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Nat Med. 2015 Nov;21(11):1280-9. doi: 10.1038/nm.3949. Epub 2015 Oct 5.

MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels.

Author information

1
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.
2
Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
3
Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
4
Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
5
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
6
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
7
Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA.
8
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
9
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
10
Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
11
Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Madrid, Spain.

Abstract

The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL cholesterol (LDL-C). Whereas the transcriptional regulation of LDLR is well characterized, the post-transcriptional mechanisms that govern LDLR expression are just beginning to emerge. Here we develop a high-throughput genome-wide screening assay to systematically identify microRNAs (miRNAs) that regulate LDLR activity in human hepatic cells. From this screen we identified and characterized miR-148a as a negative regulator of LDLR expression and activity and defined a sterol regulatory element-binding protein 1 (SREBP1)-mediated pathway through which miR-148a regulates LDL-C uptake. In mice, inhibition of miR-148a increased hepatic LDLR expression and decreased plasma LDL-C. Moreover, we found that miR-148a regulates hepatic expression of ATP-binding cassette, subfamily A, member 1 (ABCA1) and circulating high-density lipoprotein cholesterol (HDL-C) levels in vivo. These studies uncover a role for miR-148a as a key regulator of hepatic LDL-C clearance through direct modulation of LDLR expression and demonstrate the therapeutic potential of inhibiting miR-148a to ameliorate an elevated LDL-C/HDL-C ratio, a prominent risk factor for cardiovascular disease.

PMID:
26437365
PMCID:
PMC4711995
DOI:
10.1038/nm.3949
[Indexed for MEDLINE]
Free PMC Article

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