title: miR-206 controls LXRα expression and promotes LXR-mediated cholesterol efflux in macrophages.
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.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
authors.forename: Manjula
authors.initials: M
authors.lastname: Vinod
authors.affiliation: Stanford Cardiovascular Medicine, Falk CVRC, USA.
authors.forename: Indumathi
authors.initials: I
authors.lastname: Chennamsetty
authors.affiliation: Université 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Colin
authors.affiliation: Université 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.
authors.forename: Loic
authors.initials: L
authors.lastname: Belloy
authors.affiliation: Université 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.
authors.forename: Federica
authors.initials: F
authors.lastname: De Paoli
authors.affiliation: Translation Research Institute, University of Queensland, Brisbane, Australia.
authors.forename: Helmut
authors.initials: H
authors.lastname: Schaider
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
authors.forename: Saša
authors.initials: S
authors.lastname: Frank
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.affiliation: Université 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.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: Université 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.
authors.forename: Giulia
authors.initials: G
authors.lastname: Chinetti-Gbaguidi
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria. Electronic address: Gerhard.kostner@medunigraz.at.
authors.forename: Gerhard M
authors.initials: GM
authors.lastname: Kostner
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000071518:Liver X Receptors; D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D002784:Cholesterol
keywords: ABC; ApoA-I; HDL; LXR target gene; Micro-RNA; ox-LDL