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, 11, e7

Cholangiocyte Proliferation and Liver Fibrosis


Cholangiocyte Proliferation and Liver Fibrosis

Shannon S Glaser et al. Expert Rev Mol Med.


Cholangiocyte proliferation is triggered during extrahepatic bile duct obstruction induced by bile duct ligation, which is a common in vivo model used for the study of cholangiocyte proliferation and liver fibrosis. The proliferative response of cholangiocytes during cholestasis is regulated by the complex interaction of several factors, including gastrointestinal hormones, neuroendocrine hormones and autocrine or paracrine signalling mechanisms. Activation of biliary proliferation (ductular reaction) is thought to have a key role in the initiation and progression of liver fibrosis. The first part of this review provides an overview of the primary functions of cholangiocytes in terms of secretin-stimulated bicarbonate secretion--a functional index of cholangiocyte growth. In the second section, we explore the important regulators, both inhibitory and stimulatory, that regulate the cholangiocyte proliferative response during cholestasis. We discuss the role of proliferating cholangiocytes in the induction of fibrosis either directly via epithelial mesenchymal transition or indirectly via the activation of other liver cell types. The possibility of targeting cholangiocyte proliferation as potential therapy for reducing and/or preventing liver fibrosis, and future avenues for research into how cholangiocytes participate in the process of liver fibrogenesis are described.


Figure 1
Figure 1. Regulation of cholangiocyte bicarbonate secretion by secretin
Cholangiocytes are the only cell types in the liver expressing the basolateral secretin receptor. Secretin binds to the G-protein-coupled secretin receptor (SR), stimulating increased intracellular cAMP levels, which results in the activation of protein kinase A (PKA). Subsequently, PKA phosphorylates cystic fibrosis transmembrane conductance regulator (CFTR), stimulating Cl efflux from the apical domain of cholangiocytes thereby activating the ClHCO3 exchanger (AE2) and secretion of bicarbonate into the bile.
Figure 2
Figure 2. Regulation of cholangiocyte proliferation by gastrointestinal hormones
Cholangiocytes express CCKBR, SSTR2 and GLP1R G-protein-coupled receptors on their basolateral membranes. The gastrointestinal hormones gastrin and somatostatin both inhibit cholangiocyte proliferation through mechanisms that inhibit intracellular cAMP levels. In addition, the somatostatin analogue octreotide inhibits hepatic fibrosis in the polycystic kidney (PCK) rat model and in rats after bile duct ligation, indicating the potential to limit hepatic fibrosis associated with biliary proliferation via the targeting of SSTR2. Glucagon-like peptide 1 (GLP1) stimulates cholangiocyte proliferation by increasing intracellular cAMP levels with the concomitant activation of PI3K and Ca2+-CAMKIIα. Abbreviations: CCKBR, cholecystokinin-B receptor; GLP1R, glucagon-like peptide 1 receptor; SSTR2, somatostatin receptor subtype 2.
Figure 3
Figure 3. Stimulatory and inhibitory autocrine and paracrine feedback loops controlling cholangiocyte proliferation during cholestasis
During cholestasis, cholangiocytes secrete higher levels of NGF, which can stimulate cholangiocyte proliferation in autocrine or paracrine mechanisms via activation of Trk-A on the basolateral membrane of cholangiocytes through increases in ERK1/2 and AKT activity. By contrast, during cholestasis, cholangiocytes secrete higher levels of 5-HT, which negatively regulates cholangiocyte proliferation via activation of IP3–Ca2+–PKC-dependent signalling mechanisms, resulting in the downregulation of intracellular cAMP levels. Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); 5HT1A/B, 5-HT receptor 1A/B; IP3, inositol triphosphate; NGF, nerve growth factor; pAKT, phosphorylated AKT; pERK1/2, phosphorylated extracellular-regulated kinase 1/2; PKC, protein kinase C; Trk-A, neurotrophic tyrosine kinase receptor type 1.
Figure 4
Figure 4. Targeting cholangiocyte proliferation to limit or prevent fibrosis
Cholangiocyte proliferation activated by cholestasis stimulates the neuroendocrine transdifferentiation of cholangiocytes. Cholangiocytes release autocrine or paracrine factors that regulate proliferative responses and also activate fibrogenic responses of portal fibroblasts and hepatic stellate cells, resulting in activated myofibroblasts and fibrogenesis. In addition, cholangiocytes can undergo epithelial–mesenchymal transition and increase the number of fibrogenic cells in the portal areas. Therapies targeted to prevent and/or reduce cholangiocyte proliferation might play a novel role in the prevention and/or limitation of liver fibrosis.

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