Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 22, Pages 13799-13811Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku1160
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Funding
- Albert McKern Scholar Award [R01 DK-40936, U24 DK-059635, R01 HD072418]
- NIH [R01 HD072418]
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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 down-regulates 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.
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