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

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 i...

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Bibliographic Details
Published in:Nucleic acids research 2014-12, Vol.42 (22), p.13799-13811
Main Authors: Gao, Yuan, Wu, Fuju, Zhou, Jichun, Yan, Lei, Jurczak, Michael J, Lee, Hui-Young, Yang, Lihua, Mueller, Martin, Zhou, Xiao-Bo, Dandolo, Luisa, Szendroedi, Julia, Roden, Michael, Flannery, Clare, Taylor, Hugh, Carmichael, Gordon G, Shulman, Gerald I, Huang, Yingqun
Format: Article
Language:English
Subjects:
Animals
Biochemistry, Molecular Biology
Down-Regulation
Feedback, Physiological
Glucose - metabolism
Humans
Hyperinsulinism - genetics
Hyperinsulinism - metabolism
Insulin - pharmacology
Life Sciences
Male
Mice, Inbred C57BL
MicroRNAs - metabolism
Molecular Biology
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
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gku1160