| First Author | Vinod M | Year | 2014 |
| Journal | Biochim Biophys Acta | Volume | 1841 |
| Issue | 6 | Pages | 827-35 |
| PubMed ID | 24603323 | Mgi Jnum | J:211566 |
| Mgi Id | MGI:5575686 | Doi | 10.1016/j.bbalip.2014.02.006 |
| Citation | Vinod M, et al. (2014) miR-206 controls LXRalpha expression and promotes LXR-mediated cholesterol efflux in macrophages. Biochim Biophys Acta 1841(6):827-35 |
| abstractText | Liver X receptors (LXRalpha and LXRbeta) are key transcription factors in cholesterol metabolism that regulate cholesterol biosynthesis/efflux and bile acid metabolism/excretion in the liver and numerous organs. In macrophages, LXR signaling modulates cholesterol handling and the inflammatory response, pathways involved in atherosclerosis. Since regulatory pathways of LXR transcription control are well understood, in the present study we aimed at identifying post-transcriptional regulators of LXR activity. MicroRNAs (miRs) are such post-transcriptional regulators of genes that in the canonical pathway mediate mRNA inactivation. In silico analysis identified miR-206 as a putative regulator of LXRalpha but not LXRbeta. Indeed, as recently shown, we found that miR-206 represses LXRalpha activity and expression of LXRalpha and its target genes in hepatic cells. Interestingly, miR-206 regulates LXRalpha differently in macrophages. Stably overexpressing miR-206 in THP-1 human macrophages revealed an up-regulation and miR-206 knockdown led to a down-regulation of LXRalpha and its target genes. In support of these results, bone marrow-derived macrophages (BMDMs) from miR-206 KO mice also exhibited lower expression of LXRalpha target genes. The physiological relevance of these findings was proven by gain- and loss-of-function of miR-206; overexpression of miR-206 enhanced cholesterol efflux in human macrophages and knocking out miR-206 decreased cholesterol efflux from MPMs. Moreover, we show that miR-206 expression in macrophages is repressed by LXRalpha activation, while oxidized LDL and inflammatory stimuli profoundly induced miR-206 expression. We therefore propose a feed-back loop between miR-206 and LXRalpha that might be part of an LXR auto-regulatory mechanism to fine tune LXR activity. |
