Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Vinod, M.
Posttranscriptional Regulation of Liver X Receptor: Specific role for MicroRNAs
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2014. pp. 93
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- Autor*innen der Med Uni Graz:
- Vinod Manjula
- Betreuer*innen:
- Frank Sasa
- Kostner Gerhard
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- Abstract:
- ABSTRACT Liver X receptors (LXRa and LXRß) are key transcription factors in cholesterol metabolism that regulate cholesterol biosynthesis and cholesterol efflux as well as bile acid metabolism and excretion in the liver and numerous organs. In macrophages, LXR signaling modulates cholesterol handling and the inflammatory response, pathways involved in atherogenesis. Since regulatory pathways controlling LXR transcription 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 LXRa but not LXRß. Indeed, as recently shown, we found that miR-206 represses LXRa activity and expression of LXRa and its target genes in hepatic cells. Interestingly, miR-206 regulates LXRa 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 LXRa and its target genes. In support of these results, bone marrow-derived macrophages (BMDM) from miR-206 KO mice also exhibited lower expression of LXRa 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 LXRa activation, while oxidized LDL and inflammatory stimuli profoundly induced miR-206 expression. We therefore propose a feed-back loop between miR-206 and LXRa that might be part of an LXR auto-regulatory mechanism to fine tune LXR activity.