title: Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice.
abstract: Scavenger receptor class B type I (SR-BI) mediates selective uptake of cholesterol from high-density lipoprotein (HDL) particles by the liver and influences biliary cholesterol secretion. However, it is not clear, if this effect is direct or indirect. The aim of this study was to determine the impact of SR-BI on biliary cholesterol secretion, especially in a functional context with ATP-binding cassette transporter g5 (Abcg5)/Abcg8 and Abcb4. SR-BI was overexpressed by means of adenovirus (AdSR-BI) in livers of wild-type, liver X receptor-null (Lxr(-/-)), Abcg5(-/-), and Abcb4(-/-) mice. Consistent with previous reports, AdSR-BI decreased plasma HDL cholesterol levels in all models (P < 0.001). Hepatic cholesterol content increased (at least P < 0.05), whereas expression of sterol regulatory element binding protein 2 target genes was decreased (at least P < 0.05,) and established Lxr target genes were unaltered. Biliary cholesterol secretion was increased by AdSR-BI in wild-type as well as in Lxr(-/-) and Abcg5(-/-) mice, and considerably less in Abcb4(-/-) mice (each P < 0.001), independent of bile acid and phospholipid secretion. Immunogold electron microscopy and western blot showed a substantial increase of SR-BI protein localized to basolateral and canalicular membranes in response to SR-BI overexpression. Subcellular fractionation revealed a significantly higher cholesterol content of canalicular membranes (P < 0.001) upon SR-BI overexpression. Inhibition of microtubule function did not affect SR-BI-mediated biliary cholesterol secretion, indicating that transcytosis pathways are not involved.
  
  
  CONCLUSIONS
  Our data indicate that SR-BI mediates biliary cholesterol secretion independent of Abcg5, yet largely depends on Abcb4-mediated phospholipid secretion and mixed micelles as acceptors in bile. SR-BI-mediated biliary cholesterol secretion has a high capacity, can compensate for the absence of Abcg5, and does not require transcytosis pathways.
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Harmen
authors.initials: H
authors.lastname: Wiersma
authors.forename: Alberto
authors.initials: A
authors.lastname: Gatti
authors.forename: Niels
authors.initials: N
authors.lastname: Nijstad
authors.forename: Ronald P J
authors.initials: RP
authors.lastname: Oude Elferink
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
mesh_terms: D000070996:ATP Binding Cassette Transporter, Subfamily G; 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 / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000502:physiology; D023421:Models, Animal; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism*
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000070996:ATP Binding Cassette Transporter, Subfamily G; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; C486685:Abcg4 protein, mouse; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol