The biliary epithelium is organized as a single layer of biliary epithelial cells (BECs) lining the biliary tree. BECs have three major biological functions: protection, secretion and proliferation. These functions may all be controlled by bile salts, the main constituents of bile. We therefore determined if human gallbladder-derived BECs exhibited bile salt transport activities that affect their secretory functions. We could show that the apical bile acid sodium- dependent transporter (ASBT) is expressed and functional in primary cultures of human BECs. Once transported inside BECs, bile salts stimulate chloride and mucin secretion through intracellular pathways linked to calcium. In BECs, the secretion process is however mainly elicited by membrane receptors that signal through the intracellular second messenger cAMP. We could show in a subsequent study that bile salts potentiate cAMP-regulated secretion in BECs by stimulating adenylyl cyclase activity through PKC α and δ. One of the most potent bile secretagogues is the vasoactive intestinal peptide, which exerts its effects through the vasoactive intestinal peptide receptor-1 (VPAC1). We have shown that VPAC1 is expressed in all major cell types participating in bile formation in humans (i.e. hepatocytes, intrahepatic and gallbladder biliary epithelial cells). Moreover, VPAC1 displays a gradient of expression along the human biliary tree, the gallbladder showing the highest level of expression. Interestingly, we could show that bile salts regulate VPAC1 expression in BECs through the farnesoid X receptor (FXR), indicating that bile salts may also regulate BECs secretion through transcriptional control. The secretory activities of BECs may be seen as a protective mechanism avoiding excessive exposure to toxics, such as endotoxins. We have shown that bile salts may also exert protection by controlling the expression of the antimicrobial peptide cathelicidin. Bile salts induced cathelicidin expression through two distinct nuclear receptors, FXR and the vitamin D nuclear receptor (VDR). Taken together, our results indicate that bile salts control BECs biological functions through post-traductional and transcriptional control. The involvement of VDR in the control of BECs biology may be of particular interest because VDR hepatic expression is restricted to non-parenchymal liver cells, such as BECs or resident hepatic macrophages (i.e. Kupffer cells).
| Identifer | oai:union.ndltd.org:CCSD/oai:tel.archives-ouvertes.fr:tel-00726374 |
| Date | 11 May 2012 |
| Creators | Chignard, Nicolas |
| Publisher | Université Pierre et Marie Curie - Paris VI |
| Source Sets | CCSD theses-EN-ligne, France |
| Language | English |
| Detected Language | English |
| Type | habilitation ࠤiriger des recherches |
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