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      miR-206 controls LXRα expression and promotes LXR-mediated cholesterol efflux in macrophages

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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.

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          Highlights

          • Functional differences of miR-206 in the liver and macrophages

          • In the liver, miR-206 suppresses LXRα expression and signaling.

          • In macrophages, miR-206 increases LXRα abundance and promotes cholesterol efflux.

          • In macrophages, LXRα activation represses miR-206 expression.

          • In macrophages, pro-inflammatory stimuli increase miR-206 expression.

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          Most cited references27

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          Switching from repression to activation: microRNAs can up-regulate translation.

          AU-rich elements (AREs) and microRNA target sites are conserved sequences in messenger RNA (mRNA) 3' untranslated regions (3'UTRs) that control gene expression posttranscriptionally. Upon cell cycle arrest, the ARE in tumor necrosis factor-alpha (TNFalpha) mRNA is transformed into a translation activation signal, recruiting Argonaute (AGO) and fragile X mental retardation-related protein 1 (FXR1), factors associated with micro-ribonucleoproteins (microRNPs). We show that human microRNA miR369-3 directs association of these proteins with the AREs to activate translation. Furthermore, we document that two well-studied microRNAs-Let-7 and the synthetic microRNA miRcxcr4-likewise induce translation up-regulation of target mRNAs on cell cycle arrest, yet they repress translation in proliferating cells. Thus, activation is a common function of microRNPs on cell cycle arrest. We propose that translation regulation by microRNPs oscillates between repression and activation during the cell cycle.
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            MiR-33 contributes to the regulation of cholesterol homeostasis.

            Cholesterol metabolism is tightly regulated at the cellular level. Here we show that miR-33, an intronic microRNA (miRNA) located within the gene encoding sterol-regulatory element-binding factor-2 (SREBF-2), a transcriptional regulator of cholesterol synthesis, modulates the expression of genes involved in cellular cholesterol transport. In mouse and human cells, miR-33 inhibits the expression of the adenosine triphosphate-binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apolipoprotein A1. In mouse macrophages, miR-33 also targets ABCG1, reducing cholesterol efflux to nascent high-density lipoprotein (HDL). Lentiviral delivery of miR-33 to mice represses ABCA1 expression in the liver, reducing circulating HDL levels. Conversely, silencing of miR-33 in vivo increases hepatic expression of ABCA1 and plasma HDL levels. Thus, miR-33 appears to regulate both HDL biogenesis in the liver and cellular cholesterol efflux.
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              Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis.

              Plasma HDL levels have a protective role in atherosclerosis, yet clinical therapies to raise HDL levels have remained elusive. Recent advances in the understanding of lipid metabolism have revealed that miR-33, an intronic microRNA located within the SREBF2 gene, suppresses expression of the cholesterol transporter ABC transporter A1 (ABCA1) and lowers HDL levels. Conversely, mechanisms that inhibit miR-33 increase ABCA1 and circulating HDL levels, suggesting that antagonism of miR-33 may be atheroprotective. As the regression of atherosclerosis is clinically desirable, we assessed the impact of miR-33 inhibition in mice deficient for the LDL receptor (Ldlr-/- mice), with established atherosclerotic plaques. Mice treated with anti-miR33 for 4 weeks showed an increase in circulating HDL levels and enhanced reverse cholesterol transport to the plasma, liver, and feces. Consistent with this, anti-miR33-treated mice showed reductions in plaque size and lipid content, increased markers of plaque stability, and decreased inflammatory gene expression. Notably, in addition to raising ABCA1 levels in the liver, anti-miR33 oligonucleotides directly targeted the plaque macrophages, in which they enhanced ABCA1 expression and cholesterol removal. These studies establish that raising HDL levels by anti-miR33 oligonucleotide treatment promotes reverse cholesterol transport and atherosclerosis regression and suggest that it may be a promising strategy to treat atherosclerotic vascular disease.
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                Author and article information

                Contributors
                Journal
                Biochim Biophys Acta
                Biochim. Biophys. Acta
                Biochimica et Biophysica Acta
                Elsevier Pub. Co
                0006-3002
                1 June 2014
                June 2014
                : 1841
                : 6
                : 827-835
                Affiliations
                [a ]Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria
                [b ]Stanford Cardiovascular Medicine, Falk CVRC, USA
                [c ]Université Lille 2, F-59000 Lille, France
                [d ]Inserm, U1011, F-59000 Lille, France
                [e ]Institut Pasteur de Lille, F-59019 Lille, France
                [f ]European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France
                [g ]Translation Research Institute, University of Queensland, Brisbane, Australia
                Author notes
                [* ]Corresponding author at: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, A-8010 Graz, Austria. Tel.: + 43 316 380 4202; fax: + 43 316 380 9615. Gerhard.kostner@ 123456medunigraz.at
                Article
                S1388-1981(14)00033-X
                10.1016/j.bbalip.2014.02.006
                3996726
                24603323
                2e90eacf-35af-4d32-8bdb-375e4fa9360d
                © 2014 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                : 3 December 2013
                : 13 February 2014
                : 24 February 2014
                Categories
                Article

                Biochemistry
                mir, micro-rna,lxrs, liver x receptors,apoe, apolipoprotein e,abcs, atp-binding cassette transporters,ko, knockout,srebp, sterol regulatory element-binding protein,micro-rna,ox-ldl,lxr target gene,abc,apoa-i,hdl

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