNA1, and E2F1), the YAP pathway may also contribute to other SREBP2‐induced genes in ECs. For example, NOX4 and NLRP3 are regulated by YAP/transcriptional coactivator with PDZ‐binding motif (TAZ) 41,42 . Therefore, the identified SREBP2 transactivation of YAP adds a new mechanism underlying EC inflammation and dysfunction.…”