miRNAs That Regulate LDLR Expression and LDL-C Clearance
Several studies have recently identified miRNAs that regulate LDL-C metabolism via posttranscriptional regulation of LDLR. Notably, miR-27a/miR-27b, miR- 128-1, miR-130b, miR-148a, miR-185, miR-199a, and miR-301 were shown to directly target the 3’UTR of LDLR and modulate LDLR expression in human and mouse hepatic cells (Alvarez et al. 2015; Goedeke et al. 2015b; Jiang et al. 2015; Wagschal et al. 2015). Of these miRNAs, only miR-128-1, miR-148a, and miR-185 significantly altered plasma LDL-C in vivo (Goedeke et al. 2015a; Jiang et al. 2015; Wagschal et al. 2015; Yang et al. 2014). Thus, we will only discuss in greater detail how these miRNAs regulate hepatic lipid metabolism and circulating LDL-C.
miR-148a has been recently identified by two independent studies as an important regulator of hepatic LDLR expression and lipoprotein metabolism in a number of mouse models (Goedeke et al. 2015a; Wagschal et al. 2015). In the first study, Goedeke and colleagues developed a high-throughput genome-wide screening assay to systematically identify miRNAs that regulate LDLR activity in human hepatic cells (Goedeke et al. 2015a). From this screen, the authors identified and characterized miR-148a as a negative regulator of LDLR expression and activity. miR-148a is highly expressed in the liver, and its expression is regulated by dietary lipids and SREBP1. Of note, pharmacological inhibition of miR-148a using ASOs lowered plasma LDL-C levels in two different mouse models of hypercholesterolemia (Goedeke et al. 2015a; Wagschal et al. 2015). Surprisingly, targeting miR- 148a in vivo also increases hepatic ABCA1 expression and circulating HDL-C. Further experiments demonstrated that ABCA1 is also a miR-148a target gene. Collectively these studies underscore the therapeutic potential of modulating miR-148a expression to treat dyslipidemias (high plasma LDL-C and low circulating HDL-C).
Several labs independently identified SNPs (rs4722551, rs4719841, and rs6951827) in the promoter region of miR-148a associated with altered plasma TC, LDL-C, and TAG levels (Do et al. 2013; Global Lipids Genetics Consortium et al. 2013; Huan et al. 2015). In particular, a miR-eQTL analysis performed in human livers revealed a strong correlation between SNP status and miR-148a expression (Wagschal et al. 2015). Although the exact mechanism by which these SNPs contribute to altered plasma lipids remains unknown, it could be possible that these genetic variations might influence the regulation of miR-148a expression via SREBP1. However, whether these SNPs affect SREBP1-induced transcription requires further investigation. The role of miR-148a in regulating lipid metabolism is likely to be more complex and not only mediated by its targeting on LDLR and ABCA1. In particular, miR-148a was demonstrated to directly target the 3’UTR of other genes involved in lipid metabolism, including PGCla, AMPK, and INSIGl (Wagschal et al. 2015; Goedeke et al. 2015a). Taken together, these findings highlight the importance of miR-148a in regulating lipid metabolism in mice and humans and underscore the therapeutic potential of modulating miR-148a expression to treat dyslipidemias.