MicroRNA-223 coordinates cholesterol homeostasis.

Vickers KC, Landstreet SR, Levin MG, Shoucri BM, Toth CL, Taylor RC, Palmisano BT, Tabet F, Cui HL, Rye KA, Sethupathy P, Remaley AT
Proc Natl Acad Sci U S A. 2014 111 (40): 14518-23

PMID: 25246565 · PMCID: PMC4210029 · DOI:10.1073/pnas.1215767111

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.

MeSH Terms (15)

Animals Cell Line, Tumor Cells, Cultured Cholesterol Cholesterol, HDL HEK293 Cells Homeostasis Humans Liver Mice, Knockout MicroRNAs Models, Genetic Oligonucleotide Array Sequence Analysis Reverse Transcriptase Polymerase Chain Reaction Transcriptome

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