Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis
Najafi-Shoushtari, S Hani
deLemos, Andrew S
Black, Josh C
Ramírez, Cristina M
de Cabo, Rafael
Tsang, John S
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CitationWagschal, Alexandre, S Hani Najafi-Shoushtari, Lifeng Wang, Leigh Goedeke, Sumita Sinha, Andrew S deLemos, Josh C Black, et al. 2015. Genome-Wide Identification of microRNAs Regulating Cholesterol and Triglyceride Homeostasis. Nature Medicine 21, no. 11: 1290–1297. doi:10.1038/nm.3980.
AbstractGenome-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.
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