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.

Fig. 1

Immunolocalisation of cytokeratin-19 (CK-19) in proliferating cholangiocytes in the bile duct ligation (BDL) animal model. Original magnification 40×.

Fig. 2

Localisation of α-CGRP (red) by immunofluorescence in normal and 3-day BDL WT mice liver sections. Bile ducts were stained with CK-7 (green). α-CGRP-positive staining and CK-7 colocalise in the bile ducts of 3-day BDL WT mice. The scale bar represents 20 μM. Arrows indicate bile ducts. Reproduced with permission from Ref. [53].

Fig. 3

Proposed sequence of intracellular events associated to GLP-1R activation in cholangiocytes. GLP-1R activation sustains cell growth enhancing the activation state of the PI3K and cAMP/PKA cascades. Cell proliferation is also elicited by the extracellular Ca²⁺-dependent activation of CaMKIIα that can modulate cholangiocyte proliferation both directly and by cross-talking with the cAMP/PKA cascade. In contrast, GLP-1R activation does not result in any change of ERK1/2 activation state and does not increase the IP3-PKCα signalling. Reproduced with permission from Ref. [60].

Fig. 4

Immunofluorescence for key proteins in the progesterone steroidogenesis pathway [steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (p450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD)] in liver sections from normal and BDL female and male rats demonstrates that bile ducts express these steroidogenesis pathway proteins (red staining). Colocalisation with CK-19 (green staining, a cholangiocyte-specific marker) of the bile ducts expressing StAR, p450scc, and 3β-HSD is also visible. Reproduced with permission from Ref. [48].