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Journal of Lipid Research, Vol 37, 1065-1075, Copyright © 1996 by Lipid Research, Inc.
RP Oude Elferink, R Ottenhoff, M van Wijland, CM Frijters, C van Nieuwkerk and AK Groen
Mice in which the gene for mdr2 P-glycoprotein has been disrupted have a
severe deficiency in biliary phospholipid and cholesterol secretion. We
studied the relation between mdr2 gene expression and biliary lipid
secretion with emphasis on the role of bile salt hydrophobicity. Control
mice (+/+), and mice with a homozygous (-/-) or heterozygous (+/-)
disruption of the mdr2 gene, were infused with taurodeoxycholate (TDC) or
tauroursodeoxycholate (TUDC). In mdr2 (-/-) mice, virtually no
phospholipids were secreted into bile, irrespective of the type of bile
salt infused. In contrast, cholesterol secretion in (-/-) mice increased
upon TDC infusion from less than 0.1 to more than 2 nmol/min . 100 g, which
was similar to controls under the same conditions. After infusion of TUDC
in (-/-) mice. cholesterol secretion also rose (to 1.8 nmol/min . 100 g)
but remained much lower than in controls (8 nmol/min x 100 g). In (+/-)
mice, cholesterol secretion was equal to (+/+) mice during secretion of
endogenous bile salts and during TDC infusion, but was 50% of control
levels during maximal TUDC infusion. We conclude that biliary phospholipid
secretion completely depends on mdr2 gene expression but cholesterol can,
at least partially, be secreted in an mdr2 Pgp-independent mechanism. The
extent to which cholesterol is secreted via this mechanism may depend on
the hydrophobicity (i.e., cholesterol-solubilizing capacity) of the
secreted bile salt.
ARTICLES
Uncoupling of biliary phospholipid and cholesterol secretion in mice with reduced expression of mdr2 P-glycoprotein
Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.
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