Article first published online: 1 MAR 2012
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 55, Issue 4, pages 1260–1270, April 2012
How to Cite
Shepard, B. D., Tuma, D. J. and Tuma, P. L. (2012), Lysine acetylation induced by chronic ethanol consumption impairs dynamin-mediated clathrin-coated vesicle release. Hepatology, 55: 1260–1270. doi: 10.1002/hep.24785
Potential conflict of interest: Nothing to report.
This work was supported by the National Institute of Alcohol Abuse and Alcoholism grants R01 AA17626 and R21 AA15683 (awarded to P.L.T.).
- Issue published online: 27 MAR 2012
- Article first published online: 1 MAR 2012
- Accepted manuscript online: 16 NOV 2011 09:46AM EST
- Manuscript Accepted: 19 OCT 2011
- Manuscript Received: 18 AUG 2011
The liver is the major site of ethanol metabolism and thus sustains the most injury from chronic alcohol consumption. Ethanol metabolism by the hepatocyte leads to the generation of reactive metabolites and oxygen radicals that can readily adduct DNA, lipids, and proteins. More recently, it has become apparent that ethanol consumption also leads to increased post-translational modifications of the natural repertoire, including lysine hyperacetylation. Previously, we determined that alcohol consumption selectively impairs clathrin-mediated internalization in polarized hepatocytes. However, neither the step at which the block occurs nor the mechanism responsible for the defect have been identified. To identify the specific step at which clathrin-mediated internalization is impaired, we examined the distributions, levels, and assembly of selected components of the clathrin machinery in control and ethanol-treated cells. To determine whether the impairment is caused by ethanol-induced lysine acetylation, we also examined the same coat components in cells treated with trichostatin A (TSA), a deacetylase inhibitor that leads to protein hyperacetylation in the absence of ethanol. Conclusion: We determined that both ethanol and TSA impair internalization at a late stage before vesicle fission. We further determined that this defect is likely the result of decreased dynamin recruitment to the necks of clathrin-coated invaginations resulting in impaired vesicle budding. These results also raise the exciting possibility that agents that promote lysine deacetylation may be effective therapeutics for the treatment of alcoholic liver disease. (Hepatology 2012)