PMID- 21854730
OWN - NLM
STAT- MEDLINE
DCOM- 20120206
LR  - 20211020
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 141
IP  - 6
DP  - 2011 Dec
TI  - Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of 
      mice.
PG  - 2188-2199.e6
LID - 10.1053/j.gastro.2011.08.005 [doi]
AB  - BACKGROUND & AIMS: As life expectancy increases, there are greater numbers of 
      patients with liver diseases who require surgery or transplantation. Livers of 
      older patients have significantly less reparative capacity following ischemia and 
      reperfusion (I/R) injury, which occurs during these operations. There are no 
      strategies to reduce the age-dependent I/R injury. We investigated the role of 
      autophagy in the age dependence of sensitivity to I/R injury. METHODS: 
      Hepatocytes and livers from 3- and 26-month-old mice were subjected to in vitro 
      and in vivo I/R, respectively. We analyzed changes in autophagy-related proteins 
      (Atg). Mitochondrial dysfunction was visualized using confocal and intravital 
      multi-photon microscopy of isolated hepatocytes and livers from anesthetized 
      mice, respectively. RESULTS: Immunoblot, autophagic flux, genetic, and imaging 
      analyses all associated the increase in sensitivity to I/R injury with age with 
      decreased autophagy and subsequent mitochondrial dysfunction due to 
      calpain-mediated loss of Atg4B. Overexpression of either Atg4B or Beclin-1 
      recovered Atg4B, increased autophagy, blocked the onset of the mitochondrial 
      permeability transition, and suppressed cell death after I/R in old hepatocytes. 
      Coimmunoprecipitation analysis of hepatocytes and Atg3-knockout cells showed an 
      interaction between Beclin-1 and Atg3, a protein required for autophagosome 
      formation. Intravital multi-photon imaging revealed that overexpression of 
      Beclin-1 or Atg4B attenuated autophagic defects and mitochondrial dysfunction in 
      livers of older mice after I/R. CONCLUSIONS: Loss of Atg4B in livers of old mice 
      increases their sensitivity to I/R injury. Increasing autophagy might ameliorate 
      liver damage and restore mitochondrial function after I/R.
CI  - Copyright (c) 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Wang, Jin-Hee
AU  - Wang JH
AD  - Department of Surgery, Division of Biology of Aging, University of Florida, 
      Gainesville, Florida, USA.
FAU - Ahn, In-Sook
AU  - Ahn IS
FAU - Fischer, Trevan D
AU  - Fischer TD
FAU - Byeon, Jae-Il
AU  - Byeon JI
FAU - Dunn, William A Jr
AU  - Dunn WA Jr
FAU - Behrns, Kevin E
AU  - Behrns KE
FAU - Leeuwenburgh, Christiaan
AU  - Leeuwenburgh C
FAU - Kim, Jae-Sung
AU  - Kim JS
LA  - eng
GR  - R01 DK079879-02/DK/NIDDK NIH HHS/United States
GR  - R01 DK079879-04/DK/NIDDK NIH HHS/United States
GR  - R01 AG017994/AG/NIA NIH HHS/United States
GR  - 1P30 AG028740/AG/NIA NIH HHS/United States
GR  - P30 AG028740/AG/NIA NIH HHS/United States
GR  - R01 DK079879-01A1/DK/NIDDK NIH HHS/United States
GR  - T32 CA106493/CA/NCI NIH HHS/United States
GR  - R01 DK079879-03/DK/NIDDK NIH HHS/United States
GR  - AG 17994/AG/NIA NIH HHS/United States
GR  - AG 21042/AG/NIA NIH HHS/United States
GR  - R01 DK079879/DK/NIDDK NIH HHS/United States
GR  - R01 AG021042/AG/NIA NIH HHS/United States
GR  - DK079879/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110818
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Autophagy-Related Proteins)
RN  - 0 (Beclin-1)
RN  - 0 (Becn1 protein, mouse)
RN  - EC 3.4.22.- (Atg4b protein, mouse)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
SB  - IM
MH  - Age Factors
MH  - Animals
MH  - Apoptosis Regulatory Proteins/*metabolism
MH  - Autophagy/*physiology
MH  - Autophagy-Related Proteins
MH  - Beclin-1
MH  - Cysteine Endopeptidases/*metabolism
MH  - Hepatocytes/pathology
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Liver Diseases/metabolism/*prevention & control
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microscopy, Confocal
MH  - Microscopy, Fluorescence, Multiphoton
MH  - Reperfusion Injury/metabolism/*prevention & control
PMC - PMC3221865
MID - NIHMS320706
EDAT- 2011/08/23 06:00
MHDA- 2012/02/07 06:00
PMCR- 2012/12/01
CRDT- 2011/08/23 06:00
PHST- 2010/12/22 00:00 [received]
PHST- 2011/07/31 00:00 [revised]
PHST- 2011/08/08 00:00 [accepted]
PHST- 2011/08/23 06:00 [entrez]
PHST- 2011/08/23 06:00 [pubmed]
PHST- 2012/02/07 06:00 [medline]
PHST- 2012/12/01 00:00 [pmc-release]
AID - S0016-5085(11)01153-X [pii]
AID - 10.1053/j.gastro.2011.08.005 [doi]
PST - ppublish
SO  - Gastroenterology. 2011 Dec;141(6):2188-2199.e6. doi: 
      10.1053/j.gastro.2011.08.005. Epub 2011 Aug 18.