PMID- 24603323 OWN - NLM STAT- MEDLINE DCOM- 20140623 LR - 20220408 IS - 0006-3002 (Print) IS - 0006-3002 (Linking) VI - 1841 IP - 6 DP - 2014 Jun TI - miR-206 controls LXRalpha expression and promotes LXR-mediated cholesterol efflux in macrophages. PG - 827-35 LID - S1388-1981(14)00033-X [pii] LID - 10.1016/j.bbalip.2014.02.006 [doi] AB - 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. CI - Copyright (c) 2014. Published by Elsevier B.V. FAU - Vinod, Manjula AU - Vinod M AD - Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria. FAU - Chennamsetty, Indumathi AU - Chennamsetty I AD - Stanford Cardiovascular Medicine, Falk CVRC, USA. FAU - Colin, Sophie AU - Colin S AD - Universite Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France. FAU - Belloy, Loic AU - Belloy L AD - Universite Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France. FAU - De Paoli, Federica AU - De Paoli F AD - Universite Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France. FAU - Schaider, Helmut AU - Schaider H AD - Translation Research Institute, University of Queensland, Brisbane, Australia. FAU - Graier, Wolfgang F AU - Graier WF AD - Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria. FAU - Frank, Sasa AU - Frank S AD - Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria. FAU - Kratky, Dagmar AU - Kratky D AD - Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria. FAU - Staels, Bart AU - Staels B AD - Universite Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France. FAU - Chinetti-Gbaguidi, Giulia AU - Chinetti-Gbaguidi G AD - Universite Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France. FAU - Kostner, Gerhard M AU - Kostner GM AD - Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: Gerhard.kostner@medunigraz.at. LA - eng GR - F 3004/FWF_/Austrian Science Fund FWF/Austria GR - P 22832/FWF_/Austrian Science Fund FWF/Austria GR - W 1226/FWF_/Austrian Science Fund FWF/Austria PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140303 PL - Netherlands TA - Biochim Biophys Acta JT - Biochimica et biophysica acta JID - 0217513 RN - 0 (Liver X Receptors) RN - 0 (MicroRNAs) RN - 0 (Mirn206 microRNA, mouse) RN - 0 (NR1H3 protein, human) RN - 0 (Nr1h3 protein, mouse) RN - 0 (Orphan Nuclear Receptors) RN - 97C5T2UQ7J (Cholesterol) SB - IM MH - Animals MH - Atherosclerosis/genetics/pathology MH - Cholesterol/genetics/*metabolism MH - Gene Expression Regulation MH - Hep G2 Cells MH - Hepatocytes/metabolism/pathology MH - Humans MH - Lipid Metabolism/*genetics MH - Liver X Receptors MH - Macrophages/metabolism MH - Mice MH - Mice, Knockout MH - MicroRNAs/*genetics MH - Orphan Nuclear Receptors/genetics/*metabolism MH - Signal Transduction PMC - PMC3996726 MID - EMS58140 OID - NLM: EMS58140 OTO - NOTNLM OT - ABC OT - ApoA-I OT - HDL OT - LXR target gene OT - Micro-RNA OT - ox-LDL EDAT- 2014/03/08 06:00 MHDA- 2014/06/24 06:00 PMCR- 2014/06/01 CRDT- 2014/03/08 06:00 PHST- 2013/12/03 00:00 [received] PHST- 2014/02/13 00:00 [revised] PHST- 2014/02/24 00:00 [accepted] PHST- 2014/03/08 06:00 [entrez] PHST- 2014/03/08 06:00 [pubmed] PHST- 2014/06/24 06:00 [medline] PHST- 2014/06/01 00:00 [pmc-release] AID - S1388-1981(14)00033-X [pii] AID - 10.1016/j.bbalip.2014.02.006 [doi] PST - ppublish SO - Biochim Biophys Acta. 2014 Jun;1841(6):827-35. doi: 10.1016/j.bbalip.2014.02.006. Epub 2014 Mar 3.