Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.
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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
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Journal | Nat Med
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Volume | 21
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Issue | 11
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Pages | 1290-7
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Date Published | 2015 Nov
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ISSN | 1546-170X
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DOI | 10.1038/nm.3980
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PubMed ID | 26501192
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PubMed Central ID | PMC4993048
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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
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