Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH

Asmita Bhattacharya, Shengyi Sun, Heting Wang, Ming Liu, Qiaoming Long*, Lei Yin, Sander Kersten, Kezhong Zhang, Ling Qi

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)

Abstract

Fibroblast growth factor 21 (Fgf21) is a liver-derived, fasting-induced hormone with broad effects on growth, nutrient metabolism, and insulin sensitivity. Here, we report the discovery of a novel mechanism regulating Fgf21 expression under growth and fasting-feeding. The Sel1L-Hrd1 complex is the most conserved branch of mammalian endoplasmic reticulum (ER)-associated degradation (ERAD) machinery. Mice with liver-specific deletion of Sel1L exhibit growth retardation with markedly elevated circulating Fgf21, reaching levels close to those in Fgf21 transgenic mice or pharmacological models. Mechanistically, we show that the Sel1L-Hrd1 ERAD complex controls Fgf21 transcription by regulating the ubiquitination and turnover (and thus nuclear abundance) of ER-resident transcription factor Crebh, while having no effect on the other well-known Fgf21 transcription factor Pparα. Our data reveal a physiologically regulated, inverse correlation between Sel1L-Hrd1 ERAD and Crebh-Fgf21 levels under fasting-feeding and growth. This study not only establishes the importance of Sel1L-Hrd1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic “ERAD-Crebh-Fgf21” axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation.

Original languageEnglish
Article numbere99277
JournalEMBO Journal
Volume37
Issue number22
DOIs
Publication statusPublished - 15 Nov 2018

Keywords

  • ER quality control
  • FGF21
  • gene transcription
  • metabolism
  • Sel1L-Hrd1 ERAD

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