PMID- 23905631
OWN - NLM
STAT- MEDLINE
DCOM- 20140702
LR  - 20211021
IS  - 1530-0277 (Electronic)
IS  - 0145-6008 (Print)
IS  - 0145-6008 (Linking)
VI  - 37
IP  - 11
DP  - 2013 Nov
TI  - Binge ethanol-induced HDAC3 down-regulates Cpt1alpha expression leading to hepatic 
      steatosis and injury.
PG  - 1920-9
LID - 10.1111/acer.12172 [doi]
AB  - BACKGROUND: Recently, we have demonstrated that acute alcohol exposure due to 
      binge drinking leads to hepatic steatosis with the deregulation of hepatic 
      histone deacetylase (HDAC) expression. Various class I, II, and IV HDACs were 
      down-regulated, whereas expression of HDAC3 was solely up-regulated. Hence, in 
      the present work, we specifically examined the mechanistic role of HDAC3 in the 
      development of hepatic steatosis occurring in response to binge alcohol 
      administration. METHODS: C57BL/6 mice were gavaged 3 times with ethanol (EtOH) at 
      a dose of 4.5 g/kg. HDAC inhibitor, Trichostatin A (TSA) was simultaneously 
      injected intraperitoneally at a dose of 1 mg/kg. Hepatic steatosis, injury, 
      expression of HDAC3 and carnitine palmitoyltransferase 1alpha (CPT1alpha) were evaluated. 
      HDAC3 and histone H3 acetylation levels at the Cpt1alpha promoter were analyzed by 
      chromatin immunoprecipitation (ChIP). RESULTS: The binge EtOH-mediated increase 
      in HDAC3 was prevented by simultaneous administration of HDAC inhibitor, TSA, 
      which markedly attenuated hepatic steatosis and injury. Importantly, HDAC3 
      inhibition was able to normalize the down-regulation of Cpt1alpha expression. Causal 
      role of HDAC3 in the transcriptional repression of Cpt1alpha was demonstrated by 
      increased HDAC3 binding at the thyroid receptor element site in the Cpt1alpha distal 
      promoter region. Further, a resultant decrease in the transcriptionally 
      permissive histone H3 lysine 9 acetylation in the proximal promoter region near 
      the transcriptional start site was observed. Notably, TSA treatment reduced HDAC3 
      binding and increased H3K9 acetylation at Cpt1alpha promoter leading to increased 
      Cpt1alpha expression. These molecular events resulted in attenuation of binge 
      alcohol-induced hepatic steatosis. CONCLUSIONS: These findings provide insights 
      into potential epigenetic mechanisms underlying transcriptional regulation of 
      Cpt1alpha in the hepatic steatosis occurring in response to binge EtOH 
      administration.
CI  - Copyright (c) 2013 by the Research Society on Alcoholism.
FAU - Kirpich, Irina
AU  - Kirpich I
AD  - Division of Gastroenterology, Hepatology, and Nutrition , Department of Medicine, 
      University of Louisville School of Medicine, Louisville, Kentucky; University of 
      Louisville Alcohol Research Center , Louisville, Kentucky.
FAU - Zhang, Jingwen
AU  - Zhang J
FAU - Gobejishvili, Leila
AU  - Gobejishvili L
FAU - Kharebava, Giorgi
AU  - Kharebava G
FAU - Barker, David
AU  - Barker D
FAU - Ghare, Smita
AU  - Ghare S
FAU - Joshi-Barve, Swati
AU  - Joshi-Barve S
FAU - McClain, Craig J
AU  - McClain CJ
FAU - Barve, Shirish
AU  - Barve S
LA  - eng
GR  - U01 AA021901/AA/NIAAA NIH HHS/United States
GR  - K01 ES017105/ES/NIEHS NIH HHS/United States
GR  - R21 AA020849-01A1/AA/NIAAA NIH HHS/United States
GR  - P01 AA017103/AA/NIAAA NIH HHS/United States
GR  - R01 AA018869/AA/NIAAA NIH HHS/United States
GR  - RC2AA019385/AA/NIAAA NIH HHS/United States
GR  - T32 ES011564/ES/NIEHS NIH HHS/United States
GR  - P30 AA019360/AA/NIAAA NIH HHS/United States
GR  - R01 AA015970/AA/NIAAA NIH HHS/United States
GR  - R01 AAO14371/PHS HHS/United States
GR  - R01 AA014371/AA/NIAAA NIH HHS/United States
GR  - R01 AA0015970/AA/NIAAA NIH HHS/United States
GR  - R37 AA010762/AA/NIAAA NIH HHS/United States
GR  - R01 AA018016/AA/NIAAA NIH HHS/United States
GR  - R21 AA020849/AA/NIAAA NIH HHS/United States
GR  - R01 DK071765/DK/NIDDK NIH HHS/United States
GR  - RC2 AA019385/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20130726
PL  - England
TA  - Alcohol Clin Exp Res
JT  - Alcoholism, clinical and experimental research
JID - 7707242
RN  - 0 (Central Nervous System Depressants)
RN  - 3K9958V90M (Ethanol)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - EC 3.5.1.98 (histone deacetylase 3)
SB  - IM
MH  - Animals
MH  - Binge Drinking/genetics/*metabolism
MH  - Carnitine O-Palmitoyltransferase/*antagonists & inhibitors/genetics/*metabolism
MH  - Central Nervous System Depressants/adverse effects
MH  - Chemical and Drug Induced Liver Injury/*etiology/metabolism
MH  - Down-Regulation/genetics
MH  - Ethanol/adverse effects
MH  - Fatty Liver/*etiology/metabolism
MH  - Gene Expression Regulation, Enzymologic
MH  - Histone Deacetylases/genetics/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
PMC - PMC3975907
MID - NIHMS548010
OTO - NOTNLM
OT  - Binge Alcohol Exposure
OT  - CPT1alpha
OT  - HDAC3
OT  - Liver Steatosis
EDAT- 2013/08/03 06:00
MHDA- 2014/07/06 06:00
PMCR- 2014/04/04
CRDT- 2013/08/03 06:00
PHST- 2012/06/26 00:00 [received]
PHST- 2013/04/01 00:00 [accepted]
PHST- 2013/08/03 06:00 [entrez]
PHST- 2013/08/03 06:00 [pubmed]
PHST- 2014/07/06 06:00 [medline]
PHST- 2014/04/04 00:00 [pmc-release]
AID - 10.1111/acer.12172 [doi]
PST - ppublish
SO  - Alcohol Clin Exp Res. 2013 Nov;37(11):1920-9. doi: 10.1111/acer.12172. Epub 2013 
      Jul 26.