title: MicroRNA-223 coordinates cholesterol homeostasis.
abstract: MicroRNAs (miRNAs) regulate a wide variety of biological processes and contribute to metabolic homeostasis. Here, we demonstrate that microRNA-223 (miR-223), an miRNA previously associated with inflammation, also controls multiple mechanisms associated with cholesterol metabolism. miR-223 promoter activity and mature levels were found to be linked to cellular cholesterol states in hepatoma cells. Moreover, hypercholesterolemia was associated with increased hepatic miR-223 levels in athero-prone mice. miR-223 was found to regulate high-density lipoprotein-cholesterol (HDL-C) uptake, through direct targeting and repression of scavenger receptor BI, and to inhibit cholesterol biosynthesis through the direct repression of sterol enzymes 3-hydroxy-3-methylglutaryl-CoA synthase 1 and methylsterol monooxygenase 1 in humans. Additionally, miR-223 was found to indirectly promote ATP-binding cassette transporter A1 expression (mRNA and protein) through Sp3, thereby enhancing cellular cholesterol efflux. Finally, genetic ablation of miR-223 in mice resulted in increased HDL-C levels and particle size, as well as increased hepatic and plasma total cholesterol levels. In summary, we identified a critical role for miR-223 in systemic cholesterol regulation by coordinated posttranscriptional control of multiple genes in lipoprotein and cholesterol metabolism.
authors.affiliation: National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; kasey.c.vickers@Vanderbilt.edu.
authors.forename: Kasey C
authors.initials: KC
authors.lastname: Vickers
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Landstreet
authors.affiliation: National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Michael G
authors.initials: MG
authors.lastname: Levin
authors.affiliation: National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Bassem M
authors.initials: BM
authors.lastname: Shoucri
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Toth
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Robert C
authors.initials: RC
authors.lastname: Taylor
authors.affiliation: National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Brian T
authors.initials: BT
authors.lastname: Palmisano
authors.affiliation: Lipid Research Group, The Heart Research Institute, Newtown, NSW 2042, Australia;
authors.forename: Fatiha
authors.initials: F
authors.lastname: Tabet
authors.affiliation: Lipoproteins and Atherosclerosis, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; and.
authors.forename: Huanhuan L
authors.initials: HL
authors.lastname: Cui
authors.affiliation: Lipid Research Group, The Heart Research Institute, Newtown, NSW 2042, Australia;
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Praveen
authors.initials: P
authors.lastname: Sethupathy
authors.affiliation: National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000235:genetics*
chemical_list: D002784:Cholesterol; D008076:Cholesterol, HDL; D035683:MicroRNAs; C525067:MIR223, human; C544877:MIRN223 microRNA, mouse
keywords: atherosclerosis; posttranscriptional gene regulation; reverse cholesterol transport