title: Elevated Hepatic miR-22-3p Expression Impairs Gluconeogenesis by Silencing the Wnt-Responsive Transcription Factor Tcf7.
abstract: Levels of miR-22-3p, a highly abundant hepatic microRNA, are abnormally increased in mouse models of insulin resistance and type 2 diabetes, yet its contribution to deregulated hepatic metabolism under diseased states is not well understood. Here, we unravel a novel link between elevated hepatic miR-22-3p expression and impaired gluconeogenesis in diabetic db/db mice via the regulation of Tcf7 (transcription factor 7). Our data demonstrate that miR-22-3p binds to the 3' untranslated region of TCF7 and downregulates it, and this microRNA-mediated regulation of TCF7 increases the expression of enzymes of the gluconeogenic pathway in HepG2 cells. Small interfering RNA-mediated knockdown of TCF7 in HepG2 cells also causes similar upregulation of gluconeogenic genes. Furthermore, in vivo silencing of miR-22-3p by antagomiR administration lowered random as well as fasting glucose levels in diabetic mice. miR-22-3p antagonism improved glucose tolerance and insulin sensitivity. Importantly, the hepatic Tcf7 levels were restored along with reduced hepatic glucose output, which was also reflected by the decreased expression of gluconeogenic genes. Our results support a critical role for miR-22-3p and its target, Tcf7, in the pathogenesis of diabetes by upregulating gluconeogenesis. Moreover, targeting the miR-22/Tcf7/Wnt axis might hold therapeutic potential for the treatment of altered hepatic physiology during insulin resistance and type 2 diabetes.
authors.affiliation: Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology, New Delhi, India.
authors.forename: Kirandeep
authors.initials: K
authors.lastname: Kaur
authors.affiliation: Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology, New Delhi, India Academy of Scientific and Innovative Research, Training and Development Complex, Council of Scientific and Industrial Research Campus, Taramani, Chennai, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Vig
authors.affiliation: Council of Scientific and Industrial Research-Central Drug Research Institute, Jankipuram Extension, Lucknow, India.
authors.forename: Rohit
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Council of Scientific and Industrial Research-Central Drug Research Institute, Jankipuram Extension, Lucknow, India.
authors.forename: Akansha
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology, New Delhi, India.
authors.forename: Vijay Pal
authors.initials: VP
authors.lastname: Singh
authors.affiliation: Council of Scientific and Industrial Research-Central Drug Research Institute, Jankipuram Extension, Lucknow, India.
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Srivastava
authors.affiliation: Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology, New Delhi, India Academy of Scientific and Innovative Research, Training and Development Complex, Council of Scientific and Industrial Research Campus, Taramani, Chennai, India mdatta@igib.res.in.
authors.forename: Malabika
authors.initials: M
authors.lastname: Datta
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005943:Gluconeogenesis / Q000502:physiology*; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D007328:Insulin; D008055:Lipids; D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse