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 39 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.

The long non-coding RNA Gm10768 activates hepatic gluconeogenesis by sequestering microRNA-214 in mice

“…For example, miR-29a-c decreases hepatic glucose production in primary hepatocytes, and adenovirus-mediated overexpression of miR-29a-c in the liver improves glucose tolerance and insulin resistance of both db/db diabetic and diet-induced obese mice (17). Furthermore, miR-802, miR-214, miR-23a, miR-22, miR-378 and miR-451a have substantial effects on hepatic glucose production (15,16,(18)(19)(20)(21). Specifically, the expression levels of miR-214 were suppressed in the starvation or in diabetic conditions (18), and Gm10768 expression levels were elevated in these two settings.…”

“…We then analyzed the expression levels of several miRNAs, which were already known as gluconeogenic regulators (15)(16)(17)(18)(19)(20)(21), in mouse hepatocytes infected by Ad-Gm10768, in order to screen the potential target of Gm10768. Among all these miRNAs, only miR-214 and miR-22 were significantly decreased in response to Gm10768 overexpression ( Fig.…”

MiR-22 may Suppress Fibrogenesis by Targeting TGFβR I in Cardiac Fibroblasts

“…Increasing evidence showed that miR-22 participated in kinds of disease, such as cancer, diabetes [22], and cardiovascular diseases [23]. Anmad et al report that miR-22 is downregulated in peripheral blood mononuclear cells derived from chronic myeloid leukemia (CML) patients and in CML cell line K562 [24].…”

“…A study from Kaur et al showed that 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 [22].…”

Identificação de vias moduladas por microRNAs na diferenciação celular e manutenção da pluripotência em células humanas

“…Dentres os miRNAs que compõem esses clusters, o miR-22-3p possui atividade inibitória sobre WNT descrita na literatura, assim como os miRNAs da família do miR-29 (KAUR et al, 2015;LIANG et al, 2016;SUBRAMANIAN et al, 2014;TAN;CAI, 2013;ZHANG et al, 2014), os quais também apresentam inibição da via de TGFβ (LI et al, 2009). O miR-27a-3p, por sua vez, também é conhecido por inibir a via do TGFβ, agindo sobre a tradução de SMAD2, regulando negativamente a via TGFβ/Activina/Nodal, inibindo assim o efeito positivo de TGFβ sobre NANOG, que pode resultar em perda do status de pluripotência em células humanas (CHAE et al, 2017;FUCHS et al, 2014).…”