Increased carbonylation of the lipid phosphatase PTEN contributes to Akt2 activation in a murine model of early alcohol-induced steatosis
Open accessAbstract
The production of reactive aldehydes such as 4-hydroxynonenal (4-HNE) is a key event in the pathogenesis of alcoholic liver disease (ALD), which ranges from simple steatosis to fibrosis. The lipid phosphatase PTEN plays a central role in the regulation of lipid metabolism in the liver. In this study, the effects of chronic ethanol feeding and carbonylation on the PTEN signaling pathway were examined in a 9-week mouse feeding model for ALD. Chronic ethanol consumption resulted in altered redox homeostasis as evidenced by decreased GSH, decreased Trx1, and increased GST activity. Both PTEN expression and PTEN phosphorylation were significantly increased in the livers of ethanol-fed mice. Carbonylation of PTEN increased significantly in the ethanol-fed mice compared to pair-fed control animals, corresponding to decreased PTEN 3-phosphatase activity. Concomitantly, increased expression of Akt2 along with increased Akt phosphorylation at residues Thr(308), Thr(450), and Ser(473) was observed resulting in increased Akt2 activity in the ethanol-fed animals. Akt2 activation corresponded to a decrease in cytosolic SREBP and ChREBP. Subsequent LC/MS/MS analysis of 4-HNE-modified recombinant human PTEN identified Michael addition adducts of 4-HNE on Cys(71), Cys(136), Lys(147), Lys(223), Cys(250), Lys(254), Lys(313), Lys(327), and Lys(344). Computational-based molecular modeling analysis of 4-HNE adducted to Cys(71) near the active site and Lys(327) in the C2 domain of PTEN suggested inhibition of enzyme catalysis via either stearic hindrance of the active-site pocket or prevention of C2 domain-dependent PTEN function. We hypothesize that 4-HNE-mediated PTEN inhibition contributes to the observed activation of Akt2, suggesting a possible novel mechanism of lipid accumulation in response to increased reactive aldehyde production during chronic ethanol administration in mice.
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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 [175]
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 [175]
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“In addition, many other proteins such as protein disulfide isomerase [174] and Grp78 [175] in the ER, gamma-glutamyl-cysteine synthase (GCS) [176], ERK [177], PTEN [178], or AMPK [179] in cytosol could also be inactivated through interaction with 4-HNE, likely leading to ER stress, GSH depletion and alteration of the…”
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- Authors
- Shearn, C. T., Smathers, R. L., Backos, D. S., Reigan, P., Orlicky, D. J., & Petersen, D. R.
- Affiliations
- University of Colorado Anschutz (US)
- Corresponding author
- Petersen, Dennis R.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 65
- Pages
- 680-692
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC3859727
- OpenAlex
- W2083817607
- Cited by
- 69
- References
- 60
- Citations by year
- 2024: 5 · 2023: 4 · 2021: 4 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 9 · 2016: 8 · 2015: 10 · 2014: 10 · 2013: 1
- FWCI
- 7.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health (UL1TR001082)
- Cancer Center, University of Colorado
- Anschutz Medical Campus, University of Colorado
- National Institute on Alcohol Abuse and Alcoholism (F32AA018613, R37AA009300)
- National Cancer Institute (P30CA046934)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074487)
- National Center for Research Resources (UL1RR025780)
- National Center for Advancing Translational Sciences
- Colorado Clinical and Translational Sciences Institute
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- PTEN, protein carbonylation, 4-hydroxynonenal, alcoholic liver disease, alcoholic fatty liver, lipid phosphatase, reactive aldehydes, redox homeostasis, SREBP, ChREBP, chronic ethanol feeding, lipid metabolism, enzyme inhibition
- MeSH terms
- Animals, Chromatography, High Pressure Liquid, Chromatography, Liquid, Disease Models, Animal, Enzyme Activation, Fatty Liver, Alcoholic, Male, Mice, Inbred C57BL, Models, Molecular, Blotting, Western, Protein Carbonylation, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Tandem Mass Spectrometry
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