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.
Highlights
Cholestasis is a common clinical syndrome of liver dysfunction characterized by impaired bile secrection and flow that can worsen ongoing liver disease
Both low dose (LD) and high dose (HD) calcipotriol supplement reduced the level of serum total bile acid (TBA) (Figure 1B)
There was no significant difference in alkline phosphatase (AKP) and total bilirubin (TBil) between calcipotriol administration groups and BDL group (Figure 1B)
Summary
Cholestasis is a common clinical syndrome of liver dysfunction characterized by impaired bile secrection and flow that can worsen ongoing liver disease. Calcipotriol Alleviates Cholestasis of toxic bile acid (BA) can cause liver damage, fibrosis, or even cirrhosis, leading eventually to liver function failure (Li and Apte, 2015; Wu et al, 2017). Activation of the NLRP3 pathway promotes hepatic stellate cell (HSC) activation, which is critical for the initiation and development of liver fibrosis (Watanabe et al, 2009; Inzaugarat et al, 2019). We proved that NLRP3 inhibition by MCC950, a selective NLRP3 inhibitor, can significantly alleviate liver injury and retard the development of fibrosis in bile-duct-ligation (BDL)-induced cholestasis in mice (Qu et al, 2019). Inhibiting activation of the NLRP3 inflammasome may be a potential therapeutic route for effectively treating cholestatic liver injury and fibrosis
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