Dataset Information

Steroidogenic Control of Liver Metabolism Through a Nuclear Receptor-Network

ABSTRACT: 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. 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, catalyses the production of a hormone-ligand (DHEA) for 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-signalling, involving the receptors FXR, SHP and LRH-1. Together, these findings represent a novel paradigm of homeostatic control in which nutritional cues feed-forward on to metabolic pathways by influencing extragonadal steroidogenesis.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Harmjan Vos

LAB HEAD: Bryn M Owen

PROVIDER: PXD012876 | Pride | 2020-01-16

REPOSITORIES: Pride

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Publications

Steroidogenic control of liver metabolism through a nuclear receptor-network.

Milona Alexandra A Massafra Vittoria V Vos Harmjan H Naik Jyoti J Artigas Natalia N Paterson Helen A B HAB Bijsmans Ingrid T G W ITGW Willemsen Ellen C L ECL Ramos Pittol Jose M JM Miguel-Aliaga Irene I Bosma Piter P Burgering Boudewijn M T BMT Williamson Catherine C Vernia Santiago S Dhillo Waljit S WS van Mil Saskia W C SWC Owen Bryn M BM

Molecular metabolism 20190930

<h4>Objective</h4>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.<h4>Methods and results</h4>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, cata ...[more]

PMID: 31767173

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Project description:Steroid hormones regulate essential physiological processes and inadequate levels are associated with various pathological conditions. In testosterone-producing Leydig cells, steroidogenesis is strongly stimulated by LH via its receptor leading to increased cAMP production and expression of the steroidogenic acute regulatory (STAR) protein, which is essential for the initiation of steroidogenesis. Leydig cell steroidogenesis then passively decreases following the rapid degradation of cAMP into AMP by phosphodiesterases. In this study, we show that AMP-activated protein kinase (AMPK) is activated following cAMP breakdown in MA-10 and MLTC-1 Leydig cells. Activated AMPK then actively inhibits cAMP-induced steroidogenesis by repressing the expression of key regulators of steroidogenesis including Star and Nr4a1. Similar results were obtained in Y-1 adrenal cells and in the constitutive steroidogenic cell line R2C. Our data identify AMPK as an active repressor of steroid hormone biosynthesis in steroidogenic cells that is essential to preserve cellular energy and prevent excess steroid production. Steroid hormones regulate essential physiological processes and inadequate levels are associated with various pathological conditions. In testosterone-producing Leydig cells, steroidogenesis is strongly stimulated by LH via its receptor leading to increased cAMP production and expression of the steroidogenic acute regulatory (STAR) protein, which is essential for the initiation of steroidogenesis. Leydig cell steroidogenesis then passively decreases following the rapid degradation of cAMP into AMP by phosphodiesterases. In this study, we show that AMP-activated protein kinase (AMPK) is activated following cAMP breakdown in MA-10 and MLTC-1 Leydig cells. Activated AMPK then actively inhibits cAMP-induced steroidogenesis by repressing the expression of key regulators of steroidogenesis including Star and Nr4a1. Similar results were obtained in Y-1 adrenal cells and in the constitutive steroidogenic cell line R2C. Our data identify AMPK as an active repressor of steroid hormone biosynthesis in steroidogenic cells that is essential to preserve cellular energy and prevent excess steroid production. MA-10 Leydig cells were treated with either DMSO (control), 10 uM forskolin or forskolin+Aicar (1 mM) for 1.5 h before total RNA extraction

Dataset Information

Steroidogenic Control of Liver Metabolism Through a Nuclear Receptor-Network

Publications

Steroidogenic control of liver metabolism through a nuclear receptor-network.

Similar Datasets

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