Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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Nina Höller

Nariae Baik-Schneditz

Bernhard Schwaberger

Lukas Peter Mileder

Niels Hammer

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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Vinod, M; Chennamsetty, I; Colin, S; Belloy, L; De Paoli, F; Schaider, H; Graier, WF; Frank, S; Kratky, D; Staels, B; Chinetti-Gbaguidi, G; Kostner, GM.
miR-206 controls LXRα expression and promotes LXR-mediated cholesterol efflux in macrophages.
Biochim Biophys Acta. 2014; 1841(6):827-835 Doi: 10.1016/j.bbalip.2014.02.006 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz: Kostner Gerhard; Vinod Manjula
Co-Autor*innen der Med Uni Graz: Chennamsetty Indumathi; Frank Sasa; Graier Wolfgang; Kratky Dagmar; Schaider Helmut
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Abstract:: Liver X receptors (LXRα and LXRβ) 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 LXRα but not LXRβ. Indeed, as recently shown, we found that miR-206 represses LXRα activity and expression of LXRα and its target genes in hepatic cells. Interestingly, miR-206 regulates LXRα 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 LXRα and its target genes. In support of these results, bone marrow-derived macrophages (BMDMs) from miR-206 KO mice also exhibited lower expression of LXRα 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 LXRα activation, while oxidized LDL and inflammatory stimuli profoundly induced miR-206 expression. We therefore propose a feed-back loop between miR-206 and LXRα that might be part of an LXR auto-regulatory mechanism to fine tune LXR activity. Copyright © 2014. Published by Elsevier B.V.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Atherosclerosis - genetics Atherosclerosis - pathology; Cholesterol - genetics Cholesterol - metabolism; Gene Expression Regulation -; Hep G2 Cells -; Hepatocytes - metabolism Hepatocytes - pathology; Humans -; Lipid Metabolism - genetics; Macrophages - metabolism; Mice -; Mice, Knockout -; MicroRNAs - genetics; Orphan Nuclear Receptors - genetics Orphan Nuclear Receptors - metabolism; Signal Transduction -
Find related publications in this database (Keywords): Micro-RNA; ox-LDL; LXR target gene; ABC; ApoA-I; HDL