Functional Role of the Secretin/Secretin Receptor Signaling During Cholestatic Liver Injury
Nan Wu, Leonardo Baiocchi, Tianhao Zhou, Lindsey Kennedy, Ludovica Ceci, Fanyin Meng, Keisaku Sato, Chaodong Wu, Burcin Ekser, Konstantina Kyritsi, Debjyoti Kundu, Lixian Chen, Vik Meadows, Antonio Franchitto, Domenico Alvaro, Paolo Onori, Eugenio Gaudio, Ilaria Lenci, Heather Francis, Shannon Glaser, Gianfranco Alpini
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. Because the secretin (Sct)/secretin receptor (SR) axis (expressed only by cholangiocytes in the liver) 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). 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.