Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis

Nat Med. 2015 Nov;21(11):1290-7. doi: 10.1038/nm.3980. Epub 2015 Oct 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism*
  • Animals
  • Apolipoproteins E / genetics
  • Cholesterol / metabolism
  • Cholesterol, HDL / metabolism*
  • Cholesterol, LDL / metabolism*
  • Diet, High-Fat*
  • Dyslipidemias / genetics*
  • Genome-Wide Association Study
  • Homeostasis / genetics
  • Humans
  • Lipoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Polymorphism, Single Nucleotide
  • Receptors, LDL / metabolism*
  • Triglycerides / metabolism*


  • ATP Binding Cassette Transporter 1
  • Apolipoproteins E
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Lipoproteins
  • MicroRNAs
  • Receptors, LDL
  • Triglycerides
  • lipoprotein cholesterol
  • Cholesterol