Inhibition of biliary phospholipid and cholesterol secretion by bilirubin in the Sprague-Dawley and Gunn rat

Abstract

Bilirubin is one of several organic anions that selectively inhibit the biliary secretion of phospholipid and cholesterol without affecting bile salt secretion. To determine the site of this inhibition and gain insight into its mechanism, normal, Sprague-Dawley and homozygous Gunn rats were infused with unconjugated bilirubin and a water-soluble model conjugate, bilirubin ditaurate. Either unconjugated bilirubin or bilirubin ditaurate infused into Sprague-Dawley rats caused an increase in biliary bilirubin secretion from 2.1 +/- 0.3 to 315 +/- 15 nmol/min, whereas phospholipid and cholesterol secretion fell significantly, in parallel, to 25% of control. Bilirubin ditaurate infused into homozygous Gunn rats caused changes in biliary lipid and bilirubin secretion similar to those seen in Sprague-Dawley rats. Biliary bilirubin secretion rose from 0.9 +/- 0.6 to 303 +/- 9 nmol/min, whereas biliary phospholipid and cholesterol secretion fell to 28% of controls. In contrast, unconjugated bilirubin infused into Gunn rats caused only a slight increase in biliary bilirubin secretion, from 0.9 +/- 0.3 to 6.0 +/- 2.1 nmol/min, whereas biliary lipid secretion remained within 90% of control. These results indicate that the inhibition of biliary phospholipid and cholesterol secretion by bilirubin occurs after microsomal conjugation. It is possible that the more hydrophilic conjugates of bilirubin aggregate with intracellular phospholipid and cholesterol destined for bile. Consequently, micelle-forming bile salts could be prevented from recognizing or aggregating with these lipids and fail to promote their secretion into bile.