title: A mouse model of sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol.
abstract: BACKGROUND
  Mutations in either of two genes comprising the STSL locus, ATP-binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8 (encoding sterolin-2), result in sitosterolemia, a rare autosomal recessive disorder of sterol trafficking characterized by increased plasma plant sterol levels. Based upon the genetics of sitosterolemia, ABCG5/sterolin-1 and ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No phenotypic difference has yet been described in humans with complete defects in either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are responsible for regulating dietary sterol entry and biliary sterol secretion.
  
  
  METHODS
  In order to mimic the human disease, we created, by a targeted disruption, a mouse model of sitosterolemia resulting in Abcg8/sterolin-2 deficiency alone. Homozygous knockout mice are viable and exhibit sitosterolemia.
  
  
  RESULTS
  Mice deficient in Abcg8 have significantly increased plasma and tissue plant sterol levels (sitosterol and campesterol) consistent with sitosterolemia. Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in Abcg8/sterolin-2 deficient mice and continued to show an apical expression. Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol into bile, but still maintained the ability to secrete sitosterol. We also report an intermediate phenotype in the heterozygous Abcg8+/- mice that are not sitosterolemic, but have a decreased level of biliary sterol secretion relative to wild-type mice.
  
  
  CONCLUSIONS
  These data indicate that Abcg8/sterolin-2 is necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a more profound effect upon biliary cholesterol secretion than sitosterol. Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile.
authors.affiliation: Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, Charleston, SC 29403, USA. klettel@musc.edu
authors.forename: Eric L
authors.initials: EL
authors.lastname: Klett
authors.forename: Kangmo
authors.initials: K
authors.lastname: Lu
authors.forename: Astrid
authors.initials: A
authors.lastname: Kosters
authors.forename: Edwin
authors.initials: E
authors.lastname: Vink
authors.forename: Mi-Hye
authors.initials: MH
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Altenburg
authors.forename: Sarah
authors.initials: S
authors.lastname: Shefer
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Batta
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yu
authors.forename: Jianliang
authors.initials: J
authors.lastname: Chen
authors.forename: Richard
authors.initials: R
authors.lastname: Klein
authors.forename: Norbert
authors.initials: N
authors.lastname: Looije
authors.forename: Ronald
authors.initials: R
authors.lastname: Oude-Elferink
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
authors.forename: Shailendra B
authors.initials: SB
authors.lastname: Patel
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 / Q000235:genetics; D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D007422:Intestines / Q000737:chemistry; D008074:Lipoproteins / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation / Q000235:genetics*; D010840:Phytosterols / Q000097:blood; D012855:Sitosterols / Q000097:blood*
chemical_list: C462600:ABCG5 protein, mouse; C416946:ABCG8 protein, human; 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; D001647:Bile Acids and Salts; D008074:Lipoproteins; D010840:Phytosterols; D012855:Sitosterols; C021273:campesterol; C025473:gamma-sitosterol; D002784:Cholesterol