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

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

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 20μM. Arrows indicate bile ducts.

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.

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.