Control analysis of biliary lipid secretion.
Biliary lipid secretion is a complex process involving a multitude of metabolic pathways. It has always been assumed that bile salt secretion (BSec) fully controls this process. Recently we have demonstrated, that mdr2 P-glycoprotein (P-gp) is an important controlling step as well. In this study we have analysed the control structure of this pathway with Metabolic Control Analysis.


METHODS
FVB mice homozygous (+/+) or heterozygous (+/-) for mdr2 P-glycoprotein were infused via the tail vein with tauroursodeoxycholate in stepwise increasing concentrations. Bile was collected and biliary lipids were determined by standard techniques.


RESULTS
To simplify the pathway we have lumped all reactions involved in BSsec into bile in one step. Since this step is not controlled by the canalicular BS concentration, the FCC of BS secretion on phospholipid secretion (PLsec) could be calculated from a plot between BS and PL secretion. The FCC of BSsec varied from 80% at low flux to a value of 90% at maximal BS output. The FCC of mdr2 P-gp was determined by varying the gene dose of mdr2 P-gp. Since PLsec showed linear kinetics towards canalicular BS the FCC could be calculated via the Deviation index. The values for the FCC of mdr2 P-gp in (+/+) mice vary from 80% at low flux to 125% at maximal BS output.


CONCLUSIONS
Both BS secretion and mdr2 P-gp strongly control biliary phospholipid secretion. The sum of the FCCs of both steps is always much higher than 100% implicating the presence of step(s) which exert negative control. We hypothesize that steps controlling biliary water transport account for the negative control.
Groen
A K
AK
Department of Gastroenterology, Academic Medical Centre, Amsterdam, The Netherlands. Groen@amc.uva.nl
Elferink
R P
RP
Tager
J M
JM
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism*; D019295:Computational Biology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C095122:multidrug resistance protein 3