title: Binge alcohol-induced microvesicular liver steatosis and injury are associated with down-regulation of hepatic Hdac 1, 7, 9, 10, 11 and up-regulation of Hdac 3.
abstract: BACKGROUND
  Binge, as well as chronic, alcohol consumption affects global histone acetylation leading to changes in gene expression. It is becoming increasingly evident that these histone-associated epigenetic modifications play an important role in the development of alcohol-mediated hepatic injury.
  
  
  METHODS
  C57BL/6 mice were gavaged 3 times (12-hour intervals) with ethanol (EtOH; 4.5 g/kg). Hepatic histone deacetylase (Hdac) mRNAs were assessed by qRT-PCR. Total HDAC activity was estimated by a colorimetric HDAC activity/inhibition assay. Histone acetylation levels were evaluated by Western blot. Liver steatosis and injury were evaluated by histopathology, plasma aminotransferase (ALT) activity, and liver triglyceride accumulation. Expression of fatty acid synthase (Fas) and carnitine palmitoyl transferase 1a (Cpt1a) was also examined. HDAC 9 association with Fas promoter was analyzed.
  
  
  RESULTS
  Binge alcohol exposure resulted in alterations of hepatic Hdac mRNA levels. Down-regulation of HDAC Class I (Hdac 1), Class II (Hdac 7, 9, 10), and Class IV (Hdac 11) and up-regulation of HDAC Class I (Hdac 3) gene expression were observed. Correspondent to the decrease in HDAC activity, an increase in hepatic histone acetylation was observed. These molecular events were associated with microvesicular hepatic steatosis and injury characterized by increased hepatic triglycerides (48.02 ± 3.83 vs. 19.90 ± 3.48 mg/g liver, p < 0.05) and elevated plasma ALT activity (51.98 ± 6.91 vs. 20.8 ± 0.62 U/l, p < 0.05). Hepatic steatosis was associated with an increase in FAS and a decrease in CPT1a mRNA and protein expression. Fas promoter analysis revealed that binge EtOH treatment decreased HDAC 9 occupancy at the Fas promoter resulting in its transcriptional activation.
  
  
  CONCLUSIONS
  Deregulation of hepatic Hdac expression likely plays a major role in the binge alcohol-induced hepatic steatosis and liver injury by affecting lipogenesis and fatty acid β-oxidation.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Kentucky, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Kirpich
authors.forename: Smita
authors.initials: S
authors.lastname: Ghare
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Leila
authors.initials: L
authors.lastname: Gobejishvili
authors.forename: Giorgi
authors.initials: G
authors.lastname: Kharebava
authors.forename: Swati Joshi
authors.initials: SJ
authors.lastname: Barve
authors.forename: David
authors.initials: D
authors.lastname: Barker
authors.forename: Akshata
authors.initials: A
authors.lastname: Moghe
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.forename: Shirish
authors.initials: S
authors.lastname: Barve
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002492:Central Nervous System Depressants / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D000431:Ethanol / Q000633:toxicity*; D005235:Fatty Liver, Alcoholic / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D006657:Histones / Q000302:isolation & purification / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015854:Up-Regulation
chemical_list: D002492:Central Nervous System Depressants; D006657:Histones; D007527:Isoenzymes; D000431:Ethanol; D006655:Histone Deacetylases