Recent advances in the regulation of cholangiocyte proliferation and function during extrahepatic cholestasis

Abstract 

Bile duct epithelial cells (i.e., cholangiocytes), which line the intrahepatic biliary epithelium, are the target cells in a number of human cholestatic liver diseases (termed cholangiopathies). Cholangiocyte proliferation and death is present in virtually all human cholangiopathies. A number of recent studies have provided insights into the key mechanisms that regulate the proliferation and function of cholangiocytes during the pathogenesis of cholestatic liver diseases. In our review, we have summarised the most important of these recent studies over the past 3 years with a focus on those performed in the animal model of extrahepatic bile duct ligation. In the first part of the review, we provide relevant background on the biliary ductal system. We then proceed with a general discussion of the factors regulating biliary proliferation performed in the cholestatic animal model of bile duct ligation. Further characterisation of the factors that regulate cholangiocyte proliferation and function will help in elucidating the mechanisms regulating the pathogenesis of biliary tract diseases in humans and in devising new treatment approaches for these devastating diseases.

Abbreviations: AIC, autoimmune cholangitis, BDL, Bile duct ligation, CaMKII α, calmodulin-dependent protein kinase α, cAMP, cyclic adenosine 3′,5′-monophosphate, CCl₄, carbon tetrachloride, CF, cystic fibrosis, CFTR, cystic fibrosis transmembrane conductance regulator, CGRP, calcitonin gene-related peptide, CREB, cAMP response element binding, ERK1/2, extracellular signal-regulated kinase, FSH, follicle-stimulating hormone, GCDC, glycochenodeoxycholate, GLP-1, glucagon-like peptide-1, GVHD, graft-versus-host disease, 3β-HSD, 3β-hydroxysteroid dehydrogenase, IGF-1, insulin-like growth factor-1, PBC, primary biliary cirrhosis, PI3K, phosphoinositide 3-kinase, PKA, protein kinase A, PSC, primary sclerosing cholangitis, p450scc, cytochrome P450 side-chain cleavage, SR, secretin receptor, STAR, steroidogenic acute regulatory protein, TNF, tumor necrosis factor, VEGF, vascular endothelial growth factor

Keywords: Bile duct ligation, Cholangiocyte, Cholestatic liver diseases, Extrahepatic cholestasis, Proliferation