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A more recent version of this article appeared on March 1, 2003

Papers In Press, published online ahead of print December 1, 2002
J. Lipid Res., doi:10.1194/jlr.M200394-JLR200
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Submitted on October 2, 2002
Revised on November 5, 2002
Accepted on November 19, 2002

Appearance of atypical 3alpha , 6beta , 7beta , 12alpha -tetrahydroxy-5beta chol-24-oic acid in spgp knockout mice

Shahid Perwaiz, Dana Bourke, Diane Mignault, Beatriz Tuchweber, M. James Phillip, Renxue Wang, Victor Ling, and Ibrahim M Yousef

Pharmacology, University of Montreal, Montreal, Quebec H3C 3J7

Corresponding Author: ibrahim.yousef{at}umontreal.ca

Abstract: 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 (BSEP), and mutations in Spgp gene were identified as the cause of progressive familial intrahepatic cholestasis type2 (PFIC2). In the previous study, we had reported that target inactivation of spgp gene in mice results in non-progressive but persistent cholestasis and causes the secretion of unexpectedly large amount of unknown tetrahydroxylated bile acid in the bile. The present study using gas chromatography mass spectrometry (GC/MS) and electrospray tandem mass spectrometry (ES-MS/MS) confirms the identity of this tetrahydroxylated bile acid as 3á, 6â, 7â, 12á -tetrahydroxy-5âchol-24-oic acid. The data further shows 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 the newly identified tetrahydroxy-5âchol-24-oic acid. The increase in total bile acids was associated with upregulation of the mRNA of cholesterol 7á-hydroxylase in male mice. On the other hand no change was observed in the mRNA of cholesterol 7á-hydroxylase in the female mice of Spgp knockout mice. Conclusion: It is suggested that the less severity of the cholestasis in the spgp knockout mice as compared to PFIC2 may be due to the synthesis of 3á, 6â, 7â, 12á -tetrahydroxy-5âchol-24-oic acid which neutralizes in part the toxic effect of high concentration of bile acids accumulated in the liver as a result of the disruption of the bile salt export pump (bsep).


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[Abstract] [Full Text] [PDF]


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