Functional role of the ductular reaction in the maintenance of the hepatobiliary bile flow

Details

Supervisors

Leclercq, Isabelle

Faculty

Faculté de médecine et médecine dentaire

Degree label

Master [180] en médecine

Abstract

In chronic liver injury when hepatocyte proliferation is impaired or overwhelmed, expansion of ductular structures from periportal regions of the hepatic lobule, called ductular reaction (DR) is observed. Previous data from the gastro-enterology (GAEN) laboratory of the Université catholique de Louvain (UCL) show that upon hepatocellular injury caused by a choline-deficient and ethionine-supplemented (CDE) diet in mice, DR is invasive, DR-cells scarcely differentiate into hepatocytes and canalicular bile flow is impaired. The first aim of this paper is to investigate canalicular bile flow in the CDE model by assessing modifications of hepatocellular bile acid (BA) synthesis enzymes and transporters expression. We analysed mRNA and protein levels of hepatocyte BA synthesis enzymes and secretion, uptake and efflux transporters in C57Bl/6J mice fed with chow diet or CDE during 3, 9, and 21 days. Our results show unchanged expression of BA synthesis enzymes, secretion transporters and efflux transporters; but we observe significantly decreased expression of uptake transporter sodium-taurocholate cotransporting polypeptide (NTCP). This does not fit with cholestasis-induced regulation of BA synthesis enzymes and transporters by farnesoid-X receptor (FXR), which leads us to suspect pre-hepatic cholestasis secondary to NTCP inhibition to be the trigger of the invasive DR observed in CDE model. To better understand interactions between chronic liver damage, BA trafficking and DR, three separate literature reviews were carried out. A comparison of BA synthesis enzymes and transporters expression in other rodent models of DR showed that in unlike models of hepatocellular damage, DR in models of biliary damage is confined to the periportal region and resembles small bile duct proliferation, furthermore BA trafficking adaptation in biliary-damage models complies with FXR-mediated regulation. A comparison of BA synthesis enzymes and transporters expression in human liver diseases involving DR was limited by lack of data in medical literature on this subject, but showed that hepatocyte BA secretion transporter bile salt export pump (BSEP) dysfunction has different consequences in humans and mice. Finally, the third literature review lays out various strategies of NTCP inhibition and highlights that unlike humans, mice can compensate for NTCP inhibition via other uptake transporters, which is crucial information for future NTCP inhibition studies on mice. To conclude, non-invasive methods of BA transporters function assessment are presented as perspectives for future data collection in human liver diseases and as means of evaluating at a dynamic level the effect of BA trafficking modifications on DR.