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, 16 (8), 497-511

Pathobiology of Inherited Biliary Diseases: A Roadmap to Understand Acquired Liver Diseases


Pathobiology of Inherited Biliary Diseases: A Roadmap to Understand Acquired Liver Diseases

Luca Fabris et al. Nat Rev Gastroenterol Hepatol.


Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases β-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1β and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.

Conflict of interest statement

Competing interests

The authors declare no competing interests.


Fig. 1 |
Fig. 1 |. Notch signalling in biliary development and disease.
a | Between 56 and 58 days to 14 weeks gestational age, Notch signalling in the developing liver becomes activated in hepatoblasts by interaction with Jagged-1 (JAG1)-expressing mesenchymal cells. Activation of Notch is involved in the biliary specification of the hepatoblasts in contact with the portal vein mesenchyme. This process generates ductal biliary structures that become mature at ~30 weeks of gestation. b | When Notch signalling is disrupted, as in Alagille syndrome, small branches of the biliary tree do not develop, causing ductopenia, jaundice and pruritus. In some cases, the condition improves with time, whereas in 20–50% of cases, it can progress to end-stage liver disease. c | Notch signalling is also involved in biliary morphogenesis during the repair process in the context of chronic biliary damage. In this setting, Notch has a dual function that includes the activation of hepatic progenitor cells (HPCs) and ductular cells followed by the formation of the tubular structures and crosstalk with mesenchymal cells. d | Persistent overactivation of Notch signalling in HPCs, leading to downstream RBPJκ-dependent transcriptional activity, favours malignant transformation in hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCA).
Fig. 2 |
Fig. 2 |. Signalling mechanisms involved in cyst growth in ADPKD.
Autosomal dominant polycystic kidney disease (ADPKD) is associated with mutations in one of two genes, PKD1 or PKD2, which encode polycystin-1 (PC1) and PC2, respectively. ADPKD is characterized by the presence of multiple cysts in the liver parenchyma that progressively dilate and grow. PC2-defective cholangiocytes are characterized by inappropriate production of cAMP and increased protein kinase A (PKA)-dependent activation of extracellular-signal-regulated kinase 1 (ERK1)/ERK2 and subsequently mechanistic target of rapamycin (mTOR), and hypoxia-inducible factor 1α (HIF1α)-increased production of cAMP is caused by changes in intracellular Ca2+ homeostasis. In PC2-defective cholangiocytes, store-operated Ca2+ entry is inhibited and cells respond to an acute reduction in endoplasmic reticulum (ER) Ca2+ levels with stromal interacting molecule 1 (STIM1)-dependent and adenylyl cyclase 5 (AC5)-dependent stimulation of cAMP production, which drives PKA-dependent activation of ERK1/ERK2. Defective PC2 also inhibits the interaction between STIM1 and Orai channels and maximizes the functional coupling of STIM1 to AC5, resulting in increased production of cAMP. PC2-defective cells respond to conditions that decrease ER Ca2+ levels and trigger oligomerization and membrane translocation of STIM1, with an overproduction of cAMP. In turn, cAMP activates the PKA–Ras–Raf–ERK pathway and stimulates vascular endothelial growth factor (VEGF) production through an mTOR–HIF1α-mediated mechanism. VEGF produced by cystic cholangiocytes increases perivascular microvascular density and cholangiocyte proliferation through binding with VEGF receptor 2 (VEGFR2). Stimulation of mTOR through AKT, for example, by insulin-like growth factor receptor (IGFR) ligand binding, can also activate ERK1/ERK2. Signalling molecules that are druggable are highlighted in bold and detailed in TABLE 2. PI3K, phosphoinositide 3-kinase; pmTOR, phosphorylated mTOR; pAKT, phosphorylated AKT.
Fig. 3 |
Fig. 3 |. Novel mechanisms of biliary fibrosis in ARPKD.
