Abstract 19034: microRNA-145 Regulates ABCA1, SR-B1, and Reverse Cholesterol Transport

Abstract

Background - Reverse cholesterol transport, the process by which cholesterol is effluxed from cells to lipoproteins and subsequently delivered to the liver for clearance, is a promising pathway to augment for treating atherosclerosis. MicroRNA-145 (miR-145) plays a critical role in regulating smooth muscle proliferation, and has been implicated in atherosclerosis. However its function in regulating reverse cholesterol transport has not been investigated. Methods and Results - A bioinformatics screen was performed to find novel microRNAs predicted to regulate ATP-binding cassette transporter A1 (ABCA1), Scavenger receptor class B member 1 (SR-B1), and ATP-binding cassette transporter G1 (ABCG1), critical mediators of reverse cholesterol transport. Based on the results of this screen, miR-145 was further investigated. Overexpression of miR-145 in both the THP-1 macrophage cell line and the HepG2 hepatocyte cell line led to downregulation of ABCA1 and SR-B1 protein levels at 48 hours and 72 hours post-transfection, while no effect was seen on ABCG1. Conversely, knockdown of miR-145 using anti-miRs in HepG2 cells resulted in upregulation of ABCA1 protein levels. Finally, to assess the effects of miR-145 on reverse cholesterol transport, functional assays were performed using radiolabeled cholesterol in differentiated THP-1 cells and in HepG2 cells. These assays demonstrated that miR-145 overexpression in THP-1 cells reduced efflux of radiolabeled cholesterol to HDL, while miR-145 knockdown in HepG2 cells increased cholesterol efflux to the HDL acceptor. Conclusions - In summary, these results demonstrate a role for microRNA-145 in regulating ABCA1, SR-B1, and reverse cholesterol transport.