Implication of altered proteasome function in alcoholic liver injury

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28 Scopus citations

Abstract

The proteasome is a major protein-degrading enzyme, which catalyzes degradation of oxidized and aged proteins, signal transduction factors and cleaves peptides for antigen presentation. Proteasome exists in the equilibrium of 26S and 20S particles. Proteasome function is altered by ethanol metabolism, depending on oxidative stress levels: low oxidative stress induces proteasome activity, while high oxidative stress reduces it. The proposed mechanisms for modulation of proteasome activity are related to oxidative modification of proteasomal proteins with primary and secondary products derived from ethanol oxidation. Decreased proteolysis by the proteasome results in the accumulation of insoluble protein aggregates, which cannot be degraded by proteasome and which further inhibit proteasome function. Mallory bodies, a common signature of alcoholic liver diseases, are formed by liver cells, when proteasome is unable to remove cytokeratins. Proteasome inhibition by ethanol also promotes the accumulation of pro-apoptotic factors in mitochondria of ethanol-metabolizing liver cells that are normally degraded by proteasome. In addition, decreased proteasome function also induces accumulation of the negative regulators of cytokine signaling (I-κB and SOCS), thereby blocking cytokine signal transduction. Finally, ethanol-elicited blockade of interferon type 1 and 2 signaling and decreased proteasome function impairs generation of peptides for MHC class I-restricted antigen presentation.

Original languageEnglish (US)
Pages (from-to)4931-4937
Number of pages7
JournalWorld Journal of Gastroenterology
Volume13
Issue number37
DOIs
StatePublished - Oct 7 2007

Keywords

  • 20S proteasome
  • 26S proteasome
  • Apoptosis
  • CYP2E1
  • Liver
  • PA28

ASJC Scopus subject areas

  • Gastroenterology

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