Regulation of protein secretion into bile: studies in mice with a disrupted mdr2 p-glycoprotein gene.
OBJECTIVE
Protein is secreted into bile via several independent pathways. The aim of this study was to investigate whether these pathways are influenced by secretion of biliary lipid.


METHODS
Protein secretion and biliary lipid output were studied in wild-type mice (+/+), heterozygotes (+/-), and homozygotes (-/-) for mdr2 gene disruption. Biliary lipid and protein output were varied by infusion with taurocholate (TC) and tauroursodeoxycholate (TUDC).


RESULTS
Exocytosis and transcytosis were unaltered in (-/-) mice. Infusion with TC strongly induced secretion of alkaline phosphatase in (-/-) mice but had little effect in (+/-) and (+/+) mice. Infusion with TUDC had little effect on alkaline phosphatase output. In contrast, both TUDC and TC strongly stimulated secretion of aminopeptidase N and lysosomal enzymes in (+/+) mice but had no effect in (-/-) animals. Aminopeptidase N secretion correlated with phospholipid output, but only at high flux. At low flux, aminopeptidase N was secreted independently from both phospholipid and bile salts.


CONCLUSIONS
The canalicular membrane enzymes alkaline phosphatase and aminopeptidase N are secreted via separate pathways. Part of alkaline phosphatase output is controlled by bile salt hydrophobicity, whereas at high lipid flux, aminopeptidase N secretion seems to be coupled to phospholipid output. Lysosomal enzymes follow the latter pathway.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000201:enzymology / Q000378:metabolism*; D018826:CD13 Antigens / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005796:Genes; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010743:Phospholipids / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013656:Taurocholic Acid / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002756:Cholagogues and Choleretics; D010743:Phospholipids; D011506:Proteins; D013655:Taurochenodeoxycholic Acid; D013656:Taurocholic Acid; C031655:ursodoxicoltaurine; D000469:Alkaline Phosphatase; D018826:CD13 Antigens