Yes‐associated protein regulates the hepatoprotective effect of vitamin D receptor activation through promoting adaptive bile duct remodeling in cholestatic mice

Abstract

Mounting clinical evidence has revealed that the vitamin D receptor (VDR) is associated with cholestatic liver injury, although the functions of VDR in this condition remain largely unexplored. Here, we investigated the effects of VDR activation on bile duct ligation (BDL) mice, and the underlying mechanisms were further investigated. A low‐calcemic VDR agonist, paricalcitol (PAL, 200 ng/kg), was intraperitoneally injected into BDL mice every other day for 5 days or 28 days. Liver histology, liver function indicators, cholangiocyte proliferation, fibrosis scores, and inflammation were evaluated. Mice treated with PAL were rescued from the decreased survival rate induced by BDL and liver damage was reduced. Mechanistically, PAL promoted cholangiocyte proliferation, which was likely conducive to proliferating bile duct maturation and increased branching of bile ducts. PAL treatment also increased the expression of Yes‐associated protein (YAP) and its target protein epithelial cell adhesion molecule (EpCam) and decreased the level of inactive cytoplasmic phosphorylated YAP. YAP knockdown abrogated PAL‐induced primary bile duct epithelial cell proliferation, confirmed with YAP inhibitor administration. In addition, BDL‐induced liver fibrosis and inflammatory cell infiltration were reduced by PAL treatment at both day 5 and day 28 post‐BDL. In conclusion, VDR activation mitigates cholestatic liver injury by promoting adaptive bile duct remodeling through cholangiocytic YAP upregulation. Because PAL is an approved clinical drug, it may be useful for treatment of cholestatic liver disease. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Vitamin D Receptor Activation Targets ROS-Mediated Crosstalk Between Autophagy and Apoptosis in Hepatocytes in Cholestasic Mice

“…To investigate if PAL has a role in activation of VDR expression in hepatocytes of BDL mice liver, PAL was administered to mice following our previously reported protocol. 9 Figure 1 A shows the chemical structural formula of PAL. Hepatocytes were isolated from sham and BDL mouse livers at 5 days.…”

“…The common BDL was as previously described. 9 Briefly, mice were anesthetized with 2% isoflurane (Ruiwode Life Technology Co, Ltd, Shenzhen, China) and were fixed on an animal operating table with a heating pad (37°C). After a midline laparotomy, the common bile duct was separated from the surrounding tissues, and dissociated between the 2 ligatures with 6-0 nylon suture.…”

“… 8 Our previous study showed that the VDR–yes-associated protein axis promotes cholangiocyte proliferation and enhances adaptive bile duct remodeling, alleviating cholestatic liver injury in BDL mice. 9 In addition, VDR also can play a biological role in regulating autophagy and apoptosis. VDR inhibits the nuclear factor-κB pathway to promote autophagy and inhibit apoptosis, which reduces the lipopolysaccharide-induced inflammatory response in the abalone hepatopancreas.…”

Ferroportin-dependent ferroptosis induced by ellagic acid retards liver fibrosis by impairing the SNARE complexes formation

“…The sections were deparaffinized with xylene, rehydrated in graded ethanol, and stained with hematoxylin and eosin (H&E), Sirius red and Masson. Sirius Red and Masson-stained areas from 10 random fields were quantified with ImageJ software (NIH, Bethesda, MD, USA) according to previous reported [ 29 ]. For TUNEL assays, TUNEL kit (#KGA7051, Nanjing KeyGen Biotech Co., Ltd., Nanjing, China) was applied to identify apoptosis cells of fibrotic liver according to the manufacture's instruction.…”

Alpinetin: A Review of Its Pharmacology and Pharmacokinetics

“…However, many challenges for researchers are still remained. More specific and novel molecular targets of alpinetin in hepatic disorders therapy are required to be illustrated in further experiments, such as glucagon-like peptide-1 (GLP-1) (Milani et al, 2019), Sirtuin 1 (SIRT1) (Farghali et al, 2019), Yesassociated protein (YAP) (Xie et al, 2021), etc.…”