Nuclear effects of ethanol-induced proteasome inhibition in liver cells

The Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson St. Torrance, CA 90502, United States.
World Journal of Gastroenterology (Impact Factor: 2.37). 04/2009; 15(10):1163-7. DOI: 10.3748/wjg.15.1163
Source: PubMed


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.

1 Follower
12 Reads
  • Source
    • "Further, the modest decreases in proteasome activity ensure that the viability of treated cells is maintained and that the results are not due to cell death since a profound inhibition of proteasome would likely cause apoptosis/necrosis. Thus, our data indicate that in addition to previously reported methylation-mediated regulation of proteasome activity in cells at the epigenetic level [19] [20], proteasome function is also regulated at the level of SAM:SAH-dependent methylation reactions. Further, we observed greater inhibition of activity of IPr-enriched proteasome preparation with decreased SAM:SAH compared with 20S constitutive proteasome. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The proteasome is a multi-catalytic protein degradation enzyme that is regulated by ethanol-induced oxidative stress; such suppression is attributed to CYP2E1-generated metabolites. However, under certain conditions, it appears that in addition to oxidative stress, other mechanisms are also involved in proteasome regulation. This study investigated whether impaired protein methylation that occurs during exposure of liver cells to ethanol, may contribute to suppression of proteasome activity. We measured the chymotrypsin-like proteasome activity in Huh7CYP cells, hepatocytes, liver cytosols and nuclear extracts or purified 20S proteasome under conditions that maintain or prevent protein methylation. Reduction of proteasome activity of hepatoma cell and hepatocytes by ethanol or tubercidin was prevented by simultaneous treatment with S-adenosylmethionine (SAM). Moreover, the tubercidin-induced decline in proteasome activity occurred in both nuclear and cytosolic fractions. In vitro exposure of cell cytosolic fractions or highly purified 20S proteasome to low SAM:S-adenosylhomocysteine (SAH) ratios in the buffer also suppressed proteasome function, indicating that one or more methyltransferase(s) may be associated with proteasomal subunits. Immunoblotting a purified 20S rabbit red cell proteasome preparation using methyl lysine-specific antibodies revealed a 25 kDa proteasome subunit that showed positive reactivity with anti-methyl lysine. This reactivity was modified when 20S proteasome was exposed to differential SAM:SAH ratios. We conclude that impaired methylation of proteasome subunits suppressed proteasome activity in liver cells indicating an additional, yet novel mechanism of proteasome activity regulation by ethanol.
    Biochemical and Biophysical Research Communications 01/2010; 391(2-391):1291-1296. DOI:10.1016/j.bbrc.2009.12.074 · 2.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A novel configuration for two-step analog-to-digital (A/D) flash conversion is described. The coarse and fine conversions are performed with a four-bit multiplexed flash converter, so only 15 comparators are necessary for an eight-bit converter. The D/A conversion and the subtraction required for the circuit operation are performed using the charge redistribution technique. A test chip, integrated with a 3-μm CMOS technology (area=3 mm<sup>2</sup>), has demonstrated the effectiveness of the proposed configuration
    Custom Integrated Circuits Conference, 1989., Proceedings of the IEEE 1989; 06/1989
  • [Show abstract] [Hide abstract]
    ABSTRACT: A number of oxidative stress agents cause DNA and protein damage, which may compromise genomic integrity. Whereas oxidant-induced DNA damage has been extensively studied, much less is known concerning the occurrence and fate of nuclear protein damage, particularly of proteins involved in the regulation and maintenance of chromatin structure. Protein damage may be caused by the formation of reactive carbonyl species such as glyoxal, which forms after lipid peroxide degradation. It may also result from degradation of early protein glycation adducts and from methylglyoxal, formed in the process of glycolytic intermediate degradation. Major adducts indicative of protein damage include the advanced glycation end product (AGE) carboxymethyllysine (CML) and argpyrimidine protein adducts. Thus, the formation of CML and argpyrimidine protein adducts represents potential biomarkers for nuclear protein damage deriving from a variety of sources. The purpose of this study was to identify and quantify AGE adducts formed in vivo in a nuclear protein, specifically histone H1, using CML and argpyrimidine as biomarkers. Histone H1 was isolated from calf thymus collected immediately after slaughter under conditions designed to minimize AGE formation before isolation. Using antibodies directed against oxidative protein adducts, we identified CML, argpyrimidine, and protein crosslinks present in the freshly isolated histone H1. Detailed mass spectroscopy analysis of histone H1 revealed the presence of two specific lysine residues modified by CML adducts. Our results strongly suggest that glycation of important nuclear protein targets such as histone H1 occurs in vivo and that these oxidative changes may alter chromatin structure, ultimately contributing to chronic changes associated with aging and diseases such as diabetes.
    Free Radical Biology and Medicine 02/2011; 50(10):1410-6. DOI:10.1016/j.freeradbiomed.2011.01.034 · 5.74 Impact Factor
Show more


12 Reads
Available from