Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

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Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

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Title: Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis
Author: Wagschal, Alexandre; Najafi-Shoushtari, S Hani; Wang, Lifeng; Goedeke, Leigh; Sinha, Sumita; deLemos, Andrew S; Black, Josh C; Ramírez, Cristina M; Li, Yingxia; Tewhey, Ryan; Hatoum, Ida; Shah, Naisha; Lu, Yong; Kristo, Fjoralba; Psychogios, Nikolaos; Vrbanac, Vladimir; Lu, Yi-Chien; Hla, Timothy T; de Cabo, Rafael; Tsang, John S; Schadt, Eric; Sabeti, Pardis Christine; Kathiresan, Sekar; Cohen, David E; Whetstine, Johnathan; Chung, Raymond Taeyong; Fernández-Hernando, Carlos; Kaplan, Lee Michael; Bernards, Andre; Gerszten, Robert Edgardo; Naar, Anders Michael

Note: Order does not necessarily reflect citation order of authors.

Citation: Wagschal, 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.
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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.
Published Version: doi:10.1038/nm.3980
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