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Autophagy Regulates Cholesterol Efflux from Macrophage Foam Cells via Lysosomal Acid Lipase
Open accessAbstract
The lipid droplet (LD) is the major site of cholesterol storage in macrophage foam cells and is a potential therapeutic target for the treatment of atherosclerosis. Cholesterol, stored as cholesteryl esters (CEs), is liberated from this organelle and delivered to cholesterol acceptors. The current paradigm attributes all cytoplasmic CE hydrolysis to the action of neutral CE hydrolases. Here, we demonstrate an important role for lysosomes in LD CE hydrolysis in cholesterol-loaded macrophages, in addition to that mediated by neutral hydrolases. Furthermore, we demonstrate that LDs are delivered to lysosomes via autophagy, where lysosomal acid lipase (LAL) acts to hydrolyze LD CE to generate free cholesterol mainly for ABCA1-dependent efflux; this process is specifically induced upon macrophage cholesterol loading. We conclude that, in macrophage foam cells, lysosomal hydrolysis contributes to the mobilization of LD-associated cholesterol for reverse cholesterol transport.
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“Bone marrow transfer has been used to document in vivo the role of autophagy in the reverse cholesterol transport pathway from peripheral tissues or cells (e.g., macrophages) to the liver for secretion in bile and for excretion, 638”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [638]
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“Uptake of modified lipoproteins, such as oxLDL, has been shown in cultured macrophages to induce autophagy168, apoptosis170, pyroptosis (via induction of NRLP3 inflammasome activation72) and necroptosis169.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [168]
In the citing paper
“| Atherosclerosis | Macrophage‐specific deletion of Atg5 | Enhanced atherogenic plaque progression due to hyperactivation of macrophage‐mediated inflammation and impaired lipid droplets catabolism | Ouimet et al (2011), Liao et al (2012), Razani et al (2012) |”
From Autophagy in major human diseases (2021) · cites this paper as Ouimet et al (2011)
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Metadata
- Authors
- Ouimet, M., Franklin, V., Mak, E., Liao, X., Tabas, I., & Marcel, Y. L.
- Affiliations
- University of Ottawa (CA)
- Ottawa Heart Institute (CA)
- Columbia University (US)
- Corresponding author
- Marcel, Yves L.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 13
- Issue
- 6
- Pages
- 655-667
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3257518
- OpenAlex
- W1983619827
- Cited by
- 774
- References
- 57
- Citations by year
- 2026: 49 · 2025: 57 · 2024: 42 · 2023: 61 · 2022: 61 · 2021: 69 · 2020: 62 · 2019: 48 · 2018: 66 · 2017: 52 · 2016: 51 · 2015: 48 · 2014: 35 · 2013: 28 · 2012: 37
- FWCI
- 34.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 813 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research
- Heart and Stroke Foundation of Canada
- National Institutes of Health (HL057560)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- autophagy, lysosomal acid lipase, foam cells, cholesterol efflux, lipid droplets, cholesterol ester hydrolysis, lysosomes, ABCA1, reverse cholesterol transport, atherosclerosis, free cholesterol
- MeSH terms
- Autophagy-Related Protein 5, Animals, Autophagy, Bone Marrow Cells, Cells, Cultured, Chloroquine, Cholesterol, Sterol Esterase, Foam Cells, Lipolysis, Lipoproteins, LDL, Lysosomes, Mice, Inbred C57BL, Microtubule-Associated Proteins, Paraoxon, Mice, Knockout, Atherosclerosis, Lipid Metabolism, Mice, Gene Knockout Techniques
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