Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism
Abstract 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 modific...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
10 August 2023
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| In: |
EMBO reports
Year: 2023, Pages: 1-18 |
| ISSN: | 1469-3178 |
| DOI: | 10.15252/embr.202255981 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.15252/embr.202255981 Verlag, lizenzpflichtig, Volltext: https://www.embopress.org/doi/full/10.15252/embr.202255981 
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| Verfasserangaben: | Ana Jimena Alfaro, Claudia Dittner, Janina Becker, Anne Loft, Amit Mhamane, Adriano Maida, Anastasia Georgiadi, Foivos-Filippos Tsokanos, Katarina Klepac, Claudia-Eveline Molocea, Rabih El-Merahbi, Karsten Motzler, Julia Geppert, Rhoda Anane Karikari, Julia Szendrödi, Annette Feuchtinger, Susanna Hofmann, Samir Karaca, Henning Urlaub, Mauricio Berriel Diaz, Frauke Melchior & Stephan Herzig |
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| 245 | 1 | 0 | |a Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism |c Ana Jimena Alfaro, Claudia Dittner, Janina Becker, Anne Loft, Amit Mhamane, Adriano Maida, Anastasia Georgiadi, Foivos-Filippos Tsokanos, Katarina Klepac, Claudia-Eveline Molocea, Rabih El-Merahbi, Karsten Motzler, Julia Geppert, Rhoda Anane Karikari, Julia Szendrödi, Annette Feuchtinger, Susanna Hofmann, Samir Karaca, Henning Urlaub, Mauricio Berriel Diaz, Frauke Melchior & Stephan Herzig |
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| 520 | |a Abstract 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. | ||
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