Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides

Abstract

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 effects1. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention2. 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 levels3,4,5 and providing protection against atherosclerosis6; 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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Silencing of miR-33a/b in non-human primates.
Figure 2: Plasma cholesterol levels in control-treated and anti-miR33-treated monkeys.
Figure 3: Characterization of HDL.
Figure 4: Triglyceride and VLDL particle analysis.

Accession codes

Data deposits

The microarray data have been deposited in the Gene Expression Omnibus database under accession number GSE31177.

References

  1. 1

    deGoma, E. M. & Rader, D. J. Novel HDL-directed pharmacotherapeutic strategies. Nature Rev. Cardiol. 8, 266–277 (2011)

    CAS  Article  Google Scholar 

  2. 2

    Moore, K. J., Rayner, K. J., Suarez, Y. & Fernandez-Hernando, C. MicroRNAs and cholesterol metabolism. Trends Endocrinol. Metab. 21, 699–706 (2010)

    CAS  Article  Google Scholar 

  3. 3

    Marquart, T. J., Allen, R. M., Ory, D. S. & Baldan, A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc. Natl Acad. Sci. USA 107, 12228–12232 (2010)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Najafi-Shoushtari, S. H. et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328, 1566–1569 (2010)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Rayner, K. J. et al. miR-33 contributes to the regulation of cholesterol homeostasis. Science 328, 1570–1573 (2010)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Rayner, K. J. et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J. Clin. Invest. 121, 2921–2931 (2011)

    CAS  Article  Google Scholar 

  7. 7

    Davalos, A. et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc. Natl Acad. Sci. USA 108, 9232–9237 (2011)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Gerin, I. et al. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J. Biol. Chem. 285, 33652–33661 (2010)

    CAS  Article  Google Scholar 

  9. 9

    Horton, J. D., Goldstein, J. L. & Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002)

    CAS  Article  Google Scholar 

  10. 10

    Horie, T. et al. microRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo . Proc. Natl Acad. Sci. USA 107, 17321–17326 (2010)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Geary, R. S. Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin. Drug Metab. Toxicol. 5, 381–391 (2009)

    CAS  Article  Google Scholar 

  12. 12

    Chyu, K. Y., Peter, A. & Shah, P. K. Progress in HDL-based therapies for atherosclerosis. Curr. Atheroscler. Rep. 3, 405–412 (2011)

    Article  Google Scholar 

  13. 13

    Alberti, K. G. et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120, 1640–1645 (2009)

    CAS  Article  Google Scholar 

  14. 14

    Wagner, J. E. et al. Old world nonhuman primate models of type 2 diabetes mellitus. ILAR J. 47, 259–271 (2006)

    CAS  Article  Google Scholar 

  15. 15

    Fitzgerald, M. L. et al. ATP-binding cassette transporter A1 contains an NH2-terminal signal anchor sequence that translocates the protein’s first hydrophilic domain to the exoplasmic space. J. Biol. Chem. 276, 15137–15145 (2001)

    CAS  Article  Google Scholar 

  16. 16

    Yvan-Charvet, L. et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328, 1689–1693 (2010)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Kieft, K. A., Bocan, T. M. A. & Krause, B. R. Rapid on-line determination of cholesterol distribution among plasma lipoproteins after high-performance gel filtration chromatography. J. Lipid Res. 32, 859–866 (1991)

    CAS  PubMed  Google Scholar 

  18. 18

    Garber, D. W., Kulkarni, K. R. & Anantharamaiah, G. M. A sensitive and convenient method for lipoprotein profile analysis of individual mouse plasma samples. J. Lipid Res. 41, 1020–1026 (2000)

    CAS  PubMed  Google Scholar 

  19. 19

    Jeyarajah, E. J., Cromwell, W. C. & Otvos, J. D. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin. Lab. Med. 26, 847–870 (2006)

    Article  Google Scholar 

  20. 20

    Koritnik, D. L. & Rudel, L. L. Measurement of apolipoprotein A-I concentration in nonhuman primate serum by enzyme-linked immunosorbent assay (ELISA). J. Lipid Res. 24, 1639–1645 (1983)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Institutes of Health to K.J.M. (R01AG02055 and R01HL108182), E.A.F. (P01HL098055, R01HL084312 and R01HL58541), C.F.-H. (1P30HL101270 and R01HL107953), R.E.T. (R00HL088528), as well as by the Canadian Institutes of Health Research (K.J.R.)

Author information

Affiliations

Authors

Contributions

K.J.M. and R.E.T. contributed equally to this study. K.J.M., R.E.T., C.C.E. and K.J.R. designed the study. C.J.L., R.E.T., A.L.M., S.M.M. and K.J.R. assisted in the necropsy. K.J.R., R.E.T., F.N.H., J.M.V.G., F.J.S., L.G. and T.D.R. performed the biological assays. C.C.E., X.L., O.G.K. and V.K. conducted the miRNA and microarray analyses. E.A.F. and C.F.-H. assisted with the experimental design and data interpretation. K.J.M. and K.J.R. wrote the first draft of the manuscript, which was commented on by all authors.

Corresponding authors

Correspondence to Ryan E. Temel or Kathryn J. Moore.

Ethics declarations

Competing interests

E.A.F. is a Merck Advisory board member and receives honoraria for speaking engagements. C.C.E., X.L., O.G.K., V.K. are employees of Regulus Therapeutics. K.J.R., C.F-H. and K.J.M. have a pending patent on the use of miR-33 inhibitors.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-3 and Supplementary Figures 1-4 with legends. (PDF 1306 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rayner, K., Esau, C., Hussain, F. et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 478, 404–407 (2011). https://doi.org/10.1038/nature10486

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing