Implication of altered proteasome function in alcoholic liver injury

Liver Study Unit, Research Service (151), VA Medical Center, 4101 Woolworth Ave, Omaha, NE 68105, USA.
World Journal of Gastroenterology (Impact Factor: 2.37). 11/2007; 13(37):4931-7.
Source: PubMed


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.

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    • "Apoptosis and necrosis induced or exacerbated by alcohol metabolism have been studied in liver [31] [32], pancreas [33] [34], heart, brain [35] [36], developing brain [37], and skeletal muscle [38]. The important mechanisms that are thought to be involved in alcohol-induced liver injury include (1) oxidative stress and lipid peroxidation [39] [40]; (2) liver hypoxia [41] [42]; (3) endoplasmic reticulum (ER) stress and activation of mitogen activated protein kinases (MAPK) [43] [44]; and (4) inhibition of proteasome and lysosomal functions that causes hepatomegaly and Mallory inclusion bodies [45] [46] [47]. Recent evidence has also suggested that chronic alcohol consumption induces necroptosis in mouse livers, which is dependent on the receptor interacting protein 3 (RIP 3) [48]. "
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    ABSTRACT: Autophagy is a genetically programmed, evolutionarily conserved intracellular degradation pathway involved in the trafficking of long-lived proteins and cellular organelles to the lysosome for degradation to maintain cellular homeostasis. Alcohol consumption leads to injury in various tissues and organs including liver, pancreas, heart, brain, and muscle. Emerging evidence suggests that autophagy is involved in alcohol-induced tissue injury. Autophagy serves as a cellular protective mechanism against alcohol-induced tissue injury in most tissues but could be detrimental in heart and muscle. This review summarizes current knowledge about the role of autophagy in alcohol-induced injury in different tissues/organs and its potential molecular mechanisms as well as possible therapeutic targets based on modulation of autophagy.
    BioMed Research International 07/2014; 2014(1):498491. DOI:10.1155/2014/498491 · 3.17 Impact Factor
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    • "This process is ATP independent. As revealed from previous studies (Bardag-Gorce, 2009; Bardag-Gorce et al., 2006; Donohue et al., 2006; Osna and Donohue, 2007), proteasome activity in the liver is suppressed by EtOH metabolism. This suppression of proteasome function in hepatocytes and EtOH-metabolizing hepatoma cells results in decreased cleavage of antigenic peptides , causing a reduction in peptide processing and subsequent presentation of MHC class I–peptide complexes on the cell surface (Osna and Donohue, 2007; Osna et al., 2009). "
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    ABSTRACT: Data from several laboratories have shown that ethanol (EtOH) feeding impairs many essential methylation reactions that contribute to alcoholic liver disease (ALD). EtOH is also a comorbid factor in the severity of hepatitis C virus-induced liver injury. The presence of viral proteins further exacerbates the methylation defects to disrupt multiple pathways that promote the pathogenesis of liver disease. This review is a compilation of presentations that linked the methylation reaction defects with proteasome inhibition, decreased antigen presentation, and impaired interferon (IFN) signaling in the hepatocytes and dysregulated TNFα expression in macrophages. Two therapeutic modalities, betaine and S-adenosylmethionine, can correct methylation defects to attenuate many EtOH-induced liver changes, as well as improve IFN signaling pathways, thereby overcoming viral treatment resistance.
    Alcoholism Clinical and Experimental Research 05/2012; 37(1). DOI:10.1111/j.1530-0277.2012.01840.x · 3.21 Impact Factor
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    • "The amounts of 20S proteasome (a-subunits and constitutive b-subunits), IPR subunits, proteasome activator PA28a, and other PIPs were measured in the peak fractions by WB using either Odyssey Infrared Imaging System (LI-COR Biosciences, Lincoln, NE) or electrochemiluminescence-based WB (Bousquet-Dubouch et al., 2009; Osna et al., 2007). "
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    ABSTRACT: Previously, we reported that exposure of hepatitis C virus (HCV) core-expressing ethanol (EtOH)-metabolizing cells to EtOH significantly suppresses proteasome activity which exists as 26S (20S and 19S) and as an unassociated 20S particle. The replacement of the constitutive proteasomal subunits with immunoproteasome (IPR) favors antigen processing. Here, we examined the effects of EtOH consumption by HCV core transgenic mice on proteasome activity in hepatocytic lysates and in partially purified 26S proteasome and the impact of these changes on antigen presentation. HCV − and HCV + core transgenic mice were fed chow diet with or without 20% (v/v) EtOH in water for 4 weeks. Following the feeding regimen, hepatocytes were isolated and examined for chymotrypsin-like proteasome activity, oxidative stress, and the presentation of SIINFEKL–H2Kb complex. Additionally, the constitutive proteasome and IPR were purified for further analysis and identification of proteasome-interacting proteins (PIPs). EtOH significantly decreased proteasome activity in hepatocytes of HCV + mice, and this finding correlated with oxidative stress and dysregulated methylation reactions. In isolated 26S proteasome, EtOH suppressed proteasome activity equally in HCV + and HCV − mice. EtOH feeding caused proteasome instability and lowered the content of both constitutive and IPR subunits in the 20S proteasome. In addition, the level of other PIPs, PA28 and UCHL5, were also suppressed after EtOH exposure. Furthermore, in EtOH-fed mice and, especially, in HCV + mice, the presentation of SIINFEKL–H2Kb complex in hepatocytes was also decreased. Proteasomal dysfunction induced by EtOH feeding and exacerbated by the presence of HCV structural proteins led to suppression of SIINFEKL–H2Kb presentation in hepatocytes.
    Alcoholism Clinical and Experimental Research 05/2012; 36(12). DOI:10.1111/j.1530-0277.2012.01813.x · 3.21 Impact Factor
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