PMID- 36280140
OWN - NLM
STAT- MEDLINE
DCOM- 20230321
LR  - 20230323
IS  - 2352-345X (Electronic)
IS  - 2352-345X (Linking)
VI  - 15
IP  - 4
DP  - 2023
TI  - Vitamin D Receptor Activation Targets ROS-Mediated Crosstalk Between Autophagy 
      and Apoptosis in Hepatocytes in Cholestasic Mice.
PG  - 887-901
LID - S2352-345X(22)00222-3 [pii]
LID - 10.1016/j.jcmgh.2022.10.011 [doi]
AB  - BACKGROUND & AIMS: Observational epidemiologic studies have associated vitamin D 
      deficiency with cholestasis. We reported previously that activation of the 
      vitamin D/vitamin D receptor (VDR) axis in cholangiocytes mitigates cholestatic 
      liver injury by remodeling the damaged bile duct. However, the function of VDR in 
      hepatocytes during cholestasis remains unclear. METHODS: Paricalcitol (VDR 
      agonist, 200 ng/kg) was injected intraperitoneally into bile duct-ligated mice 
      every other day for 5 days. Primary hepatocytes and HepG2 hepatoma cells were 
      transfected with Vdr short hairpin RNA, control short hairpin RNA, Vdr plasmid, 
      control vector, Atg5 small interfering RNA (siRNA), and control siRNA. Liver 
      histology, cell proliferation, and autophagy were evaluated. RESULTS: Treatment 
      with the VDR agonist paricalcitol improved liver injury in bile duct-ligated mice 
      by up-regulating VDR expression in hepatocytes, which in turn reduced hepatocyte 
      apoptosis by inhibiting reactive oxygen species (ROS) generation via suppressing 
      the Ras-related C3 botulinum toxin substrate 1/reduced nicotinamide adenine 
      dinucleotide phosphate oxidase 1 pathway. Mechanistically, upon exposure to an 
      ROS-inducing compound, Vdr siRNA contributed to apoptosis, whereas the Vdr 
      overexpression caused resistance to apoptosis. Interestingly, up-regulated VDR 
      expression also increased the generation of autophagosomes and 
      macroautophagic/autophagic flux, which was the underlying mechanism for reduced 
      apoptosis following VDR activation. Autophagy depletion impaired the positive 
      effects of VDR overexpression, whereas autophagy induction was synergystic with 
      VDR overexpression. Importantly, up-regulation of VDR promoted autophagy 
      activation by suppressing the activation of the extracellular signal-regulated 
      kinase (ERK)/p38 mitogen-activated protein kinase (p38MAPK) pathway. Thus, a 
      p38MAPK inhibitor abrogated the Vdr siRNA-induced decrease in autophagy and the 
      Vdr siRNA-induced increase in apoptosis. In contrast, a Mitogen-activated protein 
      kinase kinase (MEK)/ERK activator prevented the enhancement of autophagy and 
      decreased apoptosis following Vdr overexpression. Moreover, the ROS inhibitor 
      N-acetylcystein (NAC) blocked Vdr siRNA-enhanced activation of the ERK/p38MAPK 
      pathway. CONCLUSIONS: VDR activation mitigated liver cholestatic injury by 
      reducing autophagy-dependent hepatocyte apoptosis and suppressing the activation 
      of the ROS-dependent ERK/p38MAPK pathway. Thus, VDR activation may be a potential 
      target for the treatment of cholestatic liver disease.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Zheng, Zhijian
AU  - Zheng Z
AD  - Department of General Surgery, Affiliated Wenling First People's Hospital, 
      Taizhou University, Taizhou, Zhejiang Province, P R China.
FAU - Xie, Jing
AU  - Xie J
AD  - Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, 
      Zhejiang Province, P R China.
FAU - Ma, Liman
AU  - Ma L
AD  - Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, 
      Zhejiang Province, P R China.
FAU - Hao, Zhiqing
AU  - Hao Z
AD  - Department of Pathophysiology, School of Basic Medicine, Shenyang Medical 
      College, Shenyang, Liaoning Province, PR China.
FAU - Zhang, Weiwei
AU  - Zhang W
AD  - Department of Pathophysiology, School of Basic Medicine, Shenyang Medical 
      College, Shenyang, Liaoning Province, PR China.
FAU - Li, Lihua
AU  - Li L
AD  - Department of General Surgery, Affiliated Wenling First People's Hospital, 
      Taizhou University, Taizhou, Zhejiang Province, P R China. Electronic address: 
      lilihua1018@sina.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221022
PL  - United States
TA  - Cell Mol Gastroenterol Hepatol
JT  - Cellular and molecular gastroenterology and hepatology
JID - 101648302
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Calcitriol)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Reactive Oxygen Species/metabolism
MH  - *Receptors, Calcitriol/metabolism
MH  - Hepatocytes/metabolism
MH  - Apoptosis
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - *Cholestasis/pathology
MH  - Autophagy/genetics
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - RNA, Small Interfering/metabolism
PMC - PMC9972562
OTO - NOTNLM
OT  - Apoptosis
OT  - Autophagy
OT  - ERK/p38MAPK Pathway
OT  - ROS Generation
OT  - Vitamin D-Receptor Activation
EDAT- 2022/10/25 06:00
MHDA- 2023/03/22 06:00
PMCR- 2022/10/22
CRDT- 2022/10/24 19:27
PHST- 2022/05/31 00:00 [received]
PHST- 2022/10/17 00:00 [revised]
PHST- 2022/10/17 00:00 [accepted]
PHST- 2022/10/25 06:00 [pubmed]
PHST- 2023/03/22 06:00 [medline]
PHST- 2022/10/24 19:27 [entrez]
PHST- 2022/10/22 00:00 [pmc-release]
AID - S2352-345X(22)00222-3 [pii]
AID - 10.1016/j.jcmgh.2022.10.011 [doi]
PST - ppublish
SO  - Cell Mol Gastroenterol Hepatol. 2023;15(4):887-901. doi: 
      10.1016/j.jcmgh.2022.10.011. Epub 2022 Oct 22.