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

Yuan Gao 1, 2 Fuju Wu 1, 3 Jichun Zhou 1, 4 Lei Yan 1, 5 Michael Jurczak 6, 7 Hui-Young Lee 6, 7 Lihua Yang 1, 8 Martin Mueller 9, 10 Xiao-Bo Zhou 1, 10 Luisa Dandolo 11 Julia Szendroedi 12, 13 Michael Roden 12, 13 Hugh Taylor 1 Gerald Shulman 6, 7 Clare Flannery 1 Yingqun Huang 6 Gordon Carmichael 14
1 Department of Obstetrics, Gynecology and Reproductive Sciences
2 Department of Gynecology and Obstetrics
3 Department of Obstetrics and Gynecology
4 Department of Surgical Oncology
5 Department of Obstetrics and Gynecology
6 HHMI - Howard Hughes Medical Institute
7 Departments of Internal Medicine, Cellular & Molecular Physiology
8 Obstetrics and Gynecology Department
9 Analytical, Environmental and Geo- Chemistry
10 Department of Immunology and Pathogenic Biology
11 IC UM3 (UMR 8104 / U1016) - Institut Cochin
12 Institute for Clinical Diabetology
13 Department of Metabolic Diseases
14 3Department of Genetics and Developmental Biology
Abstract : The H19 lncRNA has been implicated in develop-ment 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 de-creased in muscle of human subjects with type-2 di-abetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is re-capitulated 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 biogen-esis 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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Submitted on : Tuesday, November 18, 2014 - 11:58:17 AM
Last modification on : Friday, October 29, 2021 - 9:42:03 AM
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Yuan Gao, Fuju Wu, Jichun Zhou, Lei Yan, Michael Jurczak, et al.. The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells. Nucleic Acids Research, Oxford University Press, 2014, pp.25399420. ⟨10.1093/nar/gku1160⟩. ⟨inserm-01083965⟩

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