Appearance of atypical 3α,6β,7β,12α-tetrahydroxy-5β-cholan-24-oic acid in spgp knockout mice

被引:34
作者
Perwaiz, S
Forrest, D
Mignault, D
Tuchweber, B
Phillip, MJ
Wang, RX
Ling, V
Yousef, IM [1 ]
机构
[1] Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada
[2] Hop St Justine, Ctr Rech, Montreal, PQ H3T 1C5, Canada
[3] British Columbia Canc Agcy, British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada
[4] Univ Toronto, Hosp Sick Children, Dept Pathol, Toronto, ON M5G 1X8, Canada
关键词
bile salt; cholestasis; canalicular membrane; knockout mice; gas chromatography mass spectrometry; electrospray tandem mass spectrometry; sister-of-p-glycoprotein;
D O I
10.1194/jlr.M200394-JLR200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 3alpha,6beta,7beta,12alpha-tetrahydroxy-5beta-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-5beta-cholan-24-oic acid. The increase in total bile acids was associated with up-regulation of the mRNA of cholesterol 7alpha-hydroxylase in male mice only.jlr It is suggested that the lower severity of the cholestasis in the spgp knockout mice may be due to the synthesis of 3alpha,6beta,7beta,12alpha-tetrahydroxy-5beta-cholan-24-oic acid, which neutralizes in part the toxic effect of bile acids accumulated in the liver.
引用
收藏
页码:494 / 502
页数:9
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