Protein Carbonylation in a Murine Model for Early Alcoholic Liver Disease
Open accessAbstract
Hepatic oxidative stress and subsequent lipid peroxidation are well-recognized consequences of sustained ethanol consumption. The covalent adduction of nucleophilic amino acid side-chains by lipid electrophiles is significantly increased in patients with alcoholic liver disease (ALD); a global assessment of in vivo protein targets and the consequences of these modifications, however, has not been conducted. In this article, we describe the identification of novel protein targets for covalent adduction in a 6-week murine model for ALD. Ethanol-fed mice displayed a 2-fold increase in hepatic TBARS, while immunohistochemical analysis for the reactive aldehydes 4-hydroxynonenal (4-HNE), 4-oxononenal (4-ONE), acrolein (ACR), and malondialdehyde (MDA) revealed a marked increase in the staining of modified proteins in the ethanol-treated mice. Increased protein carbonyl content was confirmed utilizing subcellular fractionation of liver homogenates followed by biotin-tagging through hydrazide chemistry, where approximately a 2-fold increase in modified proteins was observed in microsomal and cytosolic fractions. To determine targets of protein carbonylation, a secondary hydrazide method coupled to a highly sensitive 2-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS or MuDPIT) technique was utilized. Our results have identified 414 protein targets for modification by reactive aldehydes in ALD. The presence of novel in vivo sites of protein modification by 4-HNE (2), 4-ONE (4) and ACR (2) was also confirmed in our data set. While the precise impact of protein carbonylation in ALD remains unknown, a bioinformatic analysis of the data set has revealed key pathways associated with disease progression, including fatty acid metabolism, drug metabolism, oxidative phosphorylation, and the TCA cycle. These data suggest a major role for aldehyde adduction in the pathogenesis of ALD.
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In hepatic Kupffer cells, 4-HNE adducts are present and activate infiltration of neutrophils into the liver, leading to activation of HSCs and an inflammatory cytokine response; these findings indicate a contributing role of MAA and 4-HNE adducts in promoting the hepatic immune response associated with ALD development.
“In hepatic Kupffer cells, 4-HNE adducts are also present and activate the infiltration of neutrophils into the liver, leading to the activation of HSCs and an inflammatory cytokine response226–228.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [227]
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- Authors
- Galligan, J. J., Smathers, R. L., Fritz, K. S., Epperson, L. E., Hunter, L. E., & Petersen, D. R.
- Affiliations
- University of Colorado Denver (US)
- Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, United States
- Corresponding author
- Petersen, Dennis R.
- Venue
- Chemical Research in Toxicology
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-05-01
- Volume
- 25
- Issue
- 5
- Pages
- 1012-1021
- ISSN
- 0893-228X (ISSN-L)
- 1520-5010
- PMC
- PMC3423195
- OpenAlex
- W2091643856
- Cited by
- 74
- References
- 45
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 6 · 2019: 11 · 2018: 7 · 2017: 7 · 2016: 6 · 2015: 10 · 2014: 10 · 2013: 2 · 2012: 5
- FWCI
- 6.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Chemical Research in Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1f31aa018606-01)
- Anschutz Medical Campus, University of Colorado
- National Institute on Alcohol Abuse and Alcoholism (F31 AA018606, F31AA018606-01, R37AA009300)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074487)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- protein carbonylation, alcoholic liver disease, ethanol-induced liver injury, lipid peroxidation, reactive aldehydes, 4-hydroxynonenal, acrolein, malondialdehyde, MudPIT, fatty acid metabolism, drug metabolism, oxidative phosphorylation, TCA cycle, hepatic oxidative stress
- MeSH terms
- Acrolein, Ethanol, Aldehydes, Animals, Fatty Acids, Liver, Liver Diseases, Alcoholic, Male, Malondialdehyde, Mice, Inbred C57BL, Proteins, Thiobarbituric Acid Reactive Substances, Proteomics, Protein Carbonylation, Mice, Tandem Mass Spectrometry
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