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Biomolecules 2015, 5(4), 3280-3294; doi:10.3390/biom5043280

In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses

1
Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MI 65212, USA
2
Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
3
Department of Internal Medicine, School of Medicine, University of Missouri, Columbia, MI 65212, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Natalia Osna and Kusum Kharbanda
Received: 13 August 2015 / Accepted: 17 November 2015 / Published: 20 November 2015
(This article belongs to the Collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
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Abstract

Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease. View Full-Text
Keywords: acute ethanol; acute on chronic ethanol; alcoholic liver disease; binge alcohol; chronic-binge alcohol; epigenetics; histone modifications; mouse liver acute ethanol; acute on chronic ethanol; alcoholic liver disease; binge alcohol; chronic-binge alcohol; epigenetics; histone modifications; mouse liver
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Shukla, S.D.; Aroor, A.R.; Restrepo, R.; Kharbanda, K.K.; Ibdah, J.A. In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses. Biomolecules 2015, 5, 3280-3294.

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