Author:
Marine Huillet,Frédéric Lasserre,Marie-Pierre Gratacap,Beatrice Engelmann,Justine Bruse,Arnaud Polizzi,Tiffany Fougeray,Céline Martin,Clémence Rives,Anne Fougerat,Claire Naylies,Yannick Lippi,Géraldine Garcia,Elodie Rousseau- Bacquie,Cécile Canlet,Laurent Debrauwer,Ulrike Rolle-Kampczyk,Martin von Bergen,Bernard Payrastre,Elisa Boutet-Robinet,Laurence Gamet-Payrastre,Hervé Guillou,Nicolas Loiseau,Sandrine Ellero-Simatos
Abstract
ABSTRACTBackground and AimsThe constitutive androstane receptor (CAR) is a nuclear receptor able to recognize a large panel of xenobiotics leading to the modulation of the expression of its target genes involved in xenobiotic detoxication and energy metabolism. While CAR hepatic activity is thought to be higher in women than in men, its response to an acute pharmacological activation has never been investigated in both sexes.MethodsHepatic transcriptome, plasma and hepatic metabolome, have been analyzed inCar+/+andCar-/-male and female mice treated either with the CAR-specific agonist, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), or with vehicle.ResultsWhile 90% of TCPOBOP-sensitive genes were modulated in a sex- independent way, the remaining 10% were almost exclusively impacted in female liver specifically. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation and extracellular matrix organization. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Data mining on human data confirmed that CAR activation may be involved in sexually-dimorphic drug-induced liver injury. Hepatic expression of flavin monooxygenase 3(Fmo3)was almost abolished and associated with a decrease of hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a possible role in the control of TMAO homeostasis, CAR activation decreased platelet hyperresponsiveness in female mice supplemented with dietary choline.ConclusionsOur results demonstrate that more than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic response such as platelet aggregation. Also, CAR activation may be an important mechanism of sexually- dimorphic drug-induced liver injury.
Publisher
Cold Spring Harbor Laboratory