Overview of lipid peroxidation products and hepatic protein modification in alcoholic liver disease
- PMID: 21354120
- PMCID: PMC3109208
- DOI: 10.1016/j.cbi.2011.02.021
Overview of lipid peroxidation products and hepatic protein modification in alcoholic liver disease
Abstract
Objectives: Oxidative stress is one component of alcoholic liver disease (ALD) that is manifested in the peroxidation of cellular lipids producing the electrophile, 4-hydroxynonenal (4-HNE). This electrophile is proposed to modify essential cellular proteins resulting in loss of protein function and cellular homeostasis. Studies were initiated to identify hepatic proteins that are targets of 4-HNE modification and determine their relationship with progression of the early stages of ALD.
Methods: Rat and mouse models were developed using the Lieber-DeCarli diet to simulate early stages of ALD consisting of fatty liver (steatosis) and hepatocellular injury indicated by a 1.5-2-fold elevation of plasma ALT activity. Liver samples obtained from control and ethanol treated animals were subjected to two-dimensional electrophoresis and immunoblotting using polyclonal antibodies generated against 4-HNE epitopes for detection of proteins modified by 4-HNE. Following identification of 4-HNE adducted proteins, the respective recombinant proteins modified with physiologic concentrations of 4-HNE were evaluated to determine the functional consequences of 4-HNE modification.
Results: One group of proteins identified included Hsp70, Hsp90 and protein disulfide isomerase (PDI), all of which are involved in protein folding or processing are targets of adduction. In vitro assays indicated significant impairment of the protein activities following modification with physiologically relevant concentrations of 4-HNE. Liver fatty acid binding protein, L-FABP, was also identified as a target and additional studies revealed that the levels of this protein were significantly decreased because of chronic ethanol ingestion. Erk1/2 was identified as a target for modification and subsequently determined to have impaired activity.
Conclusions: Inhibition of Hsp70, Hsp90 and PDI function could be involved in initiation of the early phases of ER stress contributing to stimulation and accumulation of hepatic lipids. Likewise, impairment of L-FABP activity could also disrupt lipid transport also contributing to steatosis. The modification and inhibition of Erk1/2 by 4-HNE may also contribute to the decreased hepatocellular proliferation associated with ALD. Collectively, these results provide new information concerning the mechanisms whereby the modification of hepatic proteins by 4-HNE contributes to ALD.
Published by Elsevier Ireland Ltd.
Figures
Similar articles
-
n-3 Polyunsaturated fatty acids for the management of alcoholic liver disease: A critical review.Crit Rev Food Sci Nutr. 2019;59(sup1):S116-S129. doi: 10.1080/10408398.2018.1544542. Epub 2018 Dec 22. Crit Rev Food Sci Nutr. 2019. PMID: 30580553 Review.
-
Characterization of 4-HNE modified L-FABP reveals alterations in structural and functional dynamics.PLoS One. 2012;7(6):e38459. doi: 10.1371/journal.pone.0038459. Epub 2012 Jun 6. PLoS One. 2012. PMID: 22701647 Free PMC article.
-
Protein carbonylation in a murine model for early alcoholic liver disease.Chem Res Toxicol. 2012 May 21;25(5):1012-21. doi: 10.1021/tx300002q. Epub 2012 May 1. Chem Res Toxicol. 2012. PMID: 22502949 Free PMC article.
-
Systems analysis of protein modification and cellular responses induced by electrophile stress.Acc Chem Res. 2010 May 18;43(5):673-83. doi: 10.1021/ar900286y. Acc Chem Res. 2010. PMID: 20218676 Free PMC article. Review.
-
Modification of heat shock protein 90 by 4-hydroxynonenal in a rat model of chronic alcoholic liver disease.J Pharmacol Exp Ther. 2005 Oct;315(1):8-15. doi: 10.1124/jpet.105.088088. Epub 2005 Jun 10. J Pharmacol Exp Ther. 2005. PMID: 15951401
Cited by
-
The Interplay between Perioperative Oxidative Stress and Hepatic Dysfunction after Human Liver Resection: A Prospective Observational Pilot Study.Antioxidants (Basel). 2024 May 11;13(5):590. doi: 10.3390/antiox13050590. Antioxidants (Basel). 2024. PMID: 38790695 Free PMC article.
-
The Roles of NFR2-Regulated Oxidative Stress and Mitochondrial Quality Control in Chronic Liver Diseases.Antioxidants (Basel). 2023 Oct 29;12(11):1928. doi: 10.3390/antiox12111928. Antioxidants (Basel). 2023. PMID: 38001781 Free PMC article. Review.
-
Stress mechanism involved in the progression of alcoholic liver disease and the therapeutic efficacy of nanoparticles.Front Immunol. 2023 Sep 29;14:1205821. doi: 10.3389/fimmu.2023.1205821. eCollection 2023. Front Immunol. 2023. PMID: 37841267 Free PMC article. Review.
-
Nanoparticle Delivery of Novel PDE4B Inhibitor for the Treatment of Alcoholic Liver Disease.Pharmaceutics. 2022 Sep 7;14(9):1894. doi: 10.3390/pharmaceutics14091894. Pharmaceutics. 2022. PMID: 36145643 Free PMC article.
-
Upregulation of Nrf2/HO-1 Signaling and Attenuation of Oxidative Stress, Inflammation, and Cell Death Mediate the Protective Effect of Apigenin against Cyclophosphamide Hepatotoxicity.Metabolites. 2022 Jul 14;12(7):648. doi: 10.3390/metabo12070648. Metabolites. 2022. PMID: 35888772 Free PMC article.
References
-
- Arteel G, Marsano L, Mendez C, Bentley F, McClain CJ. Advances in alcoholic liver disease. Best Pract Res Clin Gastroenterol. 2003;17(4):625–647. - PubMed
-
- Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360(26):2758–2769. - PubMed
-
- Litov RE, Gee DL, Downey JE, Tappel AL. The role of peroxidation during chronic and acute exposure to ethanol as determined by pentane expiration in the rat. Lipids. 1981;16(1):52–63. - PubMed
-
- Kono H, Arteel GE, Rusyn I, Sies H, Thurman RG. Ebselen prevents early alcohol-induced liver injury in rats. Free Radic Biol Med. 2001;30(4):403–411. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Miscellaneous