Akt3 Deficiency in Macrophages Promotes Foam Cell Formation and Atherosclerosis in Mice
Open accessAbstract
Akt, a serine-threonine protein kinase, exists as three isoforms. The Akt signaling pathway controls multiple cellular functions in the cardiovascular system, and the atheroprotective endothelial cell-dependent role of Akt1 has been recently demonstrated. The role of Akt3 isoform in cardiovascular pathophysiology is not known. We explored the role of Akt3 in atherosclerosis using mice with a genetic ablation of the Akt3 gene. Using hyperlipidemic ApoE(-/-) mice, we demonstrated a macrophage-dependent, atheroprotective role for Akt3. In vitro experiments demonstrated differential subcellular localization of Akt1 and Akt3 in macrophages and showed that Akt3 specifically inhibits macrophage cholesteryl ester accumulation and foam cell formation, a critical early event in atherogenesis. Mechanistically, Akt3 suppresses foam cell formation by reducing lipoprotein uptake and promoting ACAT-1 degradation via the ubiquitin-proteasome pathway. These studies demonstrate the nonredundant atheroprotective role for Akt3 exerted via the previously unknown link between the Akt signaling pathway and cholesterol metabolism.
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AKT3 has been implicated in atherosclerosis and tissue remodeling.
“Less is known about the effects of AKT3 on MΦ function, although it has been implicated in atherosclerosis (47, 48) and tissue remodeling (49).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [48]
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References 33 · Cited by 83
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- Authors
- Ding, L., Biswas, S., Morton, R. E., Smith, J. D., Hay, N., Byzova, T. V., Febbraio, M., & Podrez, E. A.
- Affiliations
- Cleveland Clinic (US)
- University of Illinois Chicago (US)
- Corresponding author
- Podrez, Eugene A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 15
- Issue
- 6
- Pages
- 861-872
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3372639
- OpenAlex
- W1974550647
- Cited by
- 83
- References
- 33
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 10 · 2021: 6 · 2020: 6 · 2019: 1 · 2018: 6 · 2017: 9 · 2016: 5 · 2015: 6 · 2014: 10 · 2013: 7 · 2012: 2
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG016927)
- National Heart, Lung, and Blood Institute (HL071625., HL077213, R01HL098193, R01HL077213, P01HL073311, R01HL071625)
- National Cancer Institute (R01CA090764)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- AKT3, Akt signaling, macrophages, foam cell formation, atherosclerosis, cholesteryl ester accumulation, lipoprotein uptake, ACAT1, ubiquitin-proteasome system, cholesterol metabolism, ApoE-deficient mice, atheroprotection
- MeSH terms
- Acetyl-CoA C-Acetyltransferase, Animals, Aorta, Apolipoproteins E, Bone Marrow Cells, Cell Survival, Cells, Cultured, Cholesterol, Cholesterol Esters, Female, Foam Cells, Hyperlipidemias, Lipoproteins, Male, Mice, Inbred C57BL, Sinus of Valsalva, Triglycerides, Signal Transduction, Macrophages, Peritoneal, Mice, Knockout, Proteasome Endopeptidase Complex, Atherosclerosis, Proto-Oncogene Proteins c-akt, Mice, Mice, 129 Strain, Proteolysis
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