Functional Role of the Secretin/Secretin Receptor Signaling During Cholestatic Liver Injury

Abstract

iver diseases are a major health concern and affect a large proportion of people worldwide. There are over 100 types of liver disorders, including cirrhosis, cholangiocarcinoma (CCA), hepatocellular carcinoma, and hepatitis. Despite the relevant number of people who are affected by liver diseases, and the increased awareness with regard to these disorders, the number of deaths corresponding to liver injury is expected to increase in the foreseeable future. One of the possible reasons for this is that a complete comprehension of the mechanisms of hepatic damage involving specific liver anatomical districts is lacking, and, as a consequence, current treatments available are suboptimal. A major burden in the clinical setting are chronic cholestatic liver diseases (e.g., primary biliary cholangitis [PBC], primary sclerosing cholangitis [PSC], biliary atresia), which target the biliary epithelium and are characterized by cholestasis. (1,2) Because the secretin (Sct)/secretin receptor (SR) axis (expressed only by cholangiocytes in the liver) (3,4) is the major regulator of ductal bile secretion, (5,6) it is intuitive that this axis plays a key role in the maintenance of biliary homeostasis during the progression of cholangiopathies. For instance, PBC is characterized by reduced bicarbonate secretion, a phenomenon possibly impeding the formation of an HCO − 3 canalicular film ("bicarbonate umbrella") on bile ducts, which has protective properties against highly concentrated bile acids (BAs). (1,7,8) In this review, we examined the molecular mechanisms by which the Sct/SR axis regulates biliary function and the homeostasis of the biliary epithelium in normal and pathophysiological conditions. Sct/SR aXIS: tHe BaSICS Sct, a neuroendocrine, gastrointestinal peptide of 27 amino acids is secreted primarily by the intestinal S cells located in the Lieberkühn crypts. There is evidence that Sct is also secreted by other epithelia in different organs including the pancreas, intestine and liver, thus exerting various biological effects in

Biliary Epithelial Senescence in Liver Disease: There Will Be SASP

“…Secretory and proliferative activities of the cholangiocytes are finely tuned by several hormones, neuropeptides and angiogenic factors (Alvaro et al, 2007;Franchitto et al, 2013). For instance, secretin binding to the cholangiocyte-specific secretin receptor (SR, a G-protein coupled receptor) stimulates bicarbonate enriched choleresis, thereby increasing intracellular cAMP and activating the biliary cAMP/protein kinase A (PKA)-dependent cystic fibrosis transmembrane conductance regulator (CFTR) opening and subsequent anion exchange protein 2 (AE2) activation (Glaser et al, 2009;Mancinelli et al, 2013;Wu et al, 2020). Fluctuations in intracellular levels of cAMP, and its role as a second messenger, are important in the biliary epithelia not only for secretory activities, but also for proliferative processes (Baiocchi et al, 2021).…”

Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?

“…Via electron microscopy, two different cholangiocyte subpopulations in rodent livers are well recognized (small and large), lining small ducts (≤15 μm in diameter) or large ducts (≥15 μm in diameter) according to their size [ 1 , 3 ]. Large cyclic adenosine monophosphate (cAMP)-dependent cholangiocytes are considered the functional part of the biliary tree since they respond to gastrointestinal hormones (e.g., secretin), neuro-peptides and other modulators [ 4 , 5 , 6 ]. On the other hand, small Ca 2+ -dependent cholangiocytes [ 7 ] do not respond to secretin and proliferate to replenish the biliary epithelium (during damage to the large, cAMP-dependent cholangiocytes) by amplification of Ca 2+ -dependent signaling and de novo acquisition of large cholangiocyte phenotypes [ 6 , 8 , 9 ].…”

“…Large cyclic adenosine monophosphate (cAMP)-dependent cholangiocytes are considered the functional part of the biliary tree since they respond to gastrointestinal hormones (e.g., secretin), neuro-peptides and other modulators [ 4 , 5 , 6 ]. On the other hand, small Ca 2+ -dependent cholangiocytes [ 7 ] do not respond to secretin and proliferate to replenish the biliary epithelium (during damage to the large, cAMP-dependent cholangiocytes) by amplification of Ca 2+ -dependent signaling and de novo acquisition of large cholangiocyte phenotypes [ 6 , 8 , 9 ]. While, at the beginning, just bile duct secretory activities were studied with regard to biliary tract diseases, lately also, biliary proliferative phenotypes have gained interest [ 10 , 11 , 12 ].…”

Liver secretin receptor predicts portoenterostomy outcomes and liver injury in biliary atresia

“…SCTR is a G-protein coupled receptor protein binding to the neuroendocrine hormone secretin, which is mainly produced by the S-cells in the small intestine 18 . Secretin and SCTR have also been demonstrated in several other organs including cholangiocytes in the liver 19 – 21 . In the liver, the secretin/SCTR axis regulates bicarbonate rich secretion from cholangiocytes maintaining ‘bicarbonate umbrella’, which protects the bile duct epithelium against high bile acid concentrations 21 .…”