Highlights
- •The biliary secretin/secretin receptor axis is diminished in late-stage PBC.
- •Secretin treatment alleviates liver damage in a late-stage PBC model.
- •Secretin restores the protective ‘bicarbonate umbrella’ in a late-stage PBC model.
- •Secretin treatment promotes choleresis and restores ductulo-canalicular junctions.
- •The secretin/secretin receptor axis promotes mature cholangiocyte differentiation.
Background & Aims
Primary biliary cholangitis (PBC) is characterised by ductopenia, ductular reaction,
impairment of anion exchanger 2 (AE2) and the ‘bicarbonate umbrella’. Ductulo-canalicular
junction (DCJ) derangement is hypothesised to promote PBC progression. The secretin
(Sct)/secretin receptor (SR) axis regulates cystic fibrosis transmembrane receptor
(CFTR) and AE2, thus promoting choleresis. We evaluated the role of Sct/SR signalling
on biliary secretory processes and subsequent injury in a late-stage PBC mouse model
and human samples.
Methods
At 32 weeks of age, female and male wild-type and dominant-negative transforming growth
factor beta receptor II (late-stage PBC model) mice were treated with Sct for 1 or
8 weeks. Bulk RNA-sequencing was performed in isolated cholangiocytes from mouse models.
Results
Biliary Sct/SR/CFTR/AE2 expression and bile bicarbonate levels were reduced in late-stage
PBC mouse models and human samples. Sct treatment decreased bile duct loss, ductular
reaction, inflammation, and fibrosis in late-stage PBC models. Sct reduced hepatic
bile acid levels, modified bile acid composition, and restored the DCJ and ‘bicarbonate
umbrella’. RNA-sequencing identified that Sct promoted mature epithelial marker expression,
specifically anterior grade protein 2 (Agr2). Late-stage PBC models and human samples
exhibited reduced biliary mucin 1 levels, which were enhanced by Sct treatment.
Conclusion
Loss of Sct/SR signalling in late-stage PBC results in a faulty ‘bicarbonate umbrella’
and reduced Agr2-mediated mucin production. Sct restores cholangiocyte secretory processes
and DCJ formation through enhanced mature cholangiocyte phenotypes and bile duct growth.
Sct treatment may be beneficial for individuals with late-stage PBC.
Impact and implications
Secretin (Sct) regulates biliary proliferation and bicarbonate secretion in cholangiocytes
via its receptor, SR, and in mouse models and human samples of late-stage primary
biliary cholangitis (PBC), the Sct/SR axis is blunted along with loss of the protective
‘bicarbonate umbrella’. We found that both short- and long-term Sct treatment ameliorated
ductular reaction, immune cell influx, and liver fibrosis in late-stage PBC mouse
models. Importantly, Sct treatment promoted bicarbonate and mucin secretion and hepatic
bile acid efflux, thus reducing cholestatic and toxic bile acid-associated injury
in late-stage PBC mouse models. Our work perpetuates the hypothesis that PBC pathogenesis
hinges on secretory defects, and restoration of secretory processes that promote the
‘bicarbonate umbrella’ may be important for amelioration of PBC-associated damage.
Graphical abstract
Graphical Abstract
Keywords
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References
- Primary biliary cirrhosis.Orphanet J Rare Dis. 2008; 3: 1
- Canals of Hering loss relates to the progression of the histological stages of primary biliary cirrhosis.J Clin Pathol. 2015; 68: 141-147
- Canal of Hering loss is an initiating step for primary biliary cholangitis (PBC): a hypothesis.Med Hypotheses. 2020; 140109680
- Ductular reaction in liver diseases: pathological mechanisms and translational significances.Hepatology. 2019; 69: 420-430
- Hepatic stem/progenitor cell activation differs between primary sclerosing and primary biliary cholangitis.Am J Pathol. 2018; 188: 627-639
- The biliary HCO3- umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies.Hepatology. 2010; 52: 1489-1496
- Large but not small intrahepatic bile ducts are involved in secretin-regulated ductal bile secretion.Am J Physiol. 1997; 272: G1064-G1074
- Up-regulation of microRNA 506 leads to decreased Cl-/HCO3- anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis.Hepatology. 2012; 56: 687-697
- Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis.Hepatology. 1997; 25: 12-17
- The physiological roles of secretin and its receptor.Ann Transl Med. 2013; 1: 29
- Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and microRNA let7a in mice.Gastroenterology. 2014; 146: 1795-1808.e1712
- Prolonged administration of secretin to normal rats increases biliary proliferation and secretin-induced ductal secretory activity.Hepatobiliary Surg Nutr. 2014; 3: 118-125
- Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis.FASEB J. 2019; 33: 10269-10279
