title: Scavenger receptor BI and ABCG5/G8 differentially impact biliary sterol secretion and reverse cholesterol transport in mice.
abstract: Biliary lipid secretion plays an important role in gallstone disease and reverse cholesterol transport (RCT). Using Sr-bI/Abcg5 double knockout mice (dko), the present study investigated the differential contribution of two of the most relevant transporters: adenosine triphosphate (ATP)-binding cassette subfamily G member 5 and 8 (ABCG5/G8) and scavenger receptor class B type I (SR-BI) to sterol metabolism and RCT. Plasma cholesterol levels increased in the following order, mainly due to differences in high density lipoprotein (HDL): Abcg5 ko < wild type < Sr-bI/Abcg5 dko < Sr-bI ko. Liver cholesterol content was elevated in Sr-bI ko only (P < 0.05). In Sr-bI/Abcg5 dko plasma plant sterols were highest, while hepatic plant sterols were lower compared with Abcg5 ko (P < 0.05). Under baseline conditions, biliary cholesterol secretion rates decreased in the following order: wild type > Sr-bI ko (-16%) > Abcg5 ko (-75%) > Sr-bI/Abcg5 dko (-94%), all at least P < 0.05, while biliary bile acid secretion did not differ between groups. However, under supraphysiological conditions, upon infusion with increasing amounts of the bile salt tauroursodeoxycholic acid, Abcg5 became fully rate-limiting for biliary cholesterol secretion. Additional in vivo macrophage-to-feces RCT studies demonstrated an almost 50% decrease in overall RCT in Sr-bI/Abcg5 dko compared with Abcg5 ko mice (P < 0.01).
  
  
  CONCLUSIONS
  These data demonstrate that (1) SR-BI contributes to ABCG5/G8-independent biliary cholesterol secretion under basal conditions; (2) biliary cholesterol mass secretion under maximal bile salt-stimulated conditions is fully dependent on ABCG5/G8; and (3) Sr-bI contributes to macrophage-to-feces RCT independent of Abcg5/g8.
authors: Department of Pediatrics, University Medical Center Groningen, University of Groningen, the Netherlands.
authors: Arne
authors: A
authors: Dikkers
authors: Jan
authors: J
authors: Freak de Boer
authors: Wijtske
authors: W
authors: Annema
authors: Albert K
authors: AK
authors: Groen
authors: Uwe J F
authors: UJ
authors: 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 / Q000502:physiology*; D000818:Animals; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D008074:Lipoproteins / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010840:Phytosterols / Q000097:blood / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000502:physiology*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology
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; D010840:Phytosterols; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D002784:Cholesterol