Secretin and cholestasis, two sides of a coin
Authors: Martin Wagner, Peter Fickert, Gernot Zollner
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. See Article on Page 865 Bile is vital for life. Bile is the main excretion route for potential harmful lipophilic endogenous and exogenous compounds, including cholesterol, and is the obligate fat emulsifier for lipid absorption in the intestine.1 Bile is channeled from the canaliculi formed by hepatocytes to the intestinal lumen by a complex three‐dimensional network of bile ducts, which constantly grow in diameter. Along its passage, bile is further modified by secretory and absorptive functions of cholangiocytes, which line the bile ducts. Although cholangiocytes represent only 3%‐5% of liver cells, cholangiocytes constitute for approximately 30% of bile production in humans.1 Proper function of cholangiocytes and bile duct maintenance are therefore important for a healthy liver. Cholangiopathies are liver diseases that impair cholangiocyte function and bile duct integrity, eventually leading to fibrosis, cirrhosis, and terminal loss of organ function. Cholangiocyte proliferation and ductular reaction are a typical response to various types of liver injury. Cholangiocyte proliferation is generally considered as an adaptive response to increase cholangiocyte reabsorptive surface and enhance cholehepatic shunting of biliary constituents aimed at alleviating cholestatic liver injury.2 Importantly, proliferating cholangiocytes and newly formed ductules become actively involved in this adaptive process and acquire neurohormonal properties as part of their reactive phenotype.4 The released molecules, including cytokines, growth factors, neuropeptides, and hormones, act in an autocrine and paracrine manner and recruit inflammatory and mesenchymal cells, which further induce cholangiocyte proliferation and maturation of ductular metaplasia.2 These adaptations may eventually help repair injury to the biliary tree and protect against further biliary insult. But these processes may also promote portal inflammation and fibrosis. The relationship between cholangiocyte proliferation and activation of fibrogenesis is so tight that ductular reaction has been considered to be the pacemaker of liver fibrosis of the biliary type.4 Secretin and its receptor are important neuroendocrine regulators of cholangiocyte function. The secretin receptor is expressed on large cholangiocytes, which is the cell type from which bile duct proliferates typically originate. One important well‐known function of secretin is the stimulation of bicarbonate secretion. Biliary bicarbonate has recently been suggested to maintain an alkaline pH near the apical surface of cholangiocytes, preventing uncontrolled permeation of potentially toxic bile acids through the cell membrane. Effects of bicarbonate aimed at protecting cholangiocytes' cellular membranes have been subsumed under the term "biliary bicarbonate umbrella,"5 and its malfunction is currently under investigation as a potential pathogenetic event in the development of cholangiopathies.5 The choleretic response to secretin, however, depends on the existence of bile duct proliferation given that under normal conditions (without bile duct proliferation), secretin does not induce bicarbonate‐dependent choleresis.6 In an elegant series of several landmark articles, the group of Alpini et al. further established the central role of the secretin/secretin receptor axis not only for bicarbonate‐rich choleresis, but also for inducing and maintaining cholangiocyte proliferation and development of bile duct proliferates in cholestatic conditions. Common bile duct ligated (CBDL) mice lacking the secretin receptor showed less cholangiocyte proliferation and bile duct proliferates. Vice versa, administration of secretion induced bile duct proliferation.7 Mechanistically, cholestasis leads to increased secretion of secretin from large cholangiocytes, which by autocrine and/or paracrine mechanisms increase growth factors (i.e., vascular endothelial growth factor and nerve growth factor [NGF]) required for ductular proliferation. These events harbor regulatory intermediate steps by microRNAs (miRNAs), such as let7a.8 Altogether, those important studies suggest secretin and its receptor as a therapeutic target for ductopenic liver disease. In this issue of Hepatology,9 Wu et al. show, for the first time, that the secretin/secretin receptor axis is also a substantial contributor to biliary fibrosis. In well‐conducted series of experiments, the investigators demonstrate that secretin not only increases bile duct mass, but, importantly, increases (biliary‐type of) liver fibrosis. These effects appear to depend on the secretin receptor, because in elegant genetic and pharmacological loss‐of‐function experiments, the investigators confirm reduced bile duct mass and liver fibrosis in two different models of cholestasis, CBDL and Mdr2 (Abcb4)‐/‐ mice, the latter one mimicking primary sclerosing cholangitis (PSC). Interestingly, markers of liver injury and cholestasis were also reduced in cholestatic animals lacking the secretin receptor or receiving a secretin antagonist. The reduction in transaminases may in part be explained by less recruitment of inflammatory and mesenchymal cells to a reduced number of reactive bile duct proliferates. As underlying mechanisms for reduced fibrosis, Wu et al. confirmed their previous mechanistic details on miRNA let7a and NGF and could additionally link transforming growth factor beta 1 (TGF‐β1) and TGF‐β1 receptor (TGF‐β1R) to the line of events leading to fibrosis. At advanced stages of cholestasis, the antisecretin strategy may modulate the close network among reactive cholangiocytes and mesenchymal cells, which are a significant source of fibrotic matrix, ultimately reducing biliary type of fibrosis. This study, however, stands out because it translates in vitro and in vivo mouse experiments into the clinical world. The investigators provide direct clinical evidence from PSC patients with biliary type of liver fibrosis demonstrating significant overexpression of secretin and its receptor along with induction of NGF, TGF‐β1, TGF‐β1R, and profibrogenic genes. These important observations therefore challenge previous perceptions of secretin as a potential therapy for ductopenic diseases and instead suggest secretin antagonistic strategies for advanced cholestatic liver disease with biliary type of fibrosis. Consequently, their findings imply a change of perspectives. What could those findings imply for patients with cholestatic liver disease? In the past years, compelling experimental evidence points out the importance of bicarbonate protection for the biliary epithelium.5 Secretin is an important promoter of adaptive bile duct proliferation and stimulator of bicarbonate secretion. Therefore, it comes somehow as a surprise that antisecretin strategies may improve markers of liver injury and cholestasis as well as fibrosis as demonstrated by Wu et al.9 Improvement of fibrosis is a particularly important aspect in the disease course of cholestatic patients because it is most likely the degree of liver fibrosis determining prognosis.10 In clinical settings, secretin effects stimulating bicarbonate‐rich bile flow may protect biliary tree integrity, but, on the contrary, may worsen fibrosis and speed up development of liver cirrhosis and liver failure. Profibrotic effects of secretin may far outweigh its protective effects by bicarbonate‐rich choleresis. Thus, combining antisecretin strategies to reduce development of biliary fibrosis with strategies to increase bicarbonate secretion without inducing biliary proliferates could eventually lead to clinically important net benefits. A potential pharmacological candidate is nor‐UDCA (ursodeoxycholic acid), a derivative of the anticholestatic, UDCA. nor‐UDCA stimulates bicarbonate choleresis even under conditions when bile duct proliferates lack,11 which is in contrast to the secretin effects on bicarbonate, which strictly dependent on the presence of bile duct proliferates.6 In conclusion, this study has addressed the important issue of biliary fibrosis in cholestasis and demonstrated that secretin antagonism not only reduces biliary fibrosis, but also bile duct proliferates as the fibrogenic source. This may, however, come at the price of reduced biliary surface and bicarbonate secretion, important biliary adaptations to cholestasis. Clearly, further studies are needed before bringing such concepts from bench to bedside. Author names in bold designate shared co‐first authorship.