Besides miR-148a, Wagschal and colleagues also found a strong association of a number of SNPs in the miR-128-1 gene locus and altered plasma lipid levels (Wagschal et al. 2015). miR-128a regulates the expression of numerous genes associated with multiple metabolic pathways. miR-128a directly targets the 3’UTR of the LDLR and ABCA1, and its inhibition in mice results in a significant decrease in circulating cholesterol and TAG. In addition to its role in controlling lipoprotein metabolism, targeting miR-128-1 in vivo also improved glucose tolerance and insulin sensitivity. Mechanistically, the authors found that miR-128-1 regulates the expression of the insulin receptor (INSR) and insulin receptor substrate 1 (IRS-1) and downstream phosphorylation levels of Akt. Finally, it was also found that miR- 128-1 controls the expression of genes associated with fatty acid synthesis, including the fatty acid synthase (FASN) and SIRT1, an NAD+-dependent energy sensor and deacetylase that can directly deacetylate and inactivate SREBP1 and thus modulate SREBP1-dependent lipogenesis. Altogether, these observations suggest that miR-128a expression might influence plasma lipid levels by regulating the expression of genes associated with lipid and glucose metabolism. Further studies are necessary to define the specific contribution of miR-128a target genes in different tissues and their impact on regulating lipid and glucose metabolism.
Several reports have recently shown that miR-185 regulates cholesterol metabolism in vitro and in vivo by regulating the expression of LDLR and SRBI, a hepatic HDL-C receptor that facilitates the uptake of cholesteryl esters from HDL in the liver (Jiang et al. 2015; Wang et al. 2013; Yang et al. 2014). Interestingly, miR-185 also targets KH-type splicing regulatory protein (KSRP), a RNA-binding protein that negatively regulates the expression of the human LDLR (Jiang et al. 2015). These findings suggest that inhibiting miR-185 in vivo might attenuate atherosclerosis by reducing circulating LDL-C and promoting reverse cholesterol transport. Indeed, a recent study demonstrated that inhibition of miR-185 in the atheroprone ApoEmice significantly reduced plasma cholesterol levels and attenuated the progression of atherosclerosis (Jiang et al. 2015).