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


The cytochrome P450 enzyme Cyp17a1 catalyzes intermediate reactions in the synthesis of all steroid hormones. Metabolic regulation by the liver is under the control of members of the nuclear receptor class of transcription factors, with farnesoid X receptor (FXR) and peroxisome proliferator activated receptor alpha (PPARα) playing important roles. Milona et al. discovered that Cyp17a1 is repressed by FXR action in the liver in the fed state. During starvation, Cyp17a1 is de-repressed and produces a hormone ligand for PPARα. The authors show that hepatic Cyp17a1-dependent PPARα-activity is essential for the maintenance of fasting glucose and ketone levels. This is an important new link between extra-gonadal steroidogenic pathways and a nutrient responsive nuclear receptor network.

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.