- The secretin/secretin receptor axis modulates liver fibrosis through changes in transforming growth factor-beta1 biliary secretion in mice.Hepatology. 2016; 64: 865-879
- The cholangiocyte glycocalyx stabilizes the 'biliary HCO3- umbrella': an integrated line of defense against toxic bile acids.Dig Dis. 2015; 33: 397-407
- Impaired mucin synthesis and bicarbonate secretion in the colon of NHE8 knockout mice.Am J Physiol Gastrointest Liver Physiol. 2012; 303: G335-G343
- Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice.J Immunol. 2006; 177: 1655-1660
- B cell depletion therapies in autoimmune disease: advances and mechanistic insights.Nat Rev Drug Discov. 2021; 20: 179-199
- The secretin/secretin receptor axis modulates ductular reaction and liver fibrosis through changes in transforming growth factor-beta1-mediated biliary senescence.Am J Pathol. 2018; 188: 2264-2280
- Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.Cell Metab. 2013; 17: 225-235
- Bile acid metabolism and signaling in liver disease and therapy.Liver Res. 2017; 1: 3-9
- Bile acids stimulate cholangiocyte fluid secretion by activation of transmembrane member 16A Cl- channels.Hepatology. 2018; 68: 187-199
- An impaired biliary bicarbonate umbrella may be involved in dysregulated autophagy in primary biliary cholangitis.Lab Invest. 2018; 98: 745-754
- Hydrophobic bile acids suppress expression of AE2 in biliary epithelial cells and induce bile duct inflammation in primary biliary cholangitis.J Autoimmun. 2016; 75: 150-160
- Bicarbonate-rich choleresis induced by secretin in normal rat is taurocholate-dependent and involves AE2 anion exchanger.Hepatology. 2006; 43: 266-275
- Biliary bicarbonate, pH, and glucose are suitable biomarkers of biliary viability during ex situ normothermic machine perfusion of human donor livers.Transplantation. 2019; 103: 1405-1413
- Assessment of biliary bicarbonate secretion in humans by positron emission tomography.Gastroenterology. 1999; 117: 167-172
- Loss of inositol 1,4,5-trisphosphate receptors from bile duct epithelia is a common event in cholestasis.Gastroenterology. 2003; 125: 1175-1187
- Post-translational regulation of the type III inositol 1,4,5-trisphosphate receptor by miRNA-506.J Biol Chem. 2015; 290: 184-196
- Increased p16INK4a-expressing senescent bile ductular cells are associated with inadequate response to ursodeoxycholic acid in primary biliary cholangitis.J Autoimmun. 2020; 107102377
- Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578
- Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.J Clin Invest. 1998; 102: 538-549
- Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor.Gastroenterology. 2005; 128: 1042-1055
- Alteration of liver-infiltrated and peripheral blood double-negative T-cells in primary biliary cholangitis.Liver Int. 2019; 39: 1755-1767
- Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants.J Hepatol. 2017; 67: 1253-1264
- Keratin 19 demonstration of canal of Hering loss in primary biliary cirrhosis: “minimal change PBC”.Hepatology. 2013; 57: 700-707
- Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia.Hepatology. 2022; 7: 89-103
- Prox1 ablation in hepatic progenitors causes defective hepatocyte specification and increases biliary cell commitment.Development. 2014; 141: 538-547
- Small proline-rich proteins (SPRR) function as SH3 domain ligands, increase resistance to injury and are associated with epithelial-mesenchymal transition (EMT) in cholangiocytes.J Hepatol. 2008; 48: 276-288
- A human liver cell atlas reveals heterogeneity and epithelial progenitors.Nature. 2019; 572: 199-204
- Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors.Nat Commun. 2019; 10: 3350
- Human AGR2 deficiency causes mucus barrier dysfunction and infantile inflammatory bowel disease.Cell Mol Gastroenterol Hepatol. 2021; 12: 1809-1830
- AGR2 is induced in asthma and promotes allergen-induced mucin overproduction.Am J Respir Cel Mol Biol. 2012; 47: 178-185
- Clinicopathology of sialomucin: MUC1, particularly KL-6 mucin, in gastrointestinal, hepatic and pancreatic cancers.Biosci Trends. 2009; 3: 220-232
- Developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands. I. Stomach. A relationship to gastric carcinoma.J Histochem Cytochem. 2000; 48: 1657-1666
- Downregulation of mucins in graft bile ducts after liver transplantation in rats.Transplantation. 2011; 92: 529-535
- Normal mucus formation requires cAMP-dependent HCO3- secretion and Ca2+-mediated mucin exocytosis.J Physiol. 2013; 591: 4581-4593
Article info
Publication history
Published online: August 17, 2022
Accepted:
July 29,
2022
Received in revised form:
July 22,
2022
Received:
December 18,
2021
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
