Proteasome inhibition affects epigenetic mechanisms
Alcohol consumption causes alteration in several cellular mechanisms, and leads to inflammation, apoptosis, immunoresponse defect, and fibrosis. These phenomena are associated to significant changes in the epigenetic mechanisms, and, subsequently, to the liver cell memory. Although inhibition of proteasome function has been widely reported in models of alcoholic liver disease (ALD), why proteasome dysfunction may enhance hepatotoxicity is not well defined. In addition, there is no evidence of the effect of ethanol feeding on the activity of nuclear proteasome and the consequences of proteasome inhibition in epigenetic mechanisms and DNA repair. A research team led by Dr. Fawzia Bardag-Gorce, from United States examined the effects of ethanol-induced proteasome inhibition, and the effects of proteasome inhibition in the regulation of epigenetic mechanisms.Their study will be published on February 14, 2009 in the World Journal of Gastroenterology.
In their study, rats were fed ethanol for one moth 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.
They found that 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 (SAMe), and, in particular, a significant decrease in the betainehomocysteine methyltransferase (BHMT) enzyme.
In conclusion, proteasome inhibition plays a critical role in regulating the gene expression of key enzymes in the remethylation pathway, such as betainehomocysteine methyltransferase (BHMT), and links to liver injury in alcoholic iver disease.