REGULATION OF PROTEIN SECRETION INTO BILE - STUDIES IN MICE WITH A DISRUPTED MDR2 P-GLYCOPROTEIN GENE

Background & Aims: Protein is secreted into bile via several independe nt pathways. The aim of this study was to investigate whether these pa thways are influenced by secretion of biliary lipid. Methods: Protein secretion and biliary lipid output were studied in wildtype mice (+/+) , heterozygotes (+/-), and homozygotes (-/-) for mdr2 gene disruption. Biliary lipid and protein output were varied by infusion with tauroch olate (TC) and tauroursodeoxycholate (TUDC). Results: Exocytosis and t ranscytosis were unaltered in (-/-) mice. infusion with TC strongly in duced secretion of alkaline phosphatase in (-/-) mice but had little e ffect in (+/-) and (+/-) mice. infusion with TUDC had little effect on alkaline phosphatase output. In contrast, both TUDC and TC strongly s timulated secretion of aminopeptidase N and lysosomal enzymes in (+/+) mice but had no effect in (-/-) animals. Aminopeptidase N secretion c orrelated with phospholipid output, but only at high flux, At low flux , aminopeptidase N was secreted independently from both phospholipid a nd bile salts. Conclusions: The canalicular membrane enzymes alkaline phosphatase and aminopeptidase N are secreted via separate pathways. P art of alkaline phosphatase output is controlled by bile salt hydropho bicity, whereas at high lipid flux, aminopeptidase N secretion seems t o be coupled to phospholipid output. Lysosomal enzymes follow the latt er pathway.