Journal
EMBO JOURNAL
Volume 37, Issue 22, Pages -Publisher
WILEY
DOI: 10.15252/embj.201899277
Keywords
ER quality control; FGF21; gene transcription; metabolism; Sel1L-Hrd1 ERAD
Categories
Funding
- NIH [R01DK099593, R01DK090313, R01GM113188, R01DK105393, R01DK120330, R01DK120047]
- University of Michigan Protein Folding Diseases Initiative
- American Diabetes Association (ADA) [1-12-CD-04]
- AHA Predoctoral Fellowship grant [16PRE29750001]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK120047, R01DK120330, R01DK090313, P30DK034933, R01DK105393, P30DK036836, R01DK111174, R01DK099593, P30DK020572] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM113188] Funding Source: NIH RePORTER
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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 Ppar alpha. 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.
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