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Cited by 221Cholesterol and Lipid MetabolismAutophagy in Disease and TherapyMicroRNA in disease regulation

microRNA-33 regulates macrophage autophagy in atherosclerosis

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Ouimet, Mireille, Ediriweera, Hasini, Afonso, Milessa Silva, Ramkhelawon, Bhama, Singaravelu, Ragunath, Liao, Xianghai, Bandler, Rachel C., Rahman, Karishma +5 more·2017·Arteriosclerosis, Thrombosis, and Vascular Biology
DOI 10.1161/atvbaha.116.308916PMC PMC5494696
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Abstract

Objective—: Defective autophagy in macrophages leads to pathological processes that contribute to atherosclerosis, including impaired cholesterol metabolism and defective efferocytosis. Autophagy promotes the degradation of cytoplasmic components in lysosomes and plays a key role in the catabolism of stored lipids to maintain cellular homeostasis. microRNA-33 (miR-33) is a post-transcriptional regulator of genes involved in cholesterol homeostasis, yet the complete mechanisms by which miR-33 controls lipid metabolism are unknown. We investigated whether miR-33 targeting of autophagy contributes to its regulation of cholesterol homeostasis and atherogenesis. Approach and Results—: Using coherent anti-Stokes Raman scattering microscopy, we show that miR-33 drives lipid droplet accumulation in macrophages, suggesting decreased lipolysis. Inhibition of neutral and lysosomal hydrolysis pathways revealed that miR-33 reduced cholesterol mobilization by a lysosomal-dependent mechanism, implicating repression of autophagy. Indeed, we show that miR-33 targets key autophagy regulators and effectors in macrophages to reduce lipid droplet catabolism, an essential process to generate free cholesterol for efflux. Notably, miR-33 regulation of autophagy lies upstream of its known effects on ABCA1 (ATP-binding cassette transporter A1)-dependent cholesterol efflux, as miR-33 inhibitors fail to increase efflux upon genetic or chemical inhibition of autophagy. Furthermore, we find that miR-33 inhibits apoptotic cell clearance via an autophagy-dependent mechanism. Macrophages treated with anti-miR-33 show increased efferocytosis, lysosomal biogenesis, and degradation of apoptotic material. Finally, we show that treating atherosclerotic Ldlr −/− mice with anti-miR-33 restores defective autophagy in macrophage foam cells and plaques and promotes apoptotic cell clearance to reduce plaque necrosis. Conclusions—: Collectively, these data provide insight into the mechanisms by which miR-33 regulates cellular cholesterol homeostasis and atherosclerosis.

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  • Another group reported similar changes in efferocytosis upon inhibition of miR-33, attributed to regulation of autophagy by miR-33.

    “another group has very recently reported similar changes in efferocytosis upon inhibition of miR-33, which were attributed to regulation of autophagy by miR-33 (Ouimet et al., 2017).”

    From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Ouimet et al., 2017

  • Inhibition of miR-33a or miR-33a deletion in macrophages affects myeloid cell differentiation, induces M2 macrophage polarization with mitochondrial respiratory and metabolic changes, and enhances autophagy.

    “Inhibition of miR-33a or miR-33a deletion in macrophages has been shown to affect myeloid cell differentiation 25) , induce M2 macrophage polarization with mitochondrial respiratory and metabolic changes 26 , 27) , and enhance autophagy 28 , 29) .”

    From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [28]

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Research works printed but not linked: 33

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Authors
Ouimet, M., Ediriweera, H., Afonso, M. S., Ramkhelawon, B., Singaravelu, R., Liao, X., Bandler, R. C., Rahman, K., Fisher, E. A., Rayner, K. J., Pezacki, J. P., Tabas, I., & Moore, K. J.
Affiliations
University of Ottawa (CA)
ORCID
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2017-06
Volume
37
Issue
6
Pages
1058-1067
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
DOI
10.1161/atvbaha.116.308916
PMC
PMC5494696
OpenAlex
W2606060101
Cited by
221
References
12
Citations by year
2026: 19 · 2025: 21 · 2024: 15 · 2023: 25 · 2022: 27 · 2021: 34 · 2020: 28 · 2019: 23 · 2018: 20 · 2017: 9
FWCI
22.42
Type
journal article
Language
en
Open access
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • NPARC (submittedVersion)
Funders
  • Canadian Institutes of Health Research (30365_1, MSH130157)
  • National Heart, Lung, and Blood Institute (R01HL132412, R00HL125667, R01HL106019, K99HL125667, R01HL129433, R35HL135799, R01HL119047)
  • National Institute of Allergy and Infectious Diseases (T32AI100853)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020541)
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 › Cancer Research › MicroRNA in disease regulation
Keywords
microRNA-33, macrophage autophagy, atherosclerosis, cholesterol homeostasis, ABCA1, cholesterol efflux, efferocytosis, lysosomal biogenesis, foam cells, plaque necrosis, Ldlr-deficient mice
MeSH terms
Autophagy-Related Protein 5, Animals, Autophagy, Cholesterol, Gene Expression Regulation, Humans, Lysosomes, Mice, Inbred C57BL, Necrosis, Phenotype, Receptors, LDL, Transfection, Signal Transduction, Macrophages, Peritoneal, Mice, Knockout, Jurkat Cells, Genetic Predisposition to Disease, MicroRNAs, Atherosclerosis, Plaque, Atherosclerotic, Lipid Droplets

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