The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
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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LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., & Yoshimori, T. (2000) · The EMBO Journal · doi:10.1093/emboj/19.21.5720 · Cited by 6,605
Autophagy regulates lipid metabolism
Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A. M., & Czaja, M. J. (2009) · Nature · doi:10.1038/nature07976 · Cited by 3,975
Goldstein, J. L., Ho, Y. K., Basu, S. K., & Brown, M. S. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.1.333 · Cited by 2,447
Dissection of Autophagosome Formation Using Apg5-Deficient Mouse Embryonic Stem Cells
Mizushima, N., Yamamoto, A., Hatano, M., Kobayashi, Y., Kabeya, Y., Suzuki, K., Tokuhisa, T., Ohsumi, Y., & Yoshimori, T. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.152.4.657 · Cited by 1,361
MiR-33 Contributes to the Regulation of Cholesterol Homeostasis
Rayner, K. J., Suárez, Y., Dávalos, A., Parathath, S., Fitzgerald, M. L., Tamehiro, N., Fisher, E. A., Moore, K. J., & Fernández-Hernando, C. (2010) · Science · doi:10.1126/science.1189862 · Cited by 1,260
Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy
Tanida, I., Minematsu-Ikeguchi, N., Ueno, T., & Kominami, E. (2005) · Autophagy · doi:10.4161/auto.1.2.1697 · Cited by 1,108 · cited 1×
“A further increase in LC3-II protein upon lysosomal inhibition was observed, indicative of a functional autophagic flux in these cells, as cellular LC3 levels per se are not a good marker for autophagy (Tanida et al., 2005).”
Lipid Droplets Finally Get a Little R-E-S-P-E-C-T
Farese, R. V., & Walther, T. C. (2009) · Cell · doi:10.1016/j.cell.2009.11.005 · Cited by 1,047
Basu, S. K., Goldstein, J. L., Anderson, G. W., & Brown, M. S. (1976) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.73.9.3178 · Cited by 1,019
The molecular machinery of autophagy: unanswered questions
Klionsky, D. J. (2004) · Journal of Cell Science · doi:10.1242/jcs.01620 · Cited by 960
Autophagy regulates adipose mass and differentiation in mice
Singh, R., Xiang, Y., Wang, Y., Baikati, K., Cuervo, A. M., Luu, Y. K., Tang, Y., Pessin, J. E., Schwartz, G. J., & Czaja, M. J. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39228 · Cited by 765
Stary, H. C., Chandler, A. B., Glagov, S. K., Guyton, J. R., Insull, W., Rosenfeld, M. E., Schaffer, S. A., Schwartz, C. J., Wagner, W. D., & Wissler, R. W. (1994) · Arteriosclerosis and Thrombosis A Journal of Vascular Biology · doi:10.1161/01.atv.14.5.840 · Cited by 738
Brown, M. S., Ho, Y. K., & Goldstein, J. L. (1980) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)70568-7 · Cited by 722
Zhang, Y., Goldman, S., Baerga, R., Zhao, Y., Komatsu, M., & Jin, S. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906048106 · Cited by 634
The origin of the autophagosomal membrane
Tooze, S. A., & Yoshimori, T. (2010) · Nature Cell Biology · doi:10.1038/ncb0910-831 · Cited by 611
Wang, N., Silver, D. L., Costet, P., & Tall, A. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005438200 · Cited by 569
Reversible accumulation of cholesteryl esters in macrophages incubated with acetylated lipoproteins.