Liver disease in autosomal recessive polycystic kidney disease (ARPKD), which is caused by mutations in the PKHD1 gene (encoding fibrocystin (FPC)), is characterized by cystic dysgenesis of the intrahepatic bile ducts that retain an immature phenotype reminiscent of the embryonic biliary structures (ductal plate malformations). The disease is associated with progressive portal fibrosis, leading to portal hypertension and related complications. In FPC-defective cholangiocytes, increased levels of cAMP activate protein kinase A (PKA)-dependent phosphorylation of β-catenin (β-Cat) at Ser675 that leads to the nuclear translocation of pSer675β-catenin and transcriptional activation. This mechanism mediates the secretion of CXC-chemokine ligand 1 (CXCL1), CXCL10 and CXCL12 that recruit inflammatory cells, mostly M1 and then M2 macrophages, around the cystic epithelium. Macrophages secrete transforming growth factor-β (TGFβ) and TNF and stimulate the expression of αVβ6 integrins on cystic cholangiocytes that in turn activate latent TGFβ. CXCL10 secretion is further increased by the production of IL-1β through the activation of the Janus kinase (JAK)–signal transducer and activator of transcription 3 (STAT3) pathway. IL-1β secretion is mediated by an activated inflammasome. Signalling molecules that are druggable are highlighted in bold and detailed in TABLE 2. ASC, apoptosis-associated speck-like protein containing a CARD; NF-κB, nuclear factor-κB; NLRP3, NOD-, LRR- and pyrin domain-containing 3.
Fig. 4 |
Fig. 4 |. CFTR function in cholangiocytes.
a | Cystic fibrosis transmembrane conductance regulator (CFTR) is located on the apical membrane of cholangiocytes where it has a major role in modifying bile properties (fluidity and pH). Bicarbonate (HCO3) secretion into bile is necessary to sustain bile flow, to enable clearance of xenobiotics and to accomplish digestive needs (digestion and absorption of fats) within the intestine. Secretin is the main hormone that controls the secretory functions of the biliary epithelium. Secretin interacts with the G protein-coupled secretin receptor (SCTR) expressed on the basolateral membrane of cholangiocytes and triggers the production of cAMP, which activates protein kinase A (PKA). In turn, PKA phosphorylates the R domain of CFTR and opens the chloride conductivity channel. Apical chloride secretion is mediated by bicarbonate exchange through the anion exchanger 2 (AE2), generating an electrolyte–osmotic gradient that favours the passive movement of water through aquaporins (AQPs). These mechanisms are responsible for the normal hydration and alkalization of bile. CFTR-dependent biliary secretion is also triggered in response to TGR5 receptor–PKA signalling when TGR5 is stimulated by bile acids. TGR5, a membrane-bound bile acid receptor coupled to a stimulatory G protein, is expressed in the liver by several non-parenchymal cells (including the sinusoidal epithelium, Kuppfer cells and hepatic stellate cells) and by cholangiocytes. On cholangiocytes, TGR5 is localized both on the apical membrane and on the primary cilium and is strongly activated by taurolithocholic acid and taurocholate. In vitro data in mouse cholangiocytes have shown that CFTR can mediate the apical release of ATP that binds to P2Y purinergic receptors on the apical membrane of biliary cells and activates the Ca2+–calmodulin chloride channel (TMEM16). CFTR also regulates the function of proteins involved in biliary innate immunity and endotoxin tolerance (such as Src family tyrosine kinase and its regulatory proteins CBP and CSK). b | Mutations in the gene encoding CFTR cause a chronic cholangiopathy that can eventually progress to biliary cirrhosis. When CFTR is absent, biliary secretion is impaired and the protein complex formed with Src and its regulatory proteins is disrupted, resulting in the self-activation of Src. Src activation is responsible for the phosphorylation of Toll-like receptor 4 (TLR4), which enhances its response to lipopolysaccharide (LPS) and increases nuclear factor-κB (NF-κB) activation and cytokine secretion. This inflammatory milieu also affects the F-actin cytoskeleton and tight junction (TJ) integrity, altering the epithelial barrier function. CFTR loss also promotes changes in the gut that favour the colonization of a more pro-inflammatory microbiota and the translocation of their products to the liver. The altered biliary epithelial innate immunity and changes in the gut microbiota synergistically lead to the progression of cystic fibrosis-related liver disease. Signalling molecules that are druggable are detailed in TABLE 2. AJ, adherens junction; DAMP, damage-associated molecular pattern; ER, endoplasmic reticulum; InsP3R, inositol-1,4,5-trisphosphate receptor; PAMP, pathogen-associated molecular pattern.

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