Implication of altered proteasome function in alcoholic liver injury

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-kappaB 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.

Ubiquitin-Proteasome Pathway, Alcohol and Hepatitis C Infection (HCV)

“…These changes in association with the 26S proteasome and proteasomeinteracting proteins certainly impair proteasome function and subsequent degradation of ubiquitylated host and viral proteins, which finally explains why ethanol provides negative impact on UPS-regulated HCV propagation, activation of protective signaling pathways and induction of immune response. In fact, we observed defective presentation of foreign peptides-MHC class I complexes in HCV+ hepatocytes isolated from ethanol-fed reduced [13], which corroborated the in vitro effects of ethanol on generation of antigenic peptides by immunoproteasome [12].…”

“…Ethanol metabolism suppresses proteasome activity and IFN signaling necessary for proteasome activation [12]. Furthermore, in HCV protein-expressing liver cells, ethanol metabolism reverses up-regulating effects of core protein on proteasome and down-regulated the proteasome activity due to induction of higher level of oxidative stress by the combination of mitochondria-associated HCV core and ethanol metabolism [8].…”

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

“…In physiological conditions only a small amount of ethanol, about 10%, is oxidized to acetaldehyde by CYP2E1 [24] but during chronic alcohol abuse there is induction of the microsomal system [25,26] , and an increase in CYP2E1 protein expression. The increase in CYP2E1 during chronic ethanol intake is correlated with a decrease in proteasomal degradation, which increases CYP2E1 protein stability [27,28] . Multiple factors such as insulin, acetone, leptin, adiponectin and cytokines regulate CYP2E1 mRNA and protein expression [29] and CYP2E1 expression levels depend on nutritional and metabolic conditions.…”

Essential Amino Acid Supplementation Decreases Liver Damage Induced by Chronic Ethanol Consumption in Rats

“…EtOH plays a dual role in regulating liver cell death by depleting adenosine triphosphate (ATP) production, facilitating hepatocyte necrosis, and promoting the accumulation of pro-apoptotic factors in mitochondria, mainly due to the suppression of proteasome activity inside cells (6). EtOH exposure affects proteasome activity in two different ways: low oxidative stress up-regulates proteasome function, while high oxidative stress suppresses it, lowers cell defenses, and enhances cell death (6).…”

“…EtOH exposure affects proteasome activity in two different ways: low oxidative stress up-regulates proteasome function, while high oxidative stress suppresses it, lowers cell defenses, and enhances cell death (6).…”