Brown, M. S., Goldstein, J. L., Krieger, M., Ho, Y. K., & Anderson, R. G. W. (1979) · The Journal of Cell Biology · doi:10.1083/jcb.82.3.597 · Cited by 551
Autophagosome Formation and Molecular Mechanism of Autophagy
Tanida, I. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3482 · Cited by 505
Zhang, Y., Zanotti, I., Reilly, M. P., Glick, J. M., Rothblat, G. H., & Rader, D. J. (2003) · Circulation · doi:10.1161/01.cir.0000086981.09834.e0 · Cited by 435
Altered lipid content inhibits autophagic vesicular fusion
Koga, H., Kaushik, S., & Cuervo, A. M. (2010) · The FASEB Journal · doi:10.1096/fj.09-144519 · Cited by 395
Goldstein, J. L., Dana, S. E., Faust, J., Beaudet, A. L., & Brown, M. (1975) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)40786-2 · Cited by 391
High-density lipoprotein heterogeneity and function in reverse cholesterol transport
Rothblat, G. H., & Phillips, M. C. (2010) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328338472d · Cited by 341
Targeted deletion of autophagy-related 5(atg5) impairs adipogenesis in a cellular model and in mice
Baerga, R., Zhang, Y., Chen, P.-H., Goldman, S., & Jin, S. V. (2009) · Autophagy · doi:10.4161/auto.5.8.9991 · Cited by 304
Cuervo, A. M., Dice, J. F., & Knecht, E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.9.5606 · Cited by 296
Macrophage Differentiation to Foam Cells
Shashkin, P. N., Dragulev, B. P., & Ley, K. F. (2005) · Current Pharmaceutical Design · doi:10.2174/1381612054865064 · Cited by 291
Lipid droplet-organelle interactions; sharing the fats
Murphy, S., Martin, S., & Parton, R. G. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2008.07.004 · Cited by 265
Nuclear Receptors in Lipid Metabolism: Targeting the Heart of Dyslipidemia
Beaven, S. W., & Tontonoz, P. (2006) · Annual Review of Medicine · doi:10.1146/annurev.med.57.121304.131428 · Cited by 230
Fluorescent Detection of Lipid Droplets and Associated Proteins
Listenberger, L. L., & Brown, D. A. (2007) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb2402s35 · Cited by 217
The MAP1-LC3 conjugation system is involved in lipid droplet formation
Shibata, M., Yoshimura, K., Furuya, N., Koike, M., Ueno, T., Komatsu, M., Arai, H., Tanaka, K., Kominami, E., & Uchiyama, Y. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.03.039 · Cited by 215
Genome-wide Localization of SREBP-2 in Hepatic Chromatin Predicts a Role in Autophagy
Seo, Y., Jeon, T.-I., Chong, H. K., Biesinger, J., Xie, X. S., & Osborne, T. F. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.03.005 · Cited by 177
Paul, A., Chang, B. H.-J., Li, L., Yechoor, V. K., & Chan, L. (2008) · Circulation Research · doi:10.1161/circresaha.107.168070 · Cited by 171
Mueller, M. A., Beutner, F., Teupser, D., Ceglarek, U., & Thiery, J. (2007) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2007.09.019 · Cited by 157
Macrophage cholesteryl ester mobilization and atherosclerosis
Ghosh, S., Zhao, B., Bie, J., & Song, J. (2009) · Vascular Pharmacology · doi:10.1016/j.vph.2009.10.002 · Cited by 149
Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy
Lépine, S., Allegood, J. C., Park, M., Dent, P., Milstien, S., & Spiegel, S. (2010) · Cell Death and Differentiation · doi:10.1038/cdd.2010.104 · Cited by 139
Cholesterol depletion induces autophagy
Cheng, J., Ohsaki, Y., Tauchi-Sato, K., Fujita, A., & Fujimoto, T. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.10.042 · Cited by 120
Future Therapeutic Directions in Reverse Cholesterol Transport
Khera, A. V., & Rader, D. J. (2010) · Current Atherosclerosis Reports · doi:10.1007/s11883-009-0080-0 · Cited by 111
Effects of cellular cholesterol loading on macrophage foam cell lysosome acidification
Cox, B. E., Griffin, E. E., Ullery, J. C., & W. Gray, J. (2007) · Journal of Lipid Research · doi:10.1194/jlr.m600390-jlr200 · Cited by 110
Rapamycin Attenuates Atherosclerotic Plaque Progression in Apolipoprotein E Knockout Mice
Pakala, R., Stabile, E., Jang, G. J., Clavijo, L., & Waksman, R. (2005) · Journal of Cardiovascular Pharmacology · doi:10.1097/01.fjc.0000177985.14305.15 · Cited by 104
Lipophagy: Selective Catabolism Designed for Lipids
Weidberg, H., Shvets, E., & Elazar, Z. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.05.001 · Cited by 97
Rosenbaum, A. I., Cosner, C. C., Mariani, C. J., Maxfield, F. R., Wiest, O., & Helquist, P. M. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm100499s · Cited by 89
