The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells

Nucleic Acids Res. 2014 Dec 16;42(22):13799-811. doi: 10.1093/nar/gku1160. Epub 2014 Nov 15.

Abstract

The H19 lncRNA has been implicated in development and growth control and is associated with human genetic disorders and cancer. Acting as a molecular sponge, H19 inhibits microRNA (miRNA) let-7. Here we report that H19 is significantly decreased in muscle of human subjects with type-2 diabetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is recapitulated in vitro where H19 depletion results in impaired insulin signaling and decreased glucose uptake. Furthermore, acute hyperinsulinemia downregulates H19, a phenomenon that occurs through PI3K/AKT-dependent phosphorylation of the miRNA processing factor KSRP, which promotes biogenesis of let-7 and its mediated H19 destabilization. Our results reveal a previously undescribed double-negative feedback loop between sponge lncRNA and target miRNA that contributes to glucose regulation in muscle cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Down-Regulation
  • Feedback, Physiological
  • Glucose / metabolism*
  • Humans
  • Hyperinsulinism / genetics
  • Hyperinsulinism / metabolism
  • Insulin / pharmacology
  • Male
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism*
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • RNA, Long Noncoding / metabolism*
  • RNA-Binding Proteins / physiology
  • Signal Transduction
  • Trans-Activators / physiology

Substances

  • H19 long non-coding RNA
  • Insulin
  • Khsrp protein, mouse
  • MicroRNAs
  • RNA, Long Noncoding
  • RNA-Binding Proteins
  • Trans-Activators
  • mirnlet7 microRNA, human
  • mirnlet7 microRNA, mouse
  • Glucose