title: Enterohepatic circulation of bile salts in farnesoid X receptor-deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein.
abstract: The bile salt-activated farnesoid X receptor (FXR; NR1H4) controls expression of several genes considered crucial in maintenance of bile salt homeostasis. We evaluated the physiological consequences of FXR deficiency on bile formation and on the kinetics of the enterohepatic circulation of cholate, the major bile salt species in mice. The pool size, fractional turnover rate, synthesis rate, and intestinal absorption of cholate were determined by stable isotope dilution and were related to expression of relevant transporters in the livers and intestines of FXR-deficient (Fxr-/-) mice. Fxr-/- mice showed only mildly elevated plasma bile salt concentrations associated with a 2.4-fold higher biliary bile salt output, whereas hepatic mRNA levels of the bile salt export pump were decreased. Cholate pool size and total bile salt pool size were increased by 67 and 39%, respectively, in Fxr-/- mice compared with wild-type mice. The cholate synthesis rate was increased by 85% in Fxr-/- mice, coinciding with a 2.5-fold increase in cholesterol 7alpha-hydroxylase (Cyp7a1) and unchanged sterol 12alpha-hydroxylase (Cyp8b1) expression in the liver. Despite a complete absence of ileal bile acid-binding protein mRNA and protein, the fractional turnover rate and cycling time of the cholate pool were not affected. The calculated amount of cholate reabsorbed from the intestine per day was approximately 2-fold higher in Fxr-/- mice than in wild-type mice. Thus, the absence of FXR in mice is associated with defective feedback inhibition of hepatic cholate synthesis, which leads to enlargement of the circulating cholate pool with an unaltered fractional turnover rate. The absence of ileal bile acid-binding protein does not negatively interfere with the enterohepatic circulation of cholate in mice.
authors.affiliation: Groningen University Institute for Drug Exploration, Center for Liver, Digestive, and Metabolic Diseases, University Hospital Groningen, CMC IV, Rm. Y2.163, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. T.Kok@med.rug.nl
authors.forename: Tineke
authors.initials: T
authors.lastname: Kok
authors.forename: Christian V
authors.initials: CV
authors.lastname: Hulzebos
authors.forename: Henk
authors.initials: H
authors.lastname: Wolters
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Luis B
authors.initials: LB
authors.lastname: Agellon
authors.forename: Frans
authors.initials: F
authors.lastname: Stellaard
authors.forename: Bei
authors.initials: B
authors.lastname: Shan
authors.forename: Margrit
authors.initials: M
authors.lastname: Schwarz
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics; D019826:Cholic Acid / Q000096:biosynthesis / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004764:Enterohepatic Circulation / Q000502:physiology*; D025461:Feedback, Physiological; D006706:Homeostasis; D006913:Hydroxysteroid Dehydrogenases; D007408:Intestinal Absorption; D008562:Membrane Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002790:Cholesterol 7-alpha-Hydroxylase; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D006913:Hydroxysteroid Dehydrogenases; D008562:Membrane Glycoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C037643:bile acid binding proteins; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)