MicroRNA-223 coordinates cholesterol homeostasis

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 a...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 40; p. 14518
Main Authors: Vickers, Kasey C, Landstreet, Stuart R, Levin, Michael G, Shoucri, Bassem M, Toth, Cynthia L, Taylor, Robert C, Palmisano, Brian T, Tabet, Fatiha, Cui, Huanhuan L, Rye, Kerry-Anne, Sethupathy, Praveen, Remaley, Alan T
Format: Journal Article
Language:English
Published: United States 07.10.2014
Subjects:
Animals
Cell Line, Tumor
Cells, Cultured
Cholesterol - metabolism
Cholesterol, HDL - metabolism
HEK293 Cells
Homeostasis
Humans
Liver - metabolism
Mice, Knockout
MicroRNAs - genetics
Models, Genetic
Oligonucleotide Array Sequence Analysis
Reverse Transcriptase Polymerase Chain Reaction
Transcriptome - genetics
atherosclerosis
reverse cholesterol transport
posttranscriptional gene regulation
ISSN:1091-6490, 1091-6490
Online Access:Get more information
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Summary: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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1215767111