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

Li, Tiefeng Cao, Xiaoli Sun, Sungho Jin, Xie, Xinmei Huang, Xiaoyong Yang, Gordon G. Carmichael, Hugh S. Taylor, Sabrina Diano and Yingqun Huang ()
Additional contact information
Li: Yale University School of Medicine
Tiefeng Cao: Yale University School of Medicine
Xiaoli Sun: Yale University School of Medicine
Sungho Jin: Yale University School of Medicine
Xie: Yale University School of Medicine
Xinmei Huang: Yale 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
Yingqun Huang: Yale University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-14185-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14185-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-14185-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().