title: Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice.
abstract: The role of the intestine in the maintenance of cholesterol homeostasis increasingly is recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport pathway, to which biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway, however, are poorly understood. We aimed to identify mechanisms that regulate and stimulate TICE.
  
  
  
  We performed studies with C57Bl/6J mice, as well as with mice with intestine-specific knockout of the farnesoid X receptor (FXR), mice that express an FXR transgene specifically in the intestine, and ABCG8-knockout mice. Mice were fed a control diet or a diet supplemented with the FXR agonist PX20606, with or without the cholesterol absorption inhibitor ezetimibe. Some mice with intestine-specific knockout of FXR were given daily injections of fibroblast growth factor (FGF)19. To determine fractional cholesterol absorption, mice were given intravenous injections of cholesterol D5and oral cholesterol D7. Mice were given13C-acetate in drinking water for measurement of cholesterol synthesis. Bile cannulations were performed and biliary cholesterol secretion rates were assessed. In a separate set of experiments, bile ducts of male Wistar rats were exteriorized, allowing replacement of endogenous bile by a model bile.
  
  
  
  In mice, we found TICE to be regulated by intestinal FXR via induction of its target gene Fgf15 (FGF19 in rats and human beings). Stimulation of this pathway caused mice to excrete up to 60% of their total cholesterol content each day. PX20606 and FGF19 each increased the ratio of muricholate:cholate in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool stimulated robust secretion of cholesterol into the intestinal lumen via the sterol-exporting heterodimer adenosine triphosphate binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, the increase in TICE induced by PX20606 was independent of changes in cholesterol absorption.
  
  
  
  Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Strategies that alter bile salt pool composition might be developed for the prevention of cardiovascular disease. Transcript profiling: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=irsrayeohfcntqx&acc=GSE74101.
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: j.f.de.boer@umcg.nl.
authors.forename: Jan Freark
authors.initials: JF
authors.lastname: de Boer
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Schonewille
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Boesjes
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Wolters
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Trijnie
authors.initials: T
authors.lastname: Bos
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Angelika
authors.initials: A
authors.lastname: Jurdzinski
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Renze
authors.initials: R
authors.lastname: Boverhof
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Justina C
authors.initials: JC
authors.lastname: Wolters
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Kuivenhoven
authors.affiliation: Department of Pediatric and Adolescent Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Hepatology and Gastroenterology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ronald P J
authors.initials: RPJ
authors.lastname: Oude Elferink
authors.affiliation: Department of Interdisciplinary Medicine, University of Bari, IRCCS Istituto Tumori "Giovanni Paolo II," Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Moschetta
authors.affiliation: Phenex Pharmaceuticals AG, Heidelberg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Kremoser
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Henkjan J
authors.initials: HJ
authors.lastname: Verkade
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
mesh_terms: D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism*; D001652:Bile Ducts; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D066237:Intestinal Elimination / Q000187:drug effects / Q000235:genetics*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D000924:Anticholesteremic Agents; D001565:Benzoates; D001647:Bile Acids and Salts; D002784:Cholesterol; D000069438:Ezetimibe; D005346:Fibroblast Growth Factors; D007555:Isoxazoles; D008074:Lipoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C000598200:4-(2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl)methoxy)phenyl)cyclopropyl)benzoic acid; C462601:ABCG8 protein, mouse; C108526:fibroblast growth factor 15, mouse
keywords: ABCG5/G8; Bile Salts; Metabolism; RCT; TICE