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Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform

Author

Listed:
  • Li

    (Yale University School of Medicine
    Shengjing Hospital of China Medical University)

  • Tiefeng Cao

    (Yale University School of Medicine
    Sun Yat-Sen University, Guangzhou)

  • Xiaoli Sun

    (Yale University School of Medicine
    Affiliated Hospital of Nantong University)

  • Sungho Jin

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Xie

    (Yale University School of Medicine
    General Hospital of Central Theater Command)

  • Xinmei Huang

    (Yale University School of Medicine
    Fudan University School of Medicine)

  • Xiaoyong Yang

    (Yale University School of Medicine)

  • Gordon G. Carmichael

    (University of Connecticut Health Center)

  • Hugh S. Taylor

    (Yale University School of Medicine)

  • Sabrina Diano

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Yingqun Huang

    (Yale University School of Medicine)

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.

Suggested Citation

  • Li & Tiefeng Cao & Xiaoli Sun & Sungho Jin & Xie & Xinmei Huang & Xiaoyong Yang & Gordon G. Carmichael & Hugh S. Taylor & Sabrina Diano & Yingqun Huang, 2020. "Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14185-z
    DOI: 10.1038/s41467-019-14185-z
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