Cited by 779Cholesterol and Lipid MetabolismAutophagy in Disease and TherapyLipid metabolism and biosynthesis

Autophagy Regulates Cholesterol Efflux from Macrophage Foam Cells via Lysosomal Acid Lipase

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Ouimet, Mireille, Franklin, Vivian, Mak, Esther, Liao, Xianghai, Tabas, Ira, Marcel, Yves L.·2011·Cell Metabolism

Abstract

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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Crossref · 10.1016/j.cmet.2011.03.023

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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 to the liver for secretion in bile and for excretion.

    “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]

    The Results section, “Lipophagy Contributes to RCT In Vivo” (page unavailable), reports that autophagy-deficient macrophages showed reduced cholesterol transport to plasma, liver, gallbladder, and feces. But the Experimental Procedures, “In Vivo RCT Studies” (page unavailable), describe injecting labeled macrophages into mice, not bone marrow transfer. The in vivo role is supported; the named method is not. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • In cultured macrophages, modified lipoproteins such as oxLDL induce autophagy, apoptosis, pyroptosis through NLRP3 inflammasome activation, and necroptosis.

    “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.”
  • Macrophage-specific deletion of Atg5 enhances atherogenic plaque progression due to hyperactivation of macrophage-mediated inflammation and impaired lipid droplets catabolism.

    “| 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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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)
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
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
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Epidemiology › 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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