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Hepatic Sel1L‐Hrd1 ER‐associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH
Author(s) -
Bhattacharya Asmita,
Sun Shengyi,
Wang Heting,
Liu Ming,
Long Qiaoming,
Yin Lei,
Kersten Sander,
Zhang Kezhong,
Qi Ling
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201899277
Subject(s) - endoplasmic reticulum associated protein degradation , fgf21 , biology , endoplasmic reticulum , transcription factor , microbiology and biotechnology , steroidogenic factor 1 , unfolded protein response , energy homeostasis , protein degradation , endocrinology , medicine , fibroblast growth factor , gene , biochemistry , nuclear receptor , receptor , obesity
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.