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Uncoupling of biliary phospholipid and cholesterol secretion in mice with reduced expression of mdr2 P-glycoprotein
R P Oude Elferink1, R Ottenhoff, M van Wijland
1Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.
Abstract:
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.
Insights
Mice lacking mdr2 P-glycoprotein show no phospholipid secretion. Cholesterol secretion is partially mdr2 P-glycoprotein-independent, influenced by bile salt hydrophobicity.
Area of Science:
- Hepatology
- Molecular Biology
- Lipid Metabolism
Background:
- Mice with disrupted mdr2 P-glycoprotein genes exhibit impaired biliary lipid secretion.
- The role of mdr2 gene expression in biliary lipid secretion requires further investigation, particularly concerning bile salt hydrophobicity.
Purpose of the Study:
- To investigate the relationship between mdr2 gene expression and biliary lipid secretion.
- To elucidate the influence of bile salt hydrophobicity on cholesterol secretion in the absence of functional mdr2 P-glycoprotein.
Main Methods:
- Utilized control, homozygous (-/-), and heterozygous (+/-) mdr2 gene-disrupted mice.
- Infused mice with taurodeoxycholate (TDC) or tauroursodeoxycholate (TUDC) to assess biliary lipid secretion.
- Quantified phospholipid and cholesterol secretion under various conditions.
Main Results:
- Mdr2 (-/-) mice demonstrated a complete absence of biliary phospholipid secretion.
- Cholesterol secretion in mdr2 (-/-) mice increased with TDC infusion, reaching levels similar to controls.
- TUDC infusion in mdr2 (-/-) mice resulted in lower cholesterol secretion compared to controls, while (+/-) mice showed reduced secretion with TUDC compared to controls.
Conclusions:
- Biliary phospholipid secretion is entirely dependent on mdr2 gene expression.
- Cholesterol can be secreted via an mdr2 P-glycoprotein-independent pathway.
- The contribution of this independent pathway to cholesterol secretion is modulated by bile salt hydrophobicity.