A mouse model of sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol.
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.
Klett
Eric L
EL
Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, Charleston, SC 29403, USA. klettel@musc.edu
Lu
Kangmo
K
Kosters
Astrid
A
Vink
Edwin
E
Lee
Mi-Hye
MH
Altenburg
Michael
M
Shefer
Sarah
S
Batta
Ashok K
AK
Yu
Hongwei
H
Chen
Jianliang
J
Klein
Richard
R
Looije
Norbert
N
Oude-Elferink
Ronald
R
Groen
Albert K
AK
Maeda
Nobuyo
N
Salen
Gerald
G
Patel
Shailendra B
SB
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*
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