PMID- 30565807
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 1386-6346 (Print)
IS  - 1386-6346 (Linking)
VI  - 49
IP  - 4
DP  - 2019 Apr
TI  - Inhibition of glycogen synthase kinase 3beta protects liver against 
      ischemia/reperfusion injury by activating 5' adenosine monophosphate-activated 
      protein kinase-mediated autophagy.
PG  - 462-472
LID - 10.1111/hepr.13287 [doi]
AB  - AIM: Autophagy has been found to play an important role in hepatic 
      ischemia/reperfusion (I/R) injury. Our previous study has also clarified that 
      rictor deficiency aggravated hepatic I/R injury by suppressing autophagy. Here, 
      we explore whether autophagy participates in glycogen synthase kinase 3beta 
      (GSK3beta)-mediated cytoprotection in liver I/R. METHODS: Mice were treated with 
      SB216763 to inhibit GSK3beta before being subjected to hepatic I/R. Liver injury was 
      evaluated by liver and blood samples. Autophagy was measured by detecting 
      expression of microtubule-associated protein 1 light chain-3B (LC3B) II and 
      autophagy protein 5 (ATG-5), as well as the number of autophagosomes by 
      transmission electron microscope. Primary hepatocytes pretreated with SB216763 
      for 2 h were subjected to hypoxia/reoxygenation to induce autophagy. The lactate 
      dehydrogenase level was used to evaluate cell death and survival. Autophagy 
      inhibitors and 5' adenosine monophosphate-activated protein kinase (AMPK) 
      inhibitor were given in vivo or in vitro. RESULTS: SB216763 significantly 
      increased the number of autophagosomes and the protein levels of LC3B II and 
      ATG-5 in liver I/R models, which was accompanied by a decline of hepatic necrosis 
      and apoptosis. Consistent with the in vivo study, autophagy and cytoprotection 
      were induced by the inhibition of GSK3beta in the in vitro study. Moreover, 
      pretreatment with autophagy inhibitors attenuated the cytoprotective role of 
      autophagy in the GSK3beta-treated liver I/R models. Further analysis showed that 
      pretreatment with an AMPK inhibitor increased mammalian target of rapamycin 
      (mTOR) activity, decreased autophagy, and abrogated GSK3beta- mediated liver 
      protection. CONCLUSION: Autophagy was induced by GSK3beta inhibition through the 
      AMPK/mTOR pathway and could substantially ameliorate liver I/R injury. Therefore, 
      our findings strongly renew the therapeutic value of the GSK3beta/autophagy axis in 
      hepatic I/R injury.
CI  - (c) 2018 The Japan Society of Hepatology.
FAU - Kong, Defu
AU  - Kong D
AD  - Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao 
      Tong University, Shanghai, China.
FAU - Hua, Xiangwei
AU  - Hua X
AD  - Center of Organ Transplantation, The Affiliated Hospital of Qingdao University 
      and Institute of Transplant Medicine, Qingdao University, Qingdao, China.
FAU - Qin, Tian
AU  - Qin T
AD  - Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao 
      Tong University, Shanghai, China.
FAU - Zhang, Jianjun
AU  - Zhang J
AD  - Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao 
      Tong University, Shanghai, China.
FAU - He, Kang
AU  - He K
AUID- ORCID: 0000-0003-4671-1337
AD  - Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao 
      Tong University, Shanghai, China.
FAU - Xia, Qiang
AU  - Xia Q
AD  - Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao 
      Tong University, Shanghai, China.
LA  - eng
GR  - 81400671/National Natural Science Foundation of China/
GR  - 81400671 to K. He/National Natural Science Foundation of China/
GR  - 101005.21.20 to K. He/Shanghai Young Physicians Training Funding Scheme/
GR  - 15411950401 to Q. Xia/Shanghai Science and Technology Committee/
PT  - Journal Article
DEP - 20181221
PL  - Netherlands
TA  - Hepatol Res
JT  - Hepatology research : the official journal of the Japan Society of Hepatology
JID - 9711801
OTO - NOTNLM
OT  - AMPK
OT  - GSK3beta
OT  - autophagy
OT  - hepatic ischemia/reperfusion injury
EDAT- 2018/12/20 06:00
MHDA- 2018/12/20 06:01
CRDT- 2018/12/20 06:00
PHST- 2018/09/04 00:00 [received]
PHST- 2018/11/13 00:00 [revised]
PHST- 2018/11/16 00:00 [accepted]
PHST- 2018/12/20 06:00 [pubmed]
PHST- 2018/12/20 06:01 [medline]
PHST- 2018/12/20 06:00 [entrez]
AID - 10.1111/hepr.13287 [doi]
PST - ppublish
SO  - Hepatol Res. 2019 Apr;49(4):462-472. doi: 10.1111/hepr.13287. Epub 2018 Dec 21.