Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

Alexandre Wagschal, Hani Najafi, Lifeng Wang, Leigh Goedeke, Sumita Sinha, Andrew S. Delemos, Josh C. Black, Cristina M. Ramírez, Yingxia Li, Ryan Tewhey, Ida Hatoum, Naisha Shah, Yong Lu, Fjoralba Kristo, Nikolaos Psychogios, Vladimir Vrbanac, Yi Chien Lu, Timothy Hla, Rafael De Cabo, John S. TsangEric Schadt, Pardis C. Sabeti, Sekar Kathiresan, David E. Cohen, Johnathan Whetstine, Raymond T. Chung, Carlos Fernández-Hernando, Lee M. Kaplan, Andre Bernards, Robert E. Gerszten, Anders M. Näär

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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.

Original languageEnglish
Pages (from-to)1290-1297
Number of pages8
JournalNature Medicine
Volume21
Issue number11
DOIs
Publication statusPublished - 1 Nov 2015

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ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wagschal, A., Najafi, H., Wang, L., Goedeke, L., Sinha, S., Delemos, A. S., Black, J. C., Ramírez, C. M., Li, Y., Tewhey, R., Hatoum, I., Shah, N., Lu, Y., Kristo, F., Psychogios, N., Vrbanac, V., Lu, Y. C., Hla, T., De Cabo, R., ... Näär, A. M. (2015). Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nature Medicine, 21(11), 1290-1297. https://doi.org/10.1038/nm.3980