Identification of 5′ AMP-activated Kinase as a Target of Reactive Aldehydes during Chronic Ingestion of High Concentrations of Ethanol
Open accessAbstract
The production of reactive aldehydes including 4-hydroxy-2-nonenal (4-HNE) is a key component of the pathogenesis in a spectrum of chronic inflammatory hepatic diseases including alcoholic liver disease (ALD). One consequence of ALD is increased oxidative stress and altered β-oxidation in hepatocytes. A major regulator of β-oxidation is 5' AMP protein kinase (AMPK). In an in vitro cellular model, we identified AMPK as a direct target of 4-HNE adduction resulting in inhibition of both H2O2 and 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR)-induced downstream signaling. By employing biotin hydrazide capture, it was confirmed that 4-HNE treatment of cells resulted in carbonylation of AMPKα/β, which was not observed in untreated cells. Using a murine model of alcoholic liver disease, treatment with high concentrations of ethanol resulted in an increase in phosphorylated as well as carbonylated AMPKα. Despite increased AMPK phosphorylation, there was no significant change in phosphorylation of acetyl CoA carboxylase. Mass spectrometry identified Michael addition adducts of 4-HNE on Cys(130), Cys(174), Cys(227), and Cys(304) on recombinant AMPKα and Cys(225) on recombinant AMPKβ. Molecular modeling analysis of identified 4-HNE adducts on AMPKα suggest that inhibition of AMPK occurs by steric hindrance of the active site pocket and by inhibition of hydrogen peroxide induced oxidation. The observed inhibition of AMPK by 4-HNE provides a novel mechanism for altered β-oxidation in ALD, and these data demonstrate for the first time that AMPK is subject to regulation by reactive aldehydes in vivo.
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Ethanol intake can induce 4-HNE to interact with mitochondrial, ER, and cytosolic proteins, inactivating them and resulting in accumulation of lipid aldehydes, ER stress, mitochondrial dysfunction, cell signaling alteration, and potentially multitissue injury.
“For instance, ethanol intake can induce 4-HNE to interact with cytochrome C oxidase (complex IV) and ALDH2 in the mitochondria, GRP78 and disulfide isomerase in the ER, and ERK1/2, phosphatase and tensin homolog (PTEN), AMP-activated protein kinase (AMPK), and gamma-glutamylcysteine synthetase (GCS) in the cytosol.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [176]
MDA and 4-HNE are reactive lipid peroxides with short half-lives that can form covalent adducts with various proteins and nucleic acids in the body.
“MDA and 4-HNE are reactive lipid peroxides with short half-lives that can form covalent adducts with various proteins and nucleic acids in the body.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [176]
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“However, we briefly describe the redox-mediated regulation of stress activated MAPKs and AMP-activated protein kinase (AMPK) in this review, based on their involvement in mitochondrial homeostasis, intermediary metabolism for steatosis and liver injury.”
BackgroundInfluentialAldehyde-Induced DNA and Protein Adducts as Biomarker Tools for Alcohol Use Disorder
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- Authors
- Shearn, C. T., Backos, D. S., Orlicky, D. J., Smathers-McCullough, R. L., & Petersen, D. R.
- Affiliations
- University of Colorado Anschutz (US)
- University of Denver (US)
- Corresponding author
- Petersen, Dennis R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 289
- Issue
- 22
- Pages
- 15449-15462
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4140901
- OpenAlex
- W2007825238
- Cited by
- 57
- References
- 63
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 1 · 2018: 10 · 2017: 3 · 2016: 5 · 2015: 12 · 2014: 6
- FWCI
- 6.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (F32 AA018613-03, R37AA009300–17)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- AMPK, 4-hydroxynonenal, reactive aldehydes, alcoholic liver disease, chronic ethanol ingestion, protein carbonylation, fatty acid beta-oxidation, oxidative stress, AMPK phosphorylation, acetyl-CoA carboxylase, hydrogen peroxide, steric hindrance, active site inhibition, molecular modeling
- MeSH terms
- Ethanol, Aldehydes, Animals, Central Nervous System Depressants, Disease Models, Animal, Fatty Liver, Humans, Liver Diseases, Alcoholic, Male, Mice, Inbred C57BL, Models, Chemical, Phosphorylation, Lipid Peroxidation, Signal Transduction, Cysteine Proteinase Inhibitors, Oxidative Stress, Protein Carbonylation, Mice, AMP-Activated Protein Kinases, Hep G2 Cells
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