Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4\u03b1 fetal isoform

Da Li Da Li,Di Xie Di Xie,Yingqun Huang,Tiefeng Cao,Sungho Jin,Sabrina Diano,Gordon G Carmichael,Xinmei Huang,Xiaoli Sun,Xiaoyong Yang,Hugh S Taylor

doi:10.1038/s41467-019-14185-z

Abstract

Precise control of hepatic glucose production (HGP) is pivotal to maintain systemic glucose homeostasis. HNF4α functions to stimulate transcription of key gluconeogenic genes. HNF4α harbors two promoters (P2 and P1) thought to be primarily active in fetal and adult livers, respectively. Here we report that the fetal version of HNF4α is required for HGP in the adult liver. This isoform is acutely induced upon fasting and chronically increased in type-2 diabetes (T2D). P2 isoform induction occurs in response to glucagon-stimulated upregulation of TET3, not previously shown to be involved in HGP. TET3 is recruited to the P2 promoter by FOXA2, leading to promoter demethylation and increased transcription. While TET3 overexpression augments HGP, knockdown of either TET3 or the P2 isoform alone in the liver improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies unmask an unanticipated, conserved regulatory mechanism in HGP and offer potential therapeutic targets for T2D.

Highlights

Precise control of hepatic glucose production (HGP) is pivotal to maintain systemic glucose homeostasis
This TET3-mediated P2 promoter reactivation in HGP appears to be conserved between human and mouse
As both FOXA2 and Teneleven translocation (TET) have been shown to act at numerous genomic loci as assessed by ChIP-seq and genome-wide 5hmC profiling[9,38], it is plausible that interactions between FOXA2 and

Summary

Introduction

Precise control of hepatic glucose production (HGP) is pivotal to maintain systemic glucose homeostasis. We report that the fetal version of HNF4α is required for HGP in the adult liver This isoform is acutely induced upon fasting and chronically increased in type-2 diabetes (T2D). While TET3 overexpression augments HGP, knockdown of either TET3 or the P2 isoform alone in the liver improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies unmask an unanticipated, conserved regulatory mechanism in HGP and offer potential therapeutic targets for T2D. In the current study we report an unexpected finding of P2 promoter reactivation in adult liver by TET3 with an essential role in control of hepatic glucose production (HGP)

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Conclusion