Publication Date:
2011-10-21
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235584/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235584/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rayner, Katey J -- Esau, Christine C -- Hussain, Farah N -- McDaniel, Allison L -- Marshall, Stephanie M -- van Gils, Janine M -- Ray, Tathagat D -- Sheedy, Frederick J -- Goedeke, Leigh -- Liu, Xueqing -- Khatsenko, Oleg G -- Kaimal, Vivek -- Lees, Cynthia J -- Fernandez-Hernando, Carlos -- Fisher, Edward A -- Temel, Ryan E -- Moore, Kathryn J -- 1P30HL101270/HL/NHLBI NIH HHS/ -- P01HL098055/HL/NHLBI NIH HHS/ -- R00 HL088528/HL/NHLBI NIH HHS/ -- R00 HL088528-04/HL/NHLBI NIH HHS/ -- R00 HL088528-05/HL/NHLBI NIH HHS/ -- R00HL088528/HL/NHLBI NIH HHS/ -- R01AG02055/AG/NIA NIH HHS/ -- R01HL084312/HL/NHLBI NIH HHS/ -- R01HL107953/HL/NHLBI NIH HHS/ -- R01HL108182/HL/NHLBI NIH HHS/ -- R01HL58541/HL/NHLBI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2011 Oct 19;478(7369):404-7. doi: 10.1038/nature10486.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22012398" target="_blank"〉PubMed〈/a〉
Keywords:
ATP Binding Cassette Transporter 1
;
ATP-Binding Cassette Transporters/metabolism
;
Animals
;
Cells, Cultured
;
*Cercopithecus aethiops/blood/genetics/metabolism
;
Cholesterol, LDL/blood
;
Gene Expression Regulation/*drug effects
;
Gene Silencing
;
HEK293 Cells
;
Humans
;
Lipoproteins, HDL/*blood
;
Lipoproteins, VLDL/*blood
;
Liver/*drug effects/metabolism
;
Male
;
MicroRNAs/*antagonists & inhibitors/metabolism
;
Oligoribonucleotides, Antisense/*pharmacology
;
Time Factors
;
Triglycerides/*blood
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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