PMID- 22142844
OWN - NLM
STAT- MEDLINE
DCOM- 20120322
LR  - 20220410
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 417
IP  - 1
DP  - 2012 Jan 6
TI  - Proteasome activity and autophagosome content in liver are reciprocally regulated 
      by ethanol treatment.
PG  - 262-7
LID - 10.1016/j.bbrc.2011.11.097 [doi]
AB  - The proteasome and autophagy are two major intracellular protein degradation 
      pathways and the regulation of each by ethanol metabolism affects cellular 
      integrity. Using acute and chronic ethanol feeding to mice in vivo, and 
      precision-cut rat liver slices (PCLS) ex vivo, we examined whether ethanol 
      treatment altered these proteolytic pathways. In acute studies, we gave C57Bl/6 
      mice either ethanol or phosphate-buffered saline (PBS) by gastric intubation and 
      sacrificed them 12h later. PCLS were exposed to 0 or 50mM ethanol for 12 and 24h 
      with or without 4-methylpyrazole (4MP). In chronic studies we pair-fed control 
      and ethanol liquid diets for 4-6 weeks to transgenic mice, expressing the green 
      fluorescent protein (GFP) fused to the autophagic marker, microtubule associated 
      protein-1 light chain 3 (LC3). Acute ethanol administration elevated 
      autophagosomes (AVs), as judged by a 1.5-fold increase in LC3II content over 
      PBS-gavaged control mice. Hepatic proteasome activity was unaffected by this 
      treatment. Compared with controls, ethanol exposure for 12 and 24h to PCLS 
      inhibited proteasome activity by 1.5- to 3-fold and simultaneously enhanced AVs 
      by 2- to 5-fold. The decrease in proteasome activity and the rise in AVs both 
      depended on ethanol oxidation as its inhibition by 4-methylpyrazole (4MP) blocked 
      both proteasome inhibition and AV induction. Hepatocytes from mice chronically 
      consuming ethanol exhibited a 1.6-fold decline in proteasome activity, and a 
      4-fold rise in GFP-LC3 puncta compared with pair-fed control mice. When we 
      exposed hepatocytes from these animals to MG262, a proteasome inhibitor, LC3II 
      puncta per cell further increased 2- to 5-fold over untreated cells. CONCLUSION: 
      Our findings demonstrate that ethanol metabolism generates oxidants, the levels 
      of which differentially influence the activities of the proteasome and autophagy.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Thomes, Paul G
AU  - Thomes PG
AD  - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 
      68105, United States. pthomes@unmc.edu
FAU - Trambly, Casey S
AU  - Trambly CS
FAU - Thiele, Geoffrey M
AU  - Thiele GM
FAU - Duryee, Michael J
AU  - Duryee MJ
FAU - Fox, Howard S
AU  - Fox HS
FAU - Haorah, James
AU  - Haorah J
FAU - Donohue, Terrence M Jr
AU  - Donohue TM Jr
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111128
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 3K9958V90M (Ethanol)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Animals
MH  - Autophagy
MH  - Ethanol/metabolism/*pharmacology
MH  - Hepatocytes/drug effects/enzymology/ultrastructure
MH  - Liver/*drug effects/enzymology/ultrastructure
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phagosomes/*drug effects
MH  - Proteasome Endopeptidase Complex/*drug effects
MH  - Rats
EDAT- 2011/12/07 06:00
MHDA- 2012/03/23 06:00
CRDT- 2011/12/07 06:00
PHST- 2011/11/03 00:00 [received]
PHST- 2011/11/18 00:00 [accepted]
PHST- 2011/12/07 06:00 [entrez]
PHST- 2011/12/07 06:00 [pubmed]
PHST- 2012/03/23 06:00 [medline]
AID - S0006-291X(11)02118-8 [pii]
AID - 10.1016/j.bbrc.2011.11.097 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2012 Jan 6;417(1):262-7. doi: 
      10.1016/j.bbrc.2011.11.097. Epub 2011 Nov 28.