SFEBES2018 Poster Presentations Obesity & metabolism (24 abstracts)
Hepatic Cyp17a1 regulates the adaptive starvation response aia a nuclear receptor network
Alexandra Milona 1, , Ellen Willemsen 3 , Natalia Artigas 1 , Helen Paterson 1 , Harmjan Vos 3 , Jyoti Naik 3 , Irene Miguel-Aliaga 1 , Piter Bosma 4 , Boudewijn Burgering 3 , Catherine Williamson 5 , Santiago Vernia 1 , Saski van Mil 3 & Bryn Owen 6
1MRC London Institute of Medical Sciences (LMS), London, UK; 2Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK; 3Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands; 4Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, Netherlands; 5Department of Women’s Health, Kings College London, London, UK; 6Section of Investigative Medicine, Imperial College London, London, UK.
Coupling metabolic processes to nutrient availability is essential for survival. The nuclear receptors PPARα and FXR regulate adaptive liver metabolism in the fasted-state and fed-state, respectively, through a complex mechanism that is incompletely understood. Here, we show that hepatic expression of the steroidogenic enzyme Cyp17al is strikingly regulated by feed-fast cycles via a repressive nuclear receptor cascade involving bile-acid:FXR signalling. Using both gain- and loss-of-function approaches, we find that Cyp17A1 likely produces a ligand for PPARα, and is essential for maintaining blood glucose levels during fasting. Together, these data identify Cyp17a1 as a novel hepatic FXR target-gene that contributes to the adaptive starvation response. These studies also suggest that targeting of hepatic Cyp17a1 may improve lipid handling under specific pathological conditions.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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