Hepatic bile formation: bile acid transport and water flow into the canalicular conduit

Abstract

Advances in molecular biology identifying the many carrier-mediated organic anion transporters and advances in microscopy that have provided a more detailed anatomy of the canalicular conduit make updating the concept of osmotically determined canalicular flow possible. For the most part water flow is not transmembrane but via specific pore proteins in both the hepatocyte and the tight junction. These pores independently regulate the rate at which water flows in response to an osmotic gradient and therefore are determinants of canalicular bile acid concentration. Review of the literature indicates that the initial effect on hepatic bile flow of cholestatic agents such as Thorazine and estradiol 17β-glucuronide are on water flow and not bile salt export pump-mediated bile acid transport and thus provides new approaches to the pathogenesis of drug-induced liver injury. Attaining a micellar concentration of bile acids in the canaliculus is essential to the formation of cholesterol-lecithin vesicles, which mostly occur in the periportal region of the canalicular conduit. The other regions, midcentral and pericentral, may transport lesser amounts of bile acid but augment water flow. Broadening the concept of how hepatic bile flow is initiated, provides new insights into the pathogenesis of canalicular cholestasis.