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

Nature volume 478, pages 404–407 (2011)Cite this article

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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.

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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.

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Data deposits

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

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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.)

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Author notes

  1. Ryan E. Temel and Kathryn J. Moore: These authors contributed equally to this work.

Authors and Affiliations

  1. Leon H. Charney Division of Cardiology, Department of Medicine, Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, 10016, New York, USA

    Katey J. Rayner, Farah N. Hussain, Janine M. van Gils, Tathagat D. Ray, Frederick J. Sheedy, Leigh Goedeke, Carlos Fernandez-Hernando, Edward A. Fisher & Kathryn J. Moore

  2. Regulus Therapeutics, San Diego, 92121, California, USA

    Christine C. Esau, Xueqing Liu, Oleg G. Khatsenko & Vivek Kaimal

  3. Department of Pathology-Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, 27157, North Carolina, USA

    Allison L. McDaniel, Stephanie M. Marshall & Ryan E. Temel

  4. Department of Pathology-Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, 27157, North Carolina, USA

    Cynthia J. Lees

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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.

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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.

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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

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