PMID- 20578144
OWN - NLM
STAT- MEDLINE
DCOM- 20100719
LR  - 20240502
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 52
IP  - 1
DP  - 2010 Jul
TI  - Macroautophagy and chaperone-mediated autophagy are required for hepatocyte 
      resistance to oxidant stress.
PG  - 266-77
LID - 10.1002/hep.23645 [doi]
AB  - The function of the lysosomal degradative pathway of autophagy in cellular injury 
      is unclear, because findings in nonhepatic cells have implicated autophagy as 
      both a mediator of cell death and as a survival response. Autophagic function is 
      impaired in steatotic and aged hepatocytes, suggesting that in these settings 
      hepatocellular injury may be altered by the decrease in autophagy. To delineate 
      the specific function of autophagy in the hepatocyte injury response, the effects 
      of menadione-induced oxidative stress were examined in the RALA255-10G rat 
      hepatocyte line when macroautophagy was inhibited by a short hairpin RNA 
      (shRNA)-mediated knockdown of the autophagy gene atg5. Loss of macroautophagy 
      sensitized cells to apoptotic and necrotic death from normally nontoxic 
      concentrations of menadione. Loss of macroautophagy led to overactivation of the 
      c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway that induced cell death. 
      Death occurred from activation of the mitochondrial death pathway with cellular 
      adenosine triphosphate (ATP) depletion, mitochondrial cytochrome c release, and 
      caspase activation. Sensitization to death from menadione occurred despite 
      up-regulation of other forms of autophagy in compensation for the loss of 
      macroautophagy. Chaperone-mediated autophagy (CMA) also mediated resistance to 
      menadione. CMA inhibition sensitized cells to death from menadione through a 
      mechanism different from that of a loss of macroautophagy, because death occurred 
      in the absence of JNK/c-Jun overactivation or ATP depletion. CONCLUSION: 
      Hepatocyte resistance to injury from menadione-induced oxidative stress is 
      mediated by distinct functions of both macroautophagy and CMA, indicating that 
      impaired function of either form of autophagy may promote oxidant-induced liver 
      injury.
FAU - Wang, Yongjun
AU  - Wang Y
AD  - Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein 
      College of Medicine, Bronx, NY 10461, USA.
FAU - Singh, Rajat
AU  - Singh R
FAU - Xiang, Youqing
AU  - Xiang Y
FAU - Czaja, Mark J
AU  - Czaja MJ
LA  - eng
GR  - R01 DK044234/DK/NIDDK NIH HHS/United States
GR  - AG031782/AG/NIA NIH HHS/United States
GR  - R56 DK044234/DK/NIDDK NIH HHS/United States
GR  - P01 AG031782-01A18478/AG/NIA NIH HHS/United States
GR  - DK044234/DK/NIDDK NIH HHS/United States
GR  - R01 DK061498/DK/NIDDK NIH HHS/United States
GR  - P01 AG031782/AG/NIA NIH HHS/United States
GR  - R01 DK044234-18/DK/NIDDK NIH HHS/United States
GR  - DK061498/DK/NIDDK NIH HHS/United States
GR  - R01 DK061498-10/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Atg5 protein, rat)
RN  - 0 (Autophagy-Related Protein 5)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Oxidants)
RN  - 0 (Proteins)
RN  - 2UMI9U37CP (Oleic Acid)
RN  - 723JX6CXY5 (Vitamin K 3)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Animals
MH  - *Autophagy
MH  - Autophagy-Related Protein 5
MH  - Caspases/metabolism
MH  - Cell Line
MH  - Gene Knockdown Techniques
MH  - Hepatocytes/drug effects/*physiology
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Liver/cytology/injuries/*physiology
MH  - *Liver Regeneration
MH  - MAP Kinase Kinase 4/metabolism
MH  - Molecular Chaperones/genetics/*metabolism
MH  - Oleic Acid/pharmacology
MH  - Oxidants/toxicity
MH  - *Oxidative Stress
MH  - Proteins/genetics
MH  - Rats
MH  - Vitamin K 3/toxicity
PMC - PMC2924621
MID - NIHMS221008
EDAT- 2010/06/26 06:00
MHDA- 2010/07/20 06:00
PMCR- 2011/07/01
CRDT- 2010/06/26 06:00
PHST- 2010/06/26 06:00 [entrez]
PHST- 2010/06/26 06:00 [pubmed]
PHST- 2010/07/20 06:00 [medline]
PHST- 2011/07/01 00:00 [pmc-release]
AID - 10.1002/hep.23645 [doi]
PST - ppublish
SO  - Hepatology. 2010 Jul;52(1):266-77. doi: 10.1002/hep.23645.