Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism.
Bile acids
Cholesterol
Liver
Prox1
SUMOylation
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
09 Oct 2023
09 Oct 2023
Historique:
revised:
12
07
2023
received:
17
08
2022
accepted:
27
07
2023
pubmed:
10
8
2023
medline:
10
8
2023
entrez:
10
8
2023
Statut:
ppublish
Résumé
Accumulation of excess nutrients hampers proper liver function and is linked to nonalcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the small ubiquitin-like modifier (SUMO) allows for a dynamic regulation of numerous processes including transcriptional reprogramming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and refed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the preservation of metabolic health.
Identifiants
pubmed: 37560809
doi: 10.15252/embr.202255981
pmc: PMC10561358
doi:
Banques de données
GEO
['GSE237590', 'GSE237593']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e55981Subventions
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 314061271
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 329628492
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : A01
Organisme : Edith-Haberland-Wagner Stiftung
Organisme : Else Köner-Fresenius-Stiftung (EKFS)
ID : 2020 EKSE.23
Organisme : Helmholtz Gemeinschaft
ID : ZT-0026
Organisme : DKFZ-ZMBH Alliance
Organisme : Open Access funding enabled and organized by Projekt DEAL
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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