Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-11

AUTHORS

Alexandre Wagschal, S Hani Najafi-Shoushtari, 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 Tsang, Eric 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

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. More... »

PAGES

1290-1297

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nm.3980

DOI

http://dx.doi.org/10.1038/nm.3980

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1015504183

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26501192


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