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

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.

Bibliographic Details

Main Authors:	Bhattacharya, Asmita, Sun, Shengyi, Wang, Heting, Liu, Ming, Long, Qiaoming, Yin, Lei, Kersten, Sander, Zhang, Kezhong, Qi, Ling
Format:	Article/Letter to editor biblioteca
Language:	English
Subjects:	ER quality control, FGF21, Sel1L-Hrd1 ERAD, gene transcription, metabolism,
Online Access:	https://research.wur.nl/en/publications/hepatic-sel1l-hrd1-er-associated-degradation-erad-manages-fgf21-l
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