Format

Send to

Choose Destination
See comment in PubMed Commons below
Nat Med. 2015 Nov;21(11):1290-7. doi: 10.1038/nm.3980. Epub 2015 Oct 26.

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.

Author information

1
Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, USA.
2
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
3
Section of Comparative Medicine, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
4
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
5
Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
7
Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
8
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
9
Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA.
10
Obesity, Metabolism and Nutrition Institute and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
11
Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
12
Harvard University Center for AIDS Research, Cambridge, Massachusetts USA.
13
Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
14
Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
15
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
16
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

Abstract

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.

PMID:
26501192
PMCID:
PMC4993048
DOI:
10.1038/nm.3980
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center