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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 17, 2018 |
| Title |
Hepatic Sel1L-Hrd1 ER-Associated Degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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 Sel1LHrd1 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 Sel1LHrd1 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 “ERADCrebh- Fgf21” axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation.
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| Overall design |
Gene expression was profiled in livers of 3-week-old and 9-week-old WT and hepatocyte-specific Sel1L-deficient mice.
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| Contributor(s) |
Bhattacharya A, Sun S, Wang H, Liu L, Long Q, Yin L, Kersten S, Zhang K, Qi L |
| Citation(s) |
30389665 |
| Submission date |
Aug 16, 2018 |
| Last update date |
Nov 16, 2018 |
| Contact name |
Guido Hooiveld |
| E-mail(s) |
guido.hooiveld@wur.nl
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| Organization name |
Wageningen University
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| Department |
Div. Human Nutrition & Health
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| Lab |
Nutrition, Metabolism & Genomics Group
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| Street address |
HELIX, Stippeneng 4
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| City |
Wageningen |
| ZIP/Postal code |
NL-6708WE |
| Country |
Netherlands |
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| Platforms (1) |
| GPL11533 |
[MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version] |
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| Samples (13)
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| GSM3336220 |
Liver, wildtype mouse, 3 wks of age, replicate 1 |
| GSM3336221 |
Liver, wildtype mouse, 3 wks of age, replicate 2 |
| GSM3336222 |
Liver, wildtype mouse, 3 wks of age, replicate 3 |
| GSM3336223 |
Liver, LiSel1lKO mouse, 3 wks of age, replicate 1 |
| GSM3336224 |
Liver, LiSel1lKO mouse, 3 wks of age, replicate 2 |
| GSM3336225 |
Liver, LiSel1lKO mouse, 3 wks of age, replicate 3 |
| GSM3336226 |
Liver, LiSel1lKO mouse, 3 wks of age, replicate 4 |
| GSM3336227 |
Liver, wildtype mouse, 9 wks of age, replicate 1 |
| GSM3336228 |
Liver, wildtype mouse, 9 wks of age, replicate 2 |
| GSM3336229 |
Liver, wildtype mouse, 9 wks of age, replicate 3 |
| GSM3336230 |
Liver, LiSel1lKO mouse, 9 wks of age, replicate 1 |
| GSM3336231 |
Liver, LiSel1lKO mouse, 9 wks of age, replicate 2 |
| GSM3336232 |
Liver, LiSel1lKO mouse, 9 wks of age, replicate 3 |
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| Relations |
| BioProject |
PRJNA486359 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE118658_RAW.tar |
54.3 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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