Impairment of Macrophage Cholesterol Efflux by Cholesterol Hydroperoxide Trafficking: Implications for Atherogenesis Under Oxidative Stress
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Objective—: Oxidative stress associated with cardiovascular disease can produce various oxidized lipids, including cholesterol oxides, such as 7-hydroperoxide (7-OOH), 7-hydroxide (7-OH), and 7-ketone (7=O). Unlike 7=O and 7-OH, 7-OOH is redox active, giving rise to the others via potentially toxic-free radical reactions. We tested the novel hypothesis that under oxidative stress conditions, steroidogenic acute regulatory (StAR) family proteins not only deliver cholesterol to/into mitochondria of vascular macrophages, but also 7-OOH, which induces peroxidative damage that impairs early stage reverse cholesterol transport. Approach and Results—: Stimulation of human monocyte-derived THP-1 macrophages with dibutyryl-cAMP resulted in substantial upregulation of StarD1 and ATP-binding cassette (ABC) transporter, ABCA1. Small interfering RNA–induced StarD1 knockdown before stimulation had no effect on StarD4, but reduced ABCA1 upregulation, linking the latter to StarD1 functionality. Mitochondria in stimulated StarD1-knockdown cells internalized 7-OOH slower than nonstimulated controls and underwent less 7-OOH–induced lipid peroxidation and membrane depolarization, as probed with C11-BODIPY (4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-inda-cene-3-undecanoic acid) and JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-benzimidazolylcarbocyanine iodide), respectively. Major functional consequences of 7-OOH exposure were (1) loss of mitochondrial CYP27A1 activity, (2) reduced 27-hydroxycholesterol (27-OH) output, and (3) downregulation of cholesterol-exporting ABCA1 and ABCG1. Consistently, 7-OOH–challenged macrophages exported less cholesterol to apoA-I or high-density lipoprotein than did nonchallenged controls. StarD1-mediated 7-OOH transport was also found to be highly cytotoxic, whereas 7=O and 7-OH were minimally toxic. Conclusions—: This study describes a previously unrecognized mechanism by which macrophage cholesterol efflux can be incapacitated under oxidative stress–linked disorders, such as chronic obesity and hypertension. Our findings provide new insights into the role of macrophage redox damage/dysfunction in atherogenesis.
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Excessive oxidized LDL cholesterol imported into macrophages leads to the development of foam cells that are deposited beneath the endothelium in arteries, forming atherosclerotic plaques.
“Excessive oxidized LDL cholesterol imported into macrophages leads to the development of foam cells that are deposited beneath the endothelium in arteries, forming atherosclerotic plaques [110].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [110]
When macrophages are under oxidative stress, oxidized lipids such as 7-hydroperoxide proceed to inactivate CYP27A1, reducing ABCA1/G1 expression and ultimately leading to impaired cholesterol efflux to the extracellular apoA-I or HDL.
“When macrophages are under oxidative stress, oxidized lipids such as 7-hydroperoxide proceed to inactivate CYP27A1, reducing ABCA1/G1 expression and ultimately leading to impaired cholesterol efflux to the extracellular apoA-I or HDL [110].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [110]
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Hong, S.-H., & Choi, K. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020494 · Cited by 390 · see citing works
- Authors
- Korytowski, W., Wawak, K., Pabisz, P., Schmitt, J. C., Chadwick, A. C., Sahoo, D., & Girotti, A. W.
- Affiliations
- Jagiellonian University (PL)
- From the Department of Biochemistry (A.W.G., W.K., D.S., A.C.C., J.C.S.) and Department of Medicine (D.S.), Medical College of Wisconsin, Milwaukee; and Department of Biophysics, Jagiellonian University, Krakow, Poland (W.K., K.W., P.P.).
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2015-10
- Volume
- 35
- Issue
- 10
- Pages
- 2104-2113
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC4601804
- OpenAlex
- W2560946835
- Cited by
- 49
- References
- 53
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 9 · 2016: 1
- FWCI
- 4.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Homo Politicus (Academy of Humanities and Economics in Lodz) (submittedVersion, cc-by-nc-nd)
- Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 58012, R01HL085677, HL85677, R01HL058012)
- National Cancer Institute (R01CA072630)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- macrophage cholesterol efflux, cholesterol hydroperoxides, oxidative stress, reverse cholesterol transport, STARD1, ABCA1, ABCG1, mitochondrial cholesterol transport, lipid peroxidation, CYP27A1, 27-hydroxycholesterol, macrophage cytotoxicity, high-density lipoprotein, THP-1 macrophages
- MeSH terms
- Biological Transport, Cells, Cultured, Cholesterol, Cyclic CMP, Humans, Macrophages, Mitochondria, Sensitivity and Specificity, Lipid Peroxidation, Oxidative Stress, Protein Transport, Atherosclerosis
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