Yancey, P. G., & Jerome, W. G. (1998) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32515-3 · Cited by 79
In Vivo Reverse Cholesterol Transport From Macrophages Lacking ABCA1 Expression Is Impaired
Wang, M., Franklin, V., & Marcel, Y. L. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.146068 · Cited by 79
Self-citationRetroendocytosis pathway of ABCA1/apoA‐I contributes to HDL formation
Azuma, Y., Takada, M., Shin, H., Kioka, N., Nakayama, K., & Ueda, K. (2009) · Genes to Cells · doi:10.1111/j.1365-2443.2008.01261.x · Cited by 78
ACAT1 Deficiency Disrupts Cholesterol Efflux and Alters Cellular Morphology in Macrophages
Dove, D. E., Su, Y. R., Zhang, W., Jerome, W. G., Swift, L. L., Linton, M. F., & Fazio, S. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000148323.94021.e5 · Cited by 68
Griffin, E. E., Cantu, J. C., Cox, B. E., & Jerome, W. G. (2005) · Journal of Lipid Research · doi:10.1194/jlr.m500059-jlr200 · Cited by 60
Rosenbaum, A. I., Rujoi, M., Huang, A. Y., Du, H., Grabowski, G. A., & Maxfield, F. R. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.08.005 · Cited by 60
Advanced Atherosclerotic Foam Cell Formation Has Features of an Acquired Lysosomal Storage Disorder
Jerome, W. G. (2006) · Rejuvenation Research · doi:10.1089/rej.2006.9.245 · Cited by 59
Ileperuma, N. R., Marshall, S. D. G., Squire, C. J., Baker, H. M., Oakeshott, J. G., Russell, R. J., Plummer, K. M., Newcomb, R. D., & Baker, E. N. (2007) · Biochemistry · doi:10.1021/bi062046w · Cited by 59
Potential role of autophagy in modulation of lipid metabolism
Kovsan, J., Bashan, N., Greenberg, A. S., & Rudich, A. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00562.2009 · Cited by 54
Attenuation of Adipocyte Triacylglycerol Hydrolase Activity Decreases Basal Fatty Acid Efflux
Wei, E., Gao, W., & Lehner, R. S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m605789200 · Cited by 52
Endolysosomal phospholipidosis and cytosolic lipid droplet storage and release in macrophages
Schmitz, G., & Grandl, M. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2008.12.007 · Cited by 51
Jerome, W. G., Cash, C., Webber, R. L., Horton, R. A., & Yancey, P. G. (1998) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32516-5 · Cited by 49
Autophagy and lipids: tightening the knot
Rodríguez‐Navarro, J. A., & Cuervo, A. M. (2010) · Seminars in Immunopathology · doi:10.1007/s00281-010-0219-7 · Cited by 46
Itabe, H., Suzuki, K., Tsukamoto, Y., Komatsu, R., Ueda, M., Mori, M., Higashi, Y., & Takano, T. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(00)00098-6 · Cited by 42
Effect of sirolimus on the cholesterol content of aortic arch in ApoE knockout mice
Basso, M., Nambi, P., & Adelman, S. J. (2003) · Transplantation Proceedings · doi:10.1016/j.transproceed.2003.10.050 · Cited by 33
Importance of macrophage cholesterol content on the flux of cholesterol mass
Sankaranarayanan, S., de la Llera-Moya, M., Drazul‐Schrader, D., Asztalos, B. F., Weibel, G. L., & Rothblat, G. H. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m008441 · Cited by 26
Cholesteryl ester hydrolysis in J774 macrophages occurs in the cytoplasm and lysosomes
Avart, S., Bernard, D. W., Jerome, W. G., & Glick, J. M. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32444-5 · Cited by 24
Everolimus, a promising medical therapy for coronary heart disease?
Jia, L., & Hui, R. (2009) · Medical Hypotheses · doi:10.1016/j.mehy.2009.03.011 · Cited by 14
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Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894
Guidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996
Macrophages in atherosclerosis: a dynamic balance
Moore, K. J., Sheedy, F. J., & Fisher, E. A. (2013) · Nature reviews. Immunology · doi:10.1038/nri3520 · Cited by 2,559
Lipid Droplets and Cellular Lipid Metabolism
Walther, T. C., & Farese, R. V. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061009-102430 · Cited by 1,701
Autophagy in major human diseases
Klionsky, D. J., Petroni, G., Amaravadi, R. K., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo‐San Pedro, J. M., Cadwell, K., Cecconi, F., Choi, A. M. K., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2021108863 · Cited by 1,585
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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