title: Evidence that the adenosine triphosphate-binding cassette G5/G8-independent pathway plays a determinant role in cholesterol gallstone formation in mice.
abstract: The adenosine triphosphate-binding cassette (ABC) sterol transporter, Abcg5/g8, is Lith9 in mice, and two gallstone-associated variants in ABCG5/G8 have been identified in humans. Although ABCG5/G8 plays a critical role in determining hepatic sterol secretion, cholesterol is still secreted to bile in sitosterolemic patients with a defect in either ABCG5 or ABCG8 and in either Abcg5/g8 double- or single-knockout mice. We hypothesize that in the defect of ABCG5/G8, an ABCG5/G8-independent pathway is essential for regulating hepatic secretion of biliary sterols, which is independent of the lithogenic mechanism of the ABCG5/G8 pathway. To elucidate the effect of the ABCG5/G8-independent pathway on cholelithogenesis, we investigated the biliary and gallstone characteristics in male wild-type (WT), ABCG5(-/-)/G8(-/-), and ABCG8 (-/-) mice fed a lithogenic diet or varying amounts of cholesterol, treated with a liver X receptor (LXR) agonist, or injected intravenously with [(3) H]sitostanol- and [(14) C]cholesterol-labeled high-density lipoprotein (HDL). We found that ABCG5(-/-)/G8(-/-) and ABCG8 (-/-) mice displayed the same biliary and gallstone phenotypes. Although both groups of knockout mice showed a significant reduction in hepatic cholesterol output compared to WT mice, they still formed gallstones. The LXR agonist significantly increased biliary cholesterol secretion and gallstones in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice. The 6-hour recovery of [(14) C]cholesterol in hepatic bile was significantly lower in both groups of knockout mice than in WT mice and [(3) H]sitostanol was detected in WT, but not ABCG5(-/-)/G8(-/-) or ABCG8 (-/-), mice.
  
  
  
  The ABCG5/G8-independent pathway plays an important role in regulating biliary cholesterol secretion, the transport of HDL-derived cholesterol from plasma to bile, and gallstone formation, which works independently of the ABCG5/G8 pathway. Further studies are needed to observe whether this pathway is also operational in humans. (Hepatology 2016;64:853-864).
authors.affiliation: Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA.|Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Shailendra B
authors.initials: SB
authors.lastname: Patel
authors.affiliation: Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA.|Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO.
authors.forename: David Q-H
authors.initials: DQ
authors.lastname: Wang
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5 / Q000235:genetics*; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8 / Q000235:genetics*; D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005704:Gallbladder / Q000502:physiology; D042882:Gallstones / Q000209:etiology* / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000235:genetics*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013449:Sulfonamides; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D001647:Bile Acids and Salts; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D008074:Lipoproteins; D013449:Sulfonamides; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides