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Research Article Free access | 10.1172/JCI3597

Class III P-glycoproteins mediate the formation of lipoprotein X in the mouse.

R P Elferink, R Ottenhoff, J van Marle, C M Frijters, A J Smith, and A K Groen

Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands. r.p.oude-elferink@amc.uva.nl

Find articles by Elferink, R. in: JCI | PubMed | Google Scholar

Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands. r.p.oude-elferink@amc.uva.nl

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Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands. r.p.oude-elferink@amc.uva.nl

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Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands. r.p.oude-elferink@amc.uva.nl

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Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands. r.p.oude-elferink@amc.uva.nl

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Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands. r.p.oude-elferink@amc.uva.nl

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Published November 1, 1998 - More info

Published in Volume 102, Issue 9 on November 1, 1998
J Clin Invest. 1998;102(9):1749–1757. https://doi.org/10.1172/JCI3597.
© 1998 The American Society for Clinical Investigation
Published November 1, 1998 - Version history
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Abstract

Cholestasis is associated with hypercholesterolemia and appearance of the abnormal lipoprotein X (LpX) in plasma. Using mice with a disrupted Mdr2 gene, we tested the hypothesis that LpX originates as a biliary lipid vesicle. Mdr2-deficient mice lack Mdr2 P-glycoprotein, the canalicular translocator for phosphatidylcholine, and secrete virtually no phospholipid and cholesterol in bile. Bile duct ligation of Mdr2(+)/+ mice induced a dramatic increase in the plasma cholesterol and phospholipid concentration. Agarose electrophoresis, density gradient ultracentrifugation, gel permeation, and electron microscopy revealed that the majority of phospholipid and cholesterol was present as LpX, a 40-100 nm vesicle with an aqueous lumen. In contrast, the plasma cholesterol and phospholipid concentration in Mdr2(-)/- mice decreased upon bile duct ligation, and plasma fractionation revealed a complete absence of LpX. In mice with various expression levels of Mdr2 or MDR3, the human homolog of Mdr2, we observed that the plasma level of cholesterol and phospholipid during cholestasis correlated very closely with the expression level of these canalicular P-glycoproteins. These data demonstrate that during cholestasis there is a quantitative shift of lipid secretion from bile to the plasma compartment in the form of LpX. The concentration of this lipoprotein is determined by the activity of the canalicular phospholipid translocator.

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