Abstract 21739: miR-33 as a Therapeutic Target for Raising HDL in Cardiovascular Disease
High density lipoproteins (HDL) have a protective role in atherosclerosis and therapeutic approaches to increase HDL levels are being intensely pursued. However, the molecular mechanisms regulating circulating levels of HDL, “the good cholesterol”, remain poorly defined. Through a genome-wide expression screen of miRNAs that respond to changes in cholesterol levels, we identified microRNA-33a (miR-33a) as a regulator of HDL homeostasis. miR-33a is located within intronic sequences of the sterol-regulatory element-binding factor (SREBF) 2 gene, a transcriptional regulator of cholesterol uptake and synthesis. As has been reported for several intronic miRNAs, we find that miR-33a is co-transcribed with its host gene, SREBF-2 in mice and non-human primates, and is regulated by dietary cholesterol. Investigation of the targets of miR-33 revealed that this microRNA inhibits the expression of the ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1, thereby attenuating cellular cholesterol efflux to apoA1 and HDL, respectively. Additionally, miR-33 represses the expression of Neimann-Pick C1 (NPC1) protein, which is involved in the intracellular transport of cholesterol to post-lysosomal compartments and acts with ABCA1 to mobilize cholesterol to ApoA1, the first step in the reverse cholesterol transport pathway. Notably, in macrophages and hepatic cells, silencing of miR-33 increases ABCA1 and ABCG1 protein levels, thereby promoting cholesterol efflux to apoA1 and HDL. Furthermore, in vivo delivery of anti-miR-33 to C57BL6 mice specifically increases hepatic expression of ABCA1 and elevates plasma HDL cholesterol by 25%. To test the therapeutic potential of miR-33, Ldlr-/- mice with established atherosclerotic lesions (12 weeks WD feeding) were treated with anti-miR-33 or control anti-miR for 4 weeks. Anti-miR-33 treatment increased circulating HDL in these hyperlipidemic mice by 36% (p≤0.05), and we are currently analyzing the impact of this change on atherosclerosis. Together, these findings identify a gene regulatory pathway controlling cholesterol homeostasis and establish the efficacy of miR-33 intervention as a strategy to raise ABCA1 and HDL levels in vivo.
- © 2010 by American Heart Association, Inc.