Cholesterol homeostasis regulation by miR-223: basic science mechanisms and translational implications.

Abstract

Cholesterol homeostasis is a tightly regulated process. Previous work has been dominated by sterol-response element—related mechanisms, but the influence of micro-RNAs (miRs) is increasingly recognized, with miR-223 becoming a recent member of this group. Several micro-RNAs (miRNAs or miR-) have been reported to be involved in cholesterol homeostasis.1–4 In a recent study, Vickers et al5 presented miR-223 as an important new player in this arena, one that they propose to be a coordinator of cholesterol homeostasis.5 This miRNA had been previously found to be rich in myeloid cells, where it regulates differentiation and inflammation,6,7 but the authors found that its abundance in hepatic cells is at least comparable with that of many functionally validated miRNAs. A relationship between miR-223 and cholesterol metabolism was suggested by finding its expression in human hepatoma (Huh7) cells was positively associated with intracellular cholesterol levels. In a series of studies in Huh7 cells, it was then shown that miR-223 (1) inhibited high-density lipoprotein cholesterol (HDL-C) uptake, (2) promoted cholesterol efflux, and (3) suppressed cholesterol biosynthesis. The authors also showed increased cholesterol levels in liver and plasma of miR-223 knockout mice, extending its involvement in cholesterol homeostasis in vitro to the in vivo setting. The experimental approaches taken are well established in the miRNA field and were coupled to a productive use of bioinformatics. This included investigating whether the effects of miR-223 on a particular RNA were direct, by cloning into a luciferase reporter plasmid the putative target sequence in the 3′-UTR of that mRNA (or this sequence deleted in nucleotides required for miR-223 binding). The effect of exogenously supplied miR-223 on luciferase activity in transfected HEK293 cells was then measured. Thus, they determined that the molecular mechanisms for the functional reductions in HDL-C uptake and cholesterol biosynthesis …