Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism

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 DiazFrauke Melchior, Stephan Herzig*

*Kontaktforfatter

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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.

OriginalsprogEngelsk
Artikelnummere55981
TidsskriftEMBO Reports
Vol/bind24
Udgave nummer10
Antal sider18
ISSN1469-221X
DOI
StatusUdgivet - 9. okt. 2023

Bibliografisk note

Funding Information:
We would like to thank Andrea Takas, Elena Vogl, Jeanette Biebl, Daniela Hass, and Sebastian Cucuruz for their technical expertise. We thank Luke Harrison for proof reading and editorial support. The graphical abstract and part of Fig 1 were created with Biorender.com . The work of the authors is supported by the German Research Foundation (DeutscheForschungsgemeinschaft, DFG) within the CRC/Transregio 205/2, Project number: 314061271 – TRR 205 “The Adrenal: Central Relay in Health and Disease” to Stephan Herzig, the SFB1321 (Project‐ID 329628492 to Stephan Herzig), and the SFB1118 (Project A01 to Stephan Herzig); Helmholtz Future Topic Aging and Metabolic Programming (AMPro, ZT‐0026) to Stephan Herzig; Else‐Kröner‐Fresenius‐Stiftung (2020 EKSE.23 to Stephan Herzig) and the Edith–Haberland–Wagner Stiftung to Stephan Her and the DKFZ‐ZMBH Alliance to Frauke Melchior and Claudia Dittner. Open Access funding enabled and organized by Projekt DEAL.

Publisher Copyright:
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

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