Nature medicine · 2015
Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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, de Cabo Rafael, Tsang John S, Schadt Eric, Sabeti Pardis C, Kathiresan Sekar, Cohen David E, Whetstine Johnathan, Chung Raymond T, Fernández-Hernando Carlos, Kaplan Lee M, Bernards Andre, Gerszten Robert E, Näär Anders M
Аннотация
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.