Nuclear effects of ethanol-induced proteasome inhibition in liver cells

Abstract

Alcohol ingestion causes alteration in several cellular mechanisms, and leads to inflammation, apoptosis, immunological response defects, and fibrosis. These phenomena are associated with significant changes in the epigenetic mechanisms, and subsequently, to liver cell memory. The ubiquitin-proteasome pathway is one of the vital pathways in the cell that becomes dysfunctional as a result of chronic ethanol consumption. Inhibition of the proteasome activity in the nucleus causes changes in the turnover of transcriptional factors, histone modifying enzymes, and therefore, affects epigenetic mechanisms. Alcohol consumption has been associated with an increase in histone acetylation and a decrease in histone methylation, which leads to gene expression changes. DNA and histone modifications that result from ethanol-induced proteasome inhibition are key players in regulating gene expression, especially genes involved in the cell cycle, immunological responses, and metabolism of ethanol. The present review highlights the consequences of ethanol-induced proteasome inhibition in the nucleus of liver cells that are chronically exposed to ethanol.

Figure 1

Illustration of methionine metabolism enzymes system and the effects of proteasome inhibition in the remethylation pathway. 1-BHMT: Betaine homocysteine Methyltransferase; 2-MS: Methionine synthase; 3-Cbs: Cystathionine beta-Synthase; 4-Ahcy: S’-adenosylhomocysteine transferase; 5-Mat1a: Methionine adenosyltransferase.