Journal
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
Volume 36, Issue 9, Pages 1578-1586Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1530-0277.2012.01751.x
Keywords
Binge Ethanol Exposure; Liver Steatosis and Injury; Histone Deacetylases
Categories
Funding
- NIH [R01 AAO14371, P01 AA017103, R01 AA0015970, R01 AA018016, R01 DK071765, R37 AA010762, R01 AA018869, P30 AA019360, RC2AA019385]
- Department of Veterans Affairs
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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; 4.5g/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 +/- 3.48mg/g liver, p<0.05) and elevated plasma ALT activity (51.98 +/- 6.91 vs. 20.8 +/- 0.62U/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 beta-oxidation.
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