Brief Article
Copyright ©2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Feb 14, 2009; 15(6): 705-712
Published online Feb 14, 2009. doi: 10.3748/wjg.15.705
Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically
Joan Oliva, Jennifer Dedes, Jun Li, Samuel W French, Fawzia Bardag-Gorce
Joan Oliva, Jennifer Dedes, Jun Li, Samuel W French, Fawzia Bardag-Gorce, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, United States
Author contributions: Oliva J, Dedes J, and Li J performed the real-time PCR experiments, the microarray analysis, and the animal care and treatments, respectively; French SW provided the resources and facilities; Bardag-Gorce F designed the study, performed the nuclei and histone isolation, proteasome activity measurement, Western blot analysis, and wrote the manuscript.
Correspondence to: Fawzia Bardag-Gorce, PhD, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson St. Torrance, CA 90502, United States. fgorce@labiomed.org
Telephone: +1-310-2221846
Fax: +1-310-2223614
Received: November 7, 2008
Revised: January 5, 2009
Accepted: January 12, 2009
Published online: February 14, 2009
Abstract

AIM: To examine the effects of ethanol-induced proteasome inhibition, and the effects of proteasome inhibition in the regulation of epigenetic mechanisms.

METHODS: Rats were fed ethanol for 1 mo using the Tsukamoto-French model and were compared to rats given the proteasome inhibitor PS-341 (Bortezomib, Velcade™) by intraperitoneal injection. Microarray analysis and real time PCR were performed and proteasome activity assays and Western blot analysis were performed using isolated nuclei.

RESULTS: Chronic ethanol feeding caused a significant inhibition of the ubiquitin proteasome pathway in the nucleus, which led to changes in the turnover of transcriptional factors, histone-modifying enzymes, and, therefore, affected epigenetic mechanisms. Chronic ethanol feeding was related to an increase in histone acetylation, and it is hypothesized that the proteasome proteolytic activity regulated histone modifications by controlling the stability of histone modifying enzymes, and, therefore, regulated the chromatin structure, allowing easy access to chromatin by RNA polymerase, and, thus, proper gene expression. Proteasome inhibition by PS-341 increased histone acetylation similar to chronic ethanol feeding. In addition, proteasome inhibition caused dramatic changes in hepatic remethylation reactions as there was a significant decrease in the enzymes responsible for the regeneration of S-adenosylmethionine, and, in particular, a significant decrease in the betaine-homocysteine methyltransferase enzyme. This suggested that hypomethylation was associated with proteasome inhibition, as indicated by the decrease in histone methylation.

CONCLUSION: The role of proteasome inhibition in regulating epigenetic mechanisms, and its link to liver injury in alcoholic liver disease, is thus a promising approach to study liver injury due to chronic ethanol consumption.

Keywords: Alcohol liver injury; Betaine; Epigenetic mechanisms; Homocysteine methyltransferase; Proteasome inhibition; S-adenosylmethionine