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

Shivendra Shukla,Ricardo Restrepo,Jamal Ibdah,Kusum Kharbanda,Annayya Aroor

doi:10.3390/biom5043280

Shivendra Shukla, Ricardo Restrepo + Show 3 more

Open Access

https://doi.org/10.3390/biom5043280

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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.

Highlights

Binge drinking associated with chronic alcohol consumption is a major public health concern in the United States and around the globe [1,2,3,4]
Chronic ethanol increased CYP2E1 protein levels only modestly (Figure 1D) while binge ethanol generated a much higher CYP2E1 levels compared with controls
We explored for the first time, dysregulated methionine metabolism, adenosine accumulation and epigenetic histone modifications and enzymes related to histone modifications as determinates of augmentation of liver injury after binge ethanol administration in chronically ethanol treated mice

Summary

Introduction

Binge drinking associated with chronic alcohol consumption is a major public health concern in the United States and around the globe [1,2,3,4]. Increase in adenosine levels, and dysregulated methionine metabolism are considered to be contributing factors for the progression of liver injury [10,11,12,13] and the role of epigenetic mechanisms mediating progression of alcoholic liver injury is increasingly being recognized [14,15]. Among the epigenetic factors regulating gene expression, differential pattern of epigenetic histone modifications determine activation of different sets of genes. Epigenetic histone modifications are implicated in liver injury by binge [14,15,18,19,20,21,22,23,24], chronic alcohol consumption [25,26,27,28], and chronic alcohol administration followed by binge [29,30]

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