Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides
Open accessAbstract
Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.
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miR-33 suppresses genes involved in mitochondrial β-oxidation, such as CPT1A, HADHB, and CROT.
“MiR-33 suppresses genes involved in mitochondrial β-oxidation, such as carnitine palmitoyltransferase 1A (CPT1A), hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit b (HADHB), and carnitine O-octanoyltransferase (CROT) 15 , 17 , 34 , 35) .”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [17]
The paper reports that anti-miR-33 derepressed HADHB, CPT1A, and CROT, which it identifies as genes involved in fatty acid oxidation (main text, Fig. 4 discussion; page unavailable in our copy). This supports the claim that miR-33 suppresses these genes, but the cited passages do not specifically characterize all three as involved in mitochondrial β-oxidation. (LLM, conf=0.82)
Experimental — accuracy not yet measuredFindings in non-human primates suggest that miR-33a and miR-33b play crucial roles in cholesterol regulation in humans.
“These findings have also been validated in non-human primates, suggesting that miR-33a and miR-33b play crucial roles in cholesterol regulation in humans 17 , 18) .”
From Critical Role of microRNA-33a/b in Cardiovascular and Metabolic Disease: Molecular Mechanisms and Therapeutic Perspectives (2026) · cites this paper as [17]
The numbers of miR-33b transcripts were greater than those of miR-33a transcripts.
“In any event, the numbers of miR-33b transcripts were greater than those of miR-33a transcripts, and this underscores the importance of miR-33b21.”
From MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo (2014) · cites this paper as [21]
Inhibition of miR-33a/b in nonhuman primates raised plasma HDL-C and lowered VLDL triglyceride levels.
“A recent report indicated that the inhibition of miR-33a/b in nonhuman primates raised plasma HDL-C and lowered VLDL triglyceride levels.47”
From MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE <sup>−/−</sup> Mice (2012) · cites this paper as [47]
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- Authors
- Rayner, K. J., Esau, C. C., Hussain, F. N., McDaniel, A. L., Marshall, S. M., van Gils, J. M., Ray, T. D., Sheedy, F. J., Goedeke, L., Liu, X., Khatsenko, O. G., Kaimal, V., Lees, C. J., Fernandez-Hernando, C., Fisher, E. A., Temel, R. E., & Moore, K. J.
- Affiliations
- New York University (US)
- Regulus Therapeutics (United States) (US)
- NYU Langone Health (US)
- Wake Forest University Health Sciences (US)
- Corresponding author
- Temel, Ryan E.
- Moore, Kathryn J.
- ORCID
- Venue
- Nature
- Published
- 2011-10
- Volume
- 478
- Issue
- 7369
- Pages
- 404-407
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3235584
- OpenAlex
- W2047043150
- Cited by
- 706
- References
- 6
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 17 · 2023: 23 · 2022: 46 · 2021: 39 · 2020: 40 · 2019: 40 · 2018: 37 · 2017: 43 · 2016: 66 · 2015: 77 · 2014: 79 · 2013: 92 · 2012: 67
- FWCI
- 79.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- National Institutes of Health (5r00hl088528-05)
- Canadian Institutes of Health Research
- National Institute on Aging (R01 AG02055)
- National Heart, Lung, and Blood Institute (R01HL084312, R01 HL58541, R00-HL088528, T32HL091797, P30HL101270, P01HL098055, R01HL058541, R01HL108182, R01HL107953)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- HDL cholesterol, VLDL triglycerides, ABCA1, SREBF1, SREBF2, lipid metabolism, dyslipidemia, cardiovascular disease, vervet monkey, non-human primates, hepatic lipid metabolism, atherosclerosis
- MeSH terms
- Animals, Cells, Cultured, Chlorocebus aethiops, Gene Expression Regulation, Humans, Lipoproteins, HDL, Cholesterol, LDL, Lipoproteins, VLDL, Liver, Male, Time Factors, Triglycerides, ATP-Binding Cassette Transporters, Oligoribonucleotides, Antisense, Gene Silencing, MicroRNAs, HEK293 Cells, ATP Binding Cassette Transporter 1
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