title: Hepatic ABCG5/G8 overexpression substantially increases biliary cholesterol secretion but does not impact in vivo macrophage-to-feces RCT.
abstract: OBJECTIVE
  Biliary cholesterol secretion is important for reverse cholesterol transport (RCT). ABCG5/G8 contribute most cholesterol mass secretion into bile. We investigated the impact of hepatic ABCG5/G8 on cholesterol metabolism and RCT.
  
  
  METHODS
  Biliary and fecal sterol excretion (FSE) as well as RCT were determined using wild-type controls, Abcg8 knockout mice, Abcg8 knockouts with adenovirus-mediated hepatocyte-specific Abcg8 reinstitution and hepatic Abcg5/g8 overexpression in wild-types.
  
  
  RESULTS
  In Abcg8 knockouts, biliary cholesterol secretion was decreased by 75% (p < 0.001), while mass FSE and RCT were unchanged. Hepatic reinstitution of Abcg8 increased biliary cholesterol secretion 5-fold (p < 0.001) without changing FSE or overall RCT. Overexpression of both ABCG5/G8 elevated biliary cholesterol secretion 5-fold and doubled FSE (p < 0.001) without affecting overall RCT.
  
  
  CONCLUSIONS
  ABCG5/G8 mediate mass biliary cholesterol secretion but not from a RCT-relevant pool. Intervention strategies aiming at increasing hepatic Abcg5/g8 expression for enhancing RCT are not likely to be successful.
authors.affiliation: Department of Pediatrics, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Arne
authors.initials: A
authors.lastname: Dikkers
authors.affiliation: Department of Pediatrics, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan Freark
authors.initials: JF
authors.lastname: de Boer
authors.affiliation: Department of Pediatrics, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Department of Pediatrics, The University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: u_tietge@yahoo.com.
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
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 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D005243:Feces / Q000737:chemistry*; D018014:Gene Transfer Techniques; D005838:Genotype; D065669:Hepatobiliary Elimination; D008074:Lipoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D015854:Up-Regulation
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; D008074:Lipoproteins; D002784:Cholesterol
keywords: Atherosclerosis; Bile; Cholesterol; Liver; Macrophages; Reverse cholesterol transport