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- Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH.
Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH.
Citation | “Hepatic Sel1L-Hrd1 Er-Associated Degradation (Erad) Manages Fgf21 Levels And Systemic Metabolism Via Crebh.”. The Embo Journal. . |
Center | University of Michigan Joslin Diabetes Center |
Multicenter |
Multicenter
|
Author | Asmita Bhattacharya, Shengyi Sun, Heting Wang, Ming Liu, Qiaoming Long, Lei Yin, Sander Kersten, Kezhong Zhang, Ling Qi |
Keywords | ER quality control, FGF21, Sel1L‐Hrd1 ERAD, gene transcription, Metabolism |
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 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 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. |
Year of Publication |
2018
|
Journal |
The EMBO journal
|
Volume |
37
|
Issue |
22
|
Date Published |
12/2018
|
ISSN Number |
1460-2075
|
DOI |
10.15252/embj.201899277
|
Alternate Journal |
EMBO J.
|
PMID |
30389665
|
PMCID |
PMC6236331
|
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