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

Manipulating plasma lipids Recent work in mice has shown that microRNA-33a is an important regulator of lipid metabolism and that its inhibition can increase plasma high-density lipoprotein (HDL) and decrease atherosclerosis. Rayner et al . take an important step in translating these findings to non-human primates (African green monkeys), which, like humans and unlike mice, express both miR-33a and miR-33b. They find that anti-miR-33 is effective at inhibiting both miR-33a and miR-33b. As seen in the mouse studies, anti-miR33 raised plasma HDL but had the additional beneficial effect of reducing very low-density lipoprotein triglycerides, making this type of 'antagomir' therapy a candidate method of treating dyslipidaemias that increase cardiovascular disease risk. 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 1 . MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention 2 . 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 3 , 4 , 5 and providing protection against atherosclerosis 6 ; 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 ,