Biliary secretion of fluid phase markers is modified under post-cholestatic conditions

Abstract

Hepatocytes take up macromolecules from the circulation by receptor-mediated and/or fluid-phase endocytosis. These molecules are either selectively or nonspecifically transported through the cell (transcytosis) and are subsequently secreted into bile. As transcytosis of diverse fluid-phase markers (FPM) is still poorly characterized, biliary secretion of two FPMs (horseradish peroxidase (HRP), FITC-Dextran) was studied in the isolated perfused rat liver following short-term (1 min) single-pulse administration. HRP was secreted into bile with a fast (5 min) and slow (15 min) transit time, while FITC-dextran appeared in bile in a single peak at 7 min. Short-time reversible cholestasis, induced by bile duct ligation (BDL), had been shown to affect HRP secretion. Here, we compare the influence of 2 h BDL on post-cholestatic biliary secretion of HRP and FITC-dextran. BDL drastically stimulated the fast component of HRP secretion into bile, but had an effect neither on the second HRP peak nor on the appearance of FITC-dextran in bile. Perfusion at low temperature (16 degrees C) under control and post-cholestatic conditions suppressed both, the second HRP peak and the appearance of FITC-dextran in bile, but uptake of FPM by endocytosis was not inhibited as the markers were secreted upon re-warming to 37 degrees C. In addition, perfusion at low temperature under control and post-cholestatic conditions delayed the appearance of the fast HRP peak in bile and it abrogated the stimulating effect of BDL on the first HRP peak. These data indicate that BDL boosts HRP secretion along a temperature-sensitive transcellular pathway and/or a paracellular route. This fast route is taken only by HRP but not by FITC-dextran, the latter being exclusively transported by a transcellular route under all conditions investigated.