title: MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels.
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.
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.|Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
authors.forename: Leigh
authors.initials: L
authors.lastname: Goedeke
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Canfrán-Duque
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Aranda
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.|Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Araldi
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.|Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
authors.forename: Chin-Sheng
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Norma N
authors.initials: NN
authors.lastname: Anderson
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Wagschal
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.|Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lasunción
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, USA.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Näär
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.|Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
authors.forename: Yajaira
authors.initials: Y
authors.lastname: Suárez
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.|Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA.|Department of Cell Biology, New York University School of Medicine, New York, New York, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D008076:Cholesterol, HDL / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C550570:MIRN148 microRNA, human; D035683:MicroRNAs; D011973:Receptors, LDL; D051780:Sterol Regulatory Element Binding Protein 1