Appearance of atypical 3 alpha,6 beta,7 beta,12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid in spgp knockout mice.
Bile formation and its canalicular secretion are essential functions of the mammalian liver. The sister-of-p-glycoprotein (spgp) gene was shown to encode the canalicular bile salt export protein, and mutations in spgp gene were identified as the cause of progressive familial intrahepatic cholestasis type 2. However, target inactivation of spgp gene in mice results in nonprogressive but persistent cholestasis and causes the secretion of unexpectedly large amounts of unknown tetrahydroxylated bile acid in the bile. The present study confirms the identity of this tetrahydroxylated bile acid as 3 alpha,6 beta,7 beta,12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid. The data further show that in serum, liver, and urine of the spgp knockout mice, there is a significant increase in the concentration of total bile salts containing a large amount of tetrahydroxy-5 beta-cholan-24-oic acid. The increase in total bile acids was associated with up-regulation of the mRNA of cholesterol 7 alpha-hydroxylase in male mice only. It is suggested that the lower severity of the cholestasis in the spgp knockout mice may be due to the synthesis of 3 alpha,6 beta,7 beta,12 alpha-tetrahydroxy-5 beta-cholan-24-oic acid, which neutralizes in part the toxic effect of bile acids accumulated in the liver.
Perwaiz
Shahid
S
Department of Pharmacology, Universitè de Montréal and Centre de Recherche de l'Hôpital Sainte-Justine, Montréal, Canada.
Forrest
Dana
D
Mignault
Diane
D
Tuchweber
Beatriz
B
Phillip
M James
MJ
Wang
Renxue
R
Ling
Victor
V
Yousef
Ibrahim M
IM
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000032:analysis / Q000097:blood / Q000652:urine; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D002793:Cholic Acids / Q000032:analysis* / Q000097:blood / Q000737:chemistry* / Q000652:urine; D005260:Female; D005704:Gallbladder / Q000737:chemistry; D008401:Gas Chromatography-Mass Spectrometry; D017353:Gene Deletion; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D001647:Bile Acids and Salts; D002793:Cholic Acids; D012333:RNA, Messenger; C474453:tetrahydroxy-5-cholan-24-oic acid; D002790:Cholesterol 7-alpha-Hydroxylase