RT Journal Article
SR Electronic
T1 Hepatic Bile Formation: Developing a New Paradigm
JF Pharmacological Reviews
JO Pharmacol Rev
FD American Society for Pharmacology and Experimental Therapeutics
SP 1036
OP 1042
DO 10.1124/pharmrev.122.000799
VO 75
IS 5
A1 Norman B. Javitt
A2 John Schuetz
YR 2023
UL http://pharmrev.aspetjournals.org/content/75/5/1036.abstract
AB In 1959, Ivar Sperber contrasted bile formation with that of urine and proposed that water flow into the canalicular conduit is in response to an osmotic, not a hydrostatic, gradient. Early attempts to support the hypothesis using a bile acid, sodium taurocholate, and the hormone secretin to stimulate bile flow led to conflicting data and a moratorium on attempts to further develop the initial proposal. However, current data amplify the initial proposal and indicate both paracellular and transcellular water flow into hepatic ductules and the canalicular conduit in response to an osmotic gradient. Also, the need to further modify the initial proposal became apparent with the recognition that bile acid aggregates (micelles), which form in the canalicular conduit, generate lecithin-cholesterol vesicles that contain water unrelated to an osmotic gradient. As part of this development is the recent introduction of the fluorescent localization after photobleaching technique for direct determination of hepatic duct flow and clarification of the role of biomarkers such as mannitol and polyethylene glycol 900. With the new paradigm, these biomarkers may prove useful for quantifying paracellular and transcellular water flow, respectively.Significance Statement It is essential to identify and characterize all the sites for water flow during hepatic bile formation to obtain more precision in evaluating the causes and possible therapeutic approaches to cholestatic syndromes. Updating the Sperber proposal provides a new paradigm that addresses the advances in knowledge that have occurred.