PMID- 34778458
OWN - NLM
STAT- MEDLINE
DCOM- 20220121
LR  - 20220428
IS  - 2314-6141 (Electronic)
IS  - 2314-6133 (Print)
VI  - 2021
DP  - 2021
TI  - Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver 
      Injury Model.
PG  - 8717565
LID - 10.1155/2021/8717565 [doi]
LID - 8717565
AB  - BACKGROUND: Activating transcription factor 6 (ATF6) and receptor-interacting 
      protein 3 (RIP3) are important signaling proteins in endoplasmic reticulum (ER) 
      stress and necroptosis, respectively. However, their regulatory relationship and 
      clinical significance are unknown. We investigate the impact of ATF6 on RIP3 
      expression, and its role in hepatocyte necroptosis in an acute liver injury 
      model. METHODS: In vivo and in vitro experiments were carried out. LO2 cells were 
      treated with thapsigargin (TG). In vivo, male BALB/c mice were treated with 
      carbon tetrachloride (CCl(4), 1 mL/kg) or tunicamycin (TM, 2 mg/kg). Then, the 
      impact of ATF6 or RIP3 silencing on liver injury, hepatocyte necroptosis, and ER 
      stress-related protein expression was examined. RESULTS: TG induced ER stress and 
      necroptosis and ATF6 and RIP3 expression in LO2 cells. The knockdown of ATF6 
      significantly decreased RIP3 expression (p < 0.05) and increased ER stress and 
      necroptosis. The downregulation of RIP3 significantly reduced necroptosis and ER 
      stress (p < 0.05). Similar results were observed in CCl(4) or the TM-induced 
      mouse model. The knockdown of ATF6 significantly decreased CCl(4)-induced RIP3 
      expression and increased liver injury, necroptosis, and ER stress in mice livers 
      (p < 0.05). In contrast, the downregulation of RIP3 significantly reduced liver 
      injury, hepatocyte necroptosis, and ER stress. CONCLUSIONS: Hepatocyte ATF6 has 
      multiple roles in acute liver injury. It reduces hepatocyte necroptosis via 
      negative feedback regulation of ER stress. In addition, ATF6 can upregulate the 
      expression of RIP3, which is not helpful to the recovery process. However, 
      downregulating RIP3 reduces hepatocyte necroptosis by promoting the alleviation 
      of ER stress. The findings suggest that RIP3 could be a plausible target for the 
      treatment of liver injury.
CI  - Copyright (c) 2021 Mei-Ying Huang et al.
FAU - Huang, Mei-Ying
AU  - Huang MY
AD  - Department of Pediatrics, The Affiliated Hospital of Zunyi Medical University, 
      Zunyi, 563000 Guizhou, China.
FAU - Wan, Dian-Wei
AU  - Wan DW
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, Zunyi, 563000 Guizhou, China.
FAU - Deng, Jie
AU  - Deng J
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, Zunyi, 563000 Guizhou, China.
FAU - Guo, Wen-Jie
AU  - Guo WJ
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, Zunyi, 563000 Guizhou, China.
FAU - Huang, Yue
AU  - Huang Y
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, Zunyi, 563000 Guizhou, China.
FAU - Chen, Huan
AU  - Chen H
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, Zunyi, 563000 Guizhou, China.
FAU - Xu, De-Lin
AU  - Xu DL
AD  - Department of Cell Biology, Zunyi Medical University, Zunyi, 563099 Guizhou, 
      China.
FAU - Jiang, Zhi-Gang
AU  - Jiang ZG
AD  - School of Public Health, Zunyi Medical University, Zunyi, 563099 Guizhou, China.
FAU - Xue, Yuan
AU  - Xue Y
AUID- ORCID: 0000-0002-5428-0058
AD  - Department of Liver Diseases, The Third People's Hospital of Changzhou, 
      Changzhou, 213000 Jiangsu Province, China.
FAU - He, Yi-Huai
AU  - He YH
AUID- ORCID: 0000-0002-8639-3436
AD  - Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical 
      University, Zunyi, 563000 Guizhou, China.
LA  - eng
PT  - Journal Article
DEP - 20211105
PL  - United States
TA  - Biomed Res Int
JT  - BioMed research international
JID - 101600173
RN  - 0 (Activating Transcription Factor 6)
RN  - 0 (Atf6 protein, mouse)
RN  - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Ripk3 protein, mouse)
SB  - IM
MH  - Activating Transcription Factor 6/genetics/*metabolism
MH  - Animals
MH  - Apoptosis
MH  - Chemical and Drug Induced Liver Injury/genetics/*metabolism
MH  - China
MH  - Disease Models, Animal
MH  - Endoplasmic Reticulum Stress/genetics
MH  - Hepatocytes/metabolism
MH  - Liver/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Models, Animal
MH  - Necroptosis/genetics/physiology
MH  - Receptor-Interacting Protein Serine-Threonine Kinases/genetics/*metabolism
MH  - Signal Transduction/genetics
PMC - PMC8589516
COIS- The authors declare no conflict of interest.
EDAT- 2021/11/16 06:00
MHDA- 2022/01/22 06:00
PMCR- 2021/11/05
CRDT- 2021/11/15 07:10
PHST- 2021/07/23 00:00 [received]
PHST- 2021/09/28 00:00 [revised]
PHST- 2021/10/11 00:00 [accepted]
PHST- 2021/11/15 07:10 [entrez]
PHST- 2021/11/16 06:00 [pubmed]
PHST- 2022/01/22 06:00 [medline]
PHST- 2021/11/05 00:00 [pmc-release]
AID - 10.1155/2021/8717565 [doi]
PST - epublish
SO  - Biomed Res Int. 2021 Nov 5;2021:8717565. doi: 10.1155/2021/8717565. eCollection 
      2021.