PMID- 35260799
OWN - NLM
STAT- MEDLINE
DCOM- 20220406
LR  - 20221023
IS  - 2092-6413 (Electronic)
IS  - 1226-3613 (Print)
IS  - 1226-3613 (Linking)
VI  - 54
IP  - 3
DP  - 2022 Mar
TI  - Sestrin2 protects against cholestatic liver injury by inhibiting endoplasmic 
      reticulum stress and NLRP3 inflammasome-mediated pyroptosis.
PG  - 239-251
LID - 10.1038/s12276-022-00737-9 [doi]
AB  - Chronic exposure to bile acid in the liver due to impaired bile flow induces 
      cholestatic liver disease, resulting in hepatotoxicity and liver fibrosis. 
      Sestrin2, a highly conserved, stress-inducible protein, has been implicated in 
      cellular responses to multiple stress conditions and the maintenance of cellular 
      homeostasis. However, its role in cholestatic liver injury is not fully 
      understood. In this study, we investigated the role of hepatic Sestrin2 in 
      cholestatic liver injury and its underlying mechanisms using in vivo and in vitro 
      approaches. Hepatic Sestrin2 expression was upregulated by activating 
      transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-beta (C/EBP-beta) 
      after treatment with bile acids and correlated with endoplasmic reticulum (ER) 
      stress responses. Bile-duct ligation (BDL)-induced hepatocellular apoptosis and 
      liver fibrosis were exacerbated in Sestrin2-knockout (Sesn2(-/-)) mice. Moreover, 
      Sestrin2 deficiency enhanced cholestasis-induced hepatic ER stress, whereas 
      Sestrin2 overexpression ameliorated bile acid-induced ER stress. Notably, the 
      mammalian target of rapamycin (mTOR) inhibitor rapamycin and the AMP-activated 
      protein kinase (AMPK) activator AICAR reversed bile acid-induced ER stress in 
      Sestrin2-deficient cells. Furthermore, Sestrin2 deficiency promoted 
      cholestasis-induced hepatic pyroptosis by activating NLRP3 inflammasomes. Thus, 
      our study provides evidence for the biological significance of Sestrin2 and its 
      relationship with cholestatic liver injury, suggesting the potential role of 
      Sestrin2 in regulating ER stress and inflammasome activation during cholestatic 
      liver injury.
CI  - (c) 2022. The Author(s).
FAU - Han, Daewon
AU  - Han D
AD  - Department of Cell Biology, Konyang University College of Medicine, Daejeon, 
      35365, Republic of Korea.
FAU - Kim, Haeil
AU  - Kim H
AD  - Department of Cell Biology, Konyang University College of Medicine, Daejeon, 
      35365, Republic of Korea.
FAU - Kim, Soojin
AU  - Kim S
AD  - Department of Cell Biology, Konyang University College of Medicine, Daejeon, 
      35365, Republic of Korea.
AD  - Department of Anatomy, Catholic Neuroscience Institute, College of Medicine, The 
      Catholic University of Korea, Seoul, 06591, Republic of Korea.
FAU - Le, Qui Anh
AU  - Le QA
AD  - Department of Cell Biology, Konyang University College of Medicine, Daejeon, 
      35365, Republic of Korea.
AD  - Cardiovascular Research Center and Department of Cardiovascular Sciences, Temple 
      University School of Medicine, Philadelphia, PA, 19140, USA.
FAU - Han, Seung Yun
AU  - Han SY
AD  - Department of Anatomy, Konyang University College of Medicine, Daejeon, 35365, 
      Republic of Korea.
FAU - Bae, Jeongyun
AU  - Bae J
AD  - Department of Cell Biology, Konyang University College of Medicine, Daejeon, 
      35365, Republic of Korea.
FAU - Shin, Hye Won
AU  - Shin HW
AD  - Department of Cell Biology, Konyang University College of Medicine, Daejeon, 
      35365, Republic of Korea.
FAU - Kang, Hyun-Goo
AU  - Kang HG
AD  - Department of Cell Biology, Konyang University College of Medicine, Daejeon, 
      35365, Republic of Korea.
FAU - Han, Kyung Ho
AU  - Han KH
AD  - Department of Biological Sciences and Biotechnology, Hannam University, Daejeon, 
      34054, Republic of Korea.
FAU - Shin, Jongdae
AU  - Shin J
AD  - Department of Cell Biology, Konyang University College of Medicine, Daejeon, 
      35365, Republic of Korea. shinjd@konyang.ac.kr.
AD  - Myunggok Medical Research Institute, Konyang University College of Medicine, 
      Daejeon, 35365, Republic of Korea. shinjd@konyang.ac.kr.
FAU - Park, Hwan-Woo
AU  - Park HW
AUID- ORCID: 0000-0001-8029-2004
AD  - Department of Cell Biology, Konyang University College of Medicine, Daejeon, 
      35365, Republic of Korea. hwanwoopark@konyang.ac.kr.
AD  - Myunggok Medical Research Institute, Konyang University College of Medicine, 
      Daejeon, 35365, Republic of Korea. hwanwoopark@konyang.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220308
PL  - United States
TA  - Exp Mol Med
JT  - Experimental & molecular medicine
JID - 9607880
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
RN  - EC 1.11.1.- (Peroxidases)
RN  - EC 1.11.1.- (Sesn2 protein, mouse)
SB  - IM
MH  - Animals
MH  - *Cholestasis/metabolism
MH  - Endoplasmic Reticulum Stress
MH  - *Inflammasomes/metabolism
MH  - Liver/metabolism
MH  - Mammals/metabolism
MH  - Mice
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism
MH  - *Peroxidases/genetics
MH  - Pyroptosis
MH  - Signal Transduction
PMC - PMC8980001
COIS- The authors declare no competing interests.
EDAT- 2022/03/10 06:00
MHDA- 2022/04/07 06:00
PMCR- 2022/03/08
CRDT- 2022/03/09 05:35
PHST- 2021/07/07 00:00 [received]
PHST- 2021/12/01 00:00 [accepted]
PHST- 2021/11/18 00:00 [revised]
PHST- 2022/03/10 06:00 [pubmed]
PHST- 2022/04/07 06:00 [medline]
PHST- 2022/03/09 05:35 [entrez]
PHST- 2022/03/08 00:00 [pmc-release]
AID - 10.1038/s12276-022-00737-9 [pii]
AID - 737 [pii]
AID - 10.1038/s12276-022-00737-9 [doi]
PST - ppublish
SO  - Exp Mol Med. 2022 Mar;54(3):239-251. doi: 10.1038/s12276-022-00737-9. Epub 2022 
      Mar 8.