Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.
Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Alexandre
A
Wagschal
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
S Hani
SH
Najafi-Shoushtari
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Lifeng
L
Wang
Section of Comparative Medicine, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Leigh
L
Goedeke
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Sumita
S
Sinha
Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Andrew S
AS
deLemos
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Josh C
JC
Black
Section of Comparative Medicine, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Cristina M
CM
Ramírez
Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Yingxia
Y
Li
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA.
Ryan
R
Tewhey
Obesity, Metabolism and Nutrition Institute and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Ida
I
Hatoum
Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Naisha
N
Shah
Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Yong
Y
Lu
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.
Fjoralba
F
Kristo
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Nikolaos
N
Psychogios
Harvard University Center for AIDS Research, Cambridge, Massachusetts USA.
Vladimir
V
Vrbanac
Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
Yi-Chien
YC
Lu
Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
Timothy
http://orcid.org/0000-0001-8355-4065
T
Hla
Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
Rafael
http://orcid.org/0000-0002-3354-2442
R
de Cabo
Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
John S
JS
Tsang
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Eric
E
Schadt
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.|Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA.
Pardis C
PC
Sabeti
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.|Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Sekar
S
Kathiresan
Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
David E
DE
Cohen
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Johnathan
J
Whetstine
Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Raymond T
RT
Chung
Section of Comparative Medicine, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Carlos
C
Fernández-Hernando
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.|Obesity, Metabolism and Nutrition Institute and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Lee M
LM
Kaplan
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Andre
A
Bernards
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Robert E
RE
Gerszten
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.|Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Anders M
AM
Näär
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism*; D059305:Diet, High-Fat; D050171:Dyslipidemias / Q000235:genetics*; D055106:Genome-Wide Association Study; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011973:Receptors, LDL / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*
D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008074:Lipoproteins; D035683:MicroRNAs; D011973:Receptors, LDL; D014280:Triglycerides; C030104:lipoprotein cholesterol; D002784:Cholesterol