Steroidogenic control of liver metabolism through a nuclear receptor-network

Alexandra Milona, Vittoria Massafra, Harmjan Vos, Jyoti Naik, Natalia Artigas, Helen A.B. Paterson, Ingrid T.G.W. Bijsmans, Ellen C.L. Willemsen, Jose M. Ramos Pittol, Irene Miguel-Aliaga, Piter Bosma, Boudewijn M.T. Burgering, Catherine Williamson, Santiago Vernia, Waljit S. Dhillo, Saskia W.C. van Mil*, Bryn M. Owen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

OBJECTIVE: Coupling metabolic and reproductive pathways is essential for the survival of species. However, the functions of steroidogenic enzymes expressed in metabolic tissues are largely unknown.

METHODS AND RESULTS: Here, we show that in the liver, the classical steroidogenic enzyme Cyp17a1 forms an essential nexus for glucose and ketone metabolism during feed-fast cycles. Both gain- and loss-of-function approaches are used to show that hepatic Cyp17a1 is induced by fasting, catalyzes the production of at least one hormone-ligand (DHEA) for the nuclear receptor PPARα, and is ultimately required for maintaining euglycemia and ketogenesis during nutrient deprivation. The feedback-loop that terminates Cyp17a1-PPARα activity, and re-establishes anabolic liver metabolism during re-feeding is mapped to postprandial bile acid-signaling, involving the receptors FXR, SHP and LRH-1.

CONCLUSIONS: Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.

Original languageEnglish
Pages (from-to)221-229
Number of pages9
JournalMolecular Metabolism
Volume30
DOIs
Publication statusPublished - Dec 2019

Keywords

  • Bile acids
  • Cyp17a1
  • Diabetes
  • Fasting
  • FGF21
  • FXR
  • Gluconeogenesis
  • Liver
  • Metabolism
  • Steroidogenesis

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