Premium
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
Author(s) -
Kirpich Irina,
Ghare Smita,
Zhang Jingwen,
Gobejishvili Leila,
Kharebava Giorgi,
Barve Swati Joshi,
Barker David,
Moghe Akshata,
McClain Craig J.,
Barve Shirish
Publication year - 2012
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2012.01751.x
Subject(s) - steatosis , histone deacetylase , liver injury , hdac1 , endocrinology , acetylation , medicine , histone , fatty liver , chemistry , biology , microbiology and biotechnology , biochemistry , gene , disease
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 C 57 BL /6 mice were gavaged 3 times (12‐hour intervals) with ethanol ( EtOH ; 4.5 g/kg). Hepatic histone deacetylase ( Hdac ) m RNA s were assessed by q RT ‐ 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 m RNA levels. Down‐regulation of HDAC C lass 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 m RNA 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.