title: Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver.
abstract: Activation of Constitutive Androstane Receptor (CAR) protects against bile acid (BA)-induced liver injury. This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12α-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, and the increases were BA-independent. CAR activation did not alter biliary excretion of total BAs, but overall BA composition changed. Excretion of muricholic (6-hydroxylated) BAs was increased in males (101%), and the 12α-OH proportion of biliary BAs was decreased in both males (37%) and females (28%). The decrease of T-CA in livers of males and females correlates with the decreased mRNA of the sterol 12α-hydroxylase Cyp8b1 in males (71%) and females (54%). As a response to restore BAs to physiologic concentrations in liver, mRNA of Cyp7a1 is upregulated following TCPOBOP (males 185%, females 132%). In ilea, mRNA of the negative feedback regulator Fgf15 was unaltered by CAR activation, indicating biliary BA excretion was sufficient to maintain concentrations of total BAs in the small intestine. In summary, the effects of CAR activation on BAs in male and female mice are quite similar, with a marked decrease in the major BA T-CA in the liver.
authors.affiliation: *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lickteig
authors.affiliation: *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital & Clinics, Kansas City, Missouri 64108; Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kansas 66160.
authors.forename: Iván L
authors.initials: IL
authors.lastname: Csanaky
authors.affiliation: *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160;
authors.forename: Matthew
authors.initials: M
authors.lastname: Pratt-Hyatt
authors.affiliation: *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160; *Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160; curtisklaassenphd@gmail.com.
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D065669:Hepatobiliary Elimination / Q000187:drug effects*; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D026901:Membrane Transport Proteins; D011725:Pyridines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D013253:Steroid 12-alpha-Hydroxylase
keywords: TCPOBOP; bile acids; biliary excretion; constitutive androstane receptor; muricholic acid; taurocholic acid