Abstract 13280: Inhibition of miR-33a and b in Non-Human Primates Raises Plasma HDL Cholesterol and Reduces VLDL Triglycerides
MicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and are thus a new class of targets for therapeutic intervention. MicroRNA-33a and b (miR-33a/b) are recently identified intronic microRNAs that regulate cholesterol homeostasis and fatty acid metabolism with their host genes, the sterol response element binding protein genes SREBF2 and SREBF1, respectively. miR-33a/b repress the cholesterol transporter ABCA1, a key regulator of HDL biogenesis and reverse cholesterol transport, and recent studies in mice suggest that antagonizing miR-33a is an effective strategy for raising plasma HDL cholesterol and protecting from atherosclerosis. However the translational relevance of these studies is limited in that mice lack miR-33b which is present only in the SREBP1 gene of higher mammals. We now show that systemic delivery of antisense oligonucleotides that target both miR-33a and b in African green monkeys over 12 weeks increases hepatic expression of ABCA1, inducing a sustained increase in plasma HDL cholesterol. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in the oxidation of fatty acids including, CROT, CPT1a, and HADHB, resulting in a marked suppression of plasma VLDL triglyceride levels, a finding not previously observed in mice. These data demonstrate the therapeutic benefits of inhibiting miR-33a and b for the treatment of dyslipidemias that increase cardiovascular disease risk.
- © 2011 by American Heart Association, Inc.