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

Nat Med
Authors
Keywords
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.

Year of Publication
2015
Journal
Nat Med
Volume
21
Issue
11
Pages
1290-7
Date Published
2015 Nov
ISSN
1546-170X
DOI
10.1038/nm.3980
PubMed ID
26501192
PubMed Central ID
PMC4993048
Links
Grant list
P30 DK040561 / DK / NIDDK NIH HHS / United States
R21DK084459 / DK / NIDDK NIH HHS / United States
P30 NS072030 / NS / NINDS NIH HHS / United States
K24 DK078772 / DK / NIDDK NIH HHS / United States
R01 HL107953 / HL / NHLBI NIH HHS / United States
R01 DK056626 / DK / NIDDK NIH HHS / United States
R01 HL049094 / HL / NHLBI NIH HHS / United States
R01HL106063 / HL / NHLBI NIH HHS / United States
R01DK094184 / DK / NIDDK NIH HHS / United States
K24DK078772 / DK / NIDDK NIH HHS / United States
R37 DK048873 / DK / NIDDK NIH HHS / United States
P30 DK034854 / DK / NIDDK NIH HHS / United States
R01 DK094184 / DK / NIDDK NIH HHS / United States
R01HL107953 / HL / NHLBI NIH HHS / United States
R21 DK084459 / DK / NIDDK NIH HHS / United States
R01 HL106063 / HL / NHLBI NIH HHS / United States
R37DK048873 / DK / NIDDK NIH HHS / United States
R01DK056626 / DK / NIDDK NIH HHS / United States
R01HL49094 / HL / NHLBI NIH HHS / United States