title: Constitutive androstane receptor activation stimulates faecal bile acid excretion and reverse cholesterol transport in mice.
abstract: OBJECTIVE
  The constitutive androstane receptor (CAR) is a nuclear receptor expressed in the liver and involved in xenobiotic metabolism. The aim of this study was to assess whether pharmacological CAR activation could affect neutral sterol and bile acid elimination under conditions of cholesterol overload.
  
  
  METHODS
  Wild type, Car-/-, ApoE-/-, and low-density lipoprotein receptor (Ldlr)-/- mice fed a western-type diet were treated with the CAR agonist TCPOBOP.
  
  
  RESULTS
  CAR activation was associated with a decrease in faecal cholesterol output related to the repression of the Abcg5/g8 cholesterol transporters. In contrast, TCPOBOP treatment induced a marked increase (up to three fold, p<0.01) in the elimination of faecal bile acids. In the liver, it was related to the coordinated induction of genes involved in synthesis, sulfo-conjugation, and excretion of bile acids as well as the repression of the ileal apical sodium-dependent bile acid transporter. Importantly, cholesterol accumulation was reduced in the liver of TCPOBOP-treated animals. In all cases, TCPOBOP had no effect in Car-/- mice. To determine directly whether CAR activation could affect the elimination of endogenous cholesterol, kinetic studies were performed with high-density lipoproteins (HDL) labelled with (3)H-cholesteryl esters. We observed that TCPOBOP-treated mice excreted more HDL cholesterol-derived bile acids in their faeces. Finally, long-term CAR activation was associated with decreases in cholesterol content of the whole body and atherosclerosis susceptibility.
  
  
  CONCLUSIONS
  CAR is involved in the control of cholesterol and bile acid homeostasis, increasing reverse cholesterol transport under hyperlipidemic conditions.
authors.affiliation: Institut Fédératif de Recherche Santé-STIC, Université de Bourgogne-BP87900, 21079 Dijon Cedex, France.
authors.forename: Anne Laure
authors.initials: AL
authors.lastname: Sberna
authors.forename: Mahfoud
authors.initials: M
authors.lastname: Assem
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.forename: Jacques
authors.initials: J
authors.lastname: Grober
authors.forename: Boris
authors.initials: B
authors.lastname: Guiu
authors.forename: Aline
authors.initials: A
authors.lastname: Jeannin
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pais de Barros
authors.forename: Anne
authors.initials: A
authors.lastname: Athias
authors.forename: Laurent
authors.initials: L
authors.lastname: Lagrost
authors.forename: David
authors.initials: D
authors.lastname: Masson
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000517:prevention & control; D001647:Bile Acids and Salts / Q000378:metabolism*; D001693:Biological Transport, Active; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D005243:Feces / Q000737:chemistry; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D001647:Bile Acids and Salts; D008076:Cholesterol, HDL; D000090702:Constitutive Androstane Receptor; D008074:Lipoproteins; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D002784:Cholesterol