Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides.
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.
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.
Katey J
KJ
Rayner
Christine C
CC
Esau
Farah N
FN
Hussain
Allison L
AL
McDaniel
Stephanie M
SM
Marshall
Janine M
JM
van Gils
Tathagat D
TD
Ray
Frederick J
FJ
Sheedy
Leigh
L
Goedeke
Xueqing
X
Liu
Oleg G
OG
Khatsenko
Vivek
V
Kaimal
Cynthia J
CJ
Lees
Carlos
C
Fernandez-Hernando
Edward A
EA
Fisher
Ryan E
RE
Temel
Kathryn J
KJ
Moore
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008079:Lipoproteins, VLDL / Q000097:blood*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008078:Cholesterol, LDL; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D035683:MicroRNAs; D020320:Oligoribonucleotides, Antisense; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride