miRNAs Regulating HDL-C Metabolism and Reverse Cholesterol Transport
In addition to lowering levels of circulating pro-atherogenic lipids, much interest has recently been focused upon developing strategies to promote the removal of cholesterol from arterial macrophages, as a means to limit plaque progression and promote plaque regression. This process, known as reverse cholesterol transport, involves efflux of cholesterol esters from arterial macrophages by the lipid transporters ATP-binding cassette transporter A1 (ABCA1) and ABCG1 onto circulating high-density lipoprotein cholesterol (HDL-C) molecules (Brooks-Wilson et al. 1999; Gelissen et al. 2006; Oram and Vaughan 2000). These cholesterol esters are then transported to the liver where they can be converted into bile acids and removed from the body (Brooks-Wilson et al. 1999; Gelissen et al. 2006; Oram and Vaughan 2000). In recent years, numerous miRNAs have been shown to control numerous aspects of the reverse cholesterol transport pathway, including HDL biogenesis and uptake, cellular cholesterol efflux, and bile acid synthesis and secretion (Fig. 2.1). These include miR-10b, miR-27b, miR-33, miR-96, miR-125a, miR-128a, miR- 144, miR-148a, miR-185, miR-223, miR-302a, and miR-455 (De Aguiar Vallim et al. 2013; Goedeke et al. 2015a, b; Ramirez et al. 2013b; Vickers et al. 2014; Wagschal et al. 2015; Wang et al. 2012, 2013). While all of these miRNAs have the
Fig. 2.1 miRNA regulation of HDL-C metabolism. Schematic overview of miRNAs involved in the regulation of HDL-C metabolism. Blue boxes highlight miRNAs, which regulate genes that control HDL-C. ABC indicates ATP-binding cassette, SR-BI scavenger receptor B1, FXR farnesoid X receptor, and LCAT lecithin-cholesterol acyltransferase (Figure was created using the Servier Medical Art illustration resources (http://www.servier.com)) potential to be important regulators of reverse cholesterol transport and atherogen- esis, only a few have thus far been shown to have a significant impact on atherosclerotic plaque progression. Two independent groups have identified miR-144 as an important regulator of ABCA1 expression in both monocyte/macrophages and the liver (De Aguiar Vallim et al. 2013; Ramirez et al. 2013b). These studies further demonstrate that overexpression of miR-144 decreases circulating HDL-C, while inhibition of miR-144 was found to increase circulating HDL-C. Importantly, further work has since demonstrated that administering miR-144 mimics to ApoE-/- mice on a pro-atherogenic diet reduces hepatic ABCA1 expression and plasma HDL-C levels leading to increased atherosclerotic plaque formation (Hu et al.
2014). More recently, miR-302a has also been found to control the expression of ABCA1, thereby influencing HDL-C levels. Treatment with inhibitors of miR-302a in vivo was demonstrated to increase hepatic ABCA1 and plasma HDL-C leading to reduce atherosclerosis (Meiler et al. 2015). While most of these miRNAs have not been extensively studied for their role in regulating atherosclerosis, a great deal of work has been done exploring the role of the miR-33 family of miRNAs in regulation of this disease.