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

• Published in: Nucleic acids research Vol. 42; no. 22; pp. 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: Journal Article
• Language: English
• Published: England Oxford University Press 16.12.2014
• 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
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gku1160

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.