Bile salts represent signalling molecules with a variety of endocrine functions. Bile salt effects are mediated by different receptor molecules, comprising ligand-activated nuclear transcription ...factors as well as G protein-coupled membrane-bound receptors. The farnesoid X receptor (FXR) and the plasma membrane-bound G protein-coupled receptor TGR5 (Gpbar-1) are prototypic bile salt receptors of both classes and are highly expressed in the liver including the biliary tree as well as in the intestine. In liver, TGR5 is localized in different non-parenchymal cells such as sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells and small and large cholangiocytes. Through TGR5 bile salts can mediate choleretic, cell-protective as well as proliferative effects in cholangiocytes.
A disturbance of these signalling mechanisms can contribute to the development of biliary diseases. In line with the important role of TGR5 for bile salt signalling, TGR5 knockout mice are more susceptible to cholestatic liver damage. Furthermore, in absence of TGR5 cholangiocyte proliferation in response to cholestasis is attenuated and intrahepatic and extrahepatic bile ducts show increased cell damage, underscoring the role of the receptor for biliary physiology. Decreased TGR5 expression may also contribute to the development or progression of cholangiopathies like primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) since reduced TGR5-dependent cell-protective mechanisms such as bicarbonate secretion renders cholangiocytes more vulnerable towards bile salt toxicity. Nevertheless, TGR5 overexpression or constant stimulation of the receptor can promote cholangiocyte proliferation leading to cyst growth in polycystic liver disease or even progression of cholangiocarcinoma.
Not only the stimulation of TGR5-mediated pathways by suitable TGR5 agonists but also the inhibition of TGR5 signalling by the use of antagonists represent potential therapeutic approaches for different types of biliary diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
•Cholangiocytes express different nuclear and G protein-coupled bile acid receptors.•TGR5 activation promotes chloride secretion, cell proliferation and cytoprotection.•TGR5 expression is reduced in cholangiocytes from PSC and Mdr2 livers.•Overexpression of TGR5 is found in cholangiocarcinoma cells and cystic cholangiocytes.•For biliary diseases both activation and inhibition of TGR5 signalling may prove useful.
Summary Bile acids are signaling molecules with diverse endocrine functions. Bile acid effects are mediated through the nuclear receptor farnesoid X receptor (FXR), the G-protein coupled receptor ...TGR5 (Gpbar-1) and various other bile acid sensing molecules. TGR5 is almost ubiquitously expressed and has been detected in different non-parenchymal cells of human and rodent liver. Here, TGR5 has anti-inflammatory, anti-apoptotic and choleretic functions. Mice with targeted deletion of TGR5 are protected from the development of cholesterol gallstones. Administration of specific TGR5 agonists lowers serum and liver triglyceride levels thereby reducing liver steatosis. Furthermore, activation of TGR5 promotes intestinal glucagon-like peptide-1 (GLP-1) release, thereby modulating glucose homeostasis and energy expenditure in brown adipose tissue and skeletal muscle. Additionally, TGR5 exerts anti-inflammatory actions resulting in decreased liver injury in animal models of sepsis. These beneficial effects make TGR5 an attractive therapeutic target for metabolic diseases, such as diabetes, obesity, atherosclerosis and steatohepatitis.
Kupffer cells are resident macrophages in the liver and play a central role in the hepatic response to injury. Bile acids can impair macrophage function leading to decreased cytokine release. TGR5 is ...a novel, membrane-bound bile acid receptor, and it has been suggested that the immunosuppressive effect of bile acids can be mediated by TGR5. However, the function of TGR5 in Kupffer cells has not been studied and a direct link between TGR5 and cytokine production in macrophages has not been established. The present study demonstrates that TGR5 is localized in the plasma membrane of isolated Kupffer cells and is responsive to bile acids. Furthermore, bile acids inhibited LPS-induced cytokine expression in Kupffer cells via TGR5-cAMP dependent pathways. TGR5-immunoreactivity in Kupffer cells was increased in rat livers following bile-duct ligation, suggesting that TGR5 may play a protective role in obstructive cholestasis preventing excessive cytokine production thereby reducing liver injury.
Pancreatic cystic lesions (PCL) are increasingly diagnosed. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) cytology is often used for diagnostic confirmation but can be inconclusive. In this ...study, the role of molecular analyses in the pre-operative diagnostics of PCL is evaluated. Targeted Next Generation Sequencing (NGS) applied on cytology smears was retrospectively evaluated in a cohort of 37 resected PCL. Usefulness of NGS on fresh cyst fluids was tested in a prospective cohort of patients with newly diagnosed PCL (n = 71). In the retrospective cohort, cytology plus NGS displayed higher sensitivity (94.1% vs. 87.1%) and specificity (100% vs. 50%) than cytology alone for the detection of mucinous neoplasms. In the prospective cohort, sensitivity and specificity of conventional cytology alone were 54.2% and 100% for the detection of mucinous neoplasia and 50.0% and 100% for the detection of high-grade dysplasia, respectively. Adding NGS, all lesions which underwent histopathologic verification (12/71, 17%) could be classified without false positive or false negative results regarding the detection of mucinous neoplasm so far. NGS analysis of cfDNA in PCL fluids is feasible and can increase diagnostic accuracy in the detection of mucinous neoplasms compared to cytology alone. However, algorithms for the detection of high-risk lesions need further improvement.
TGR5 (Gpbar‐1) is a plasma membrane‐bound, G protein–coupled receptor for bile acids. TGR5 messenger RNA (mRNA) has been detected in many tissues, including rat cholangiocytes and mouse gallbladder. ...A role for TGR5 in gallstone formation has been suggested, because TGR5 knockout mice did not develop gallstones when fed a lithogenic diet. In this study, expression and localization of TGR5 was studied in human gallbladders. TGR5 mRNA and protein were detected in all 19 gallbladders. Although TGR5 mRNA was significantly elevated in the presence of gallstones, no such relation was found for TGR5 protein levels. In order to study the localization of TGR5 in human gallbladders, a novel antibody was generated. The receptor was localized in the apical membrane and the rab11‐positive recycling endosome of gallbladder epithelial cells. Furthermore, the TGR5 staining colocalized with the cyclic adenosine monophosphate–regulated chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) and the apical sodium‐dependent bile salt uptake transporter, suggesting a functional coupling of TGR5 to bile acid uptake and chloride secretion. Stimulation with bile acids significantly increased cyclic adenosine monophosphate concentration in human gallbladder tissue. Incubation of gallbladder epithelial cells with a TGR5 agonist led to a rise of N‐(ethoxycarbonylmethyl)‐6‐methoxyquinolinium bromide (MQAE)‐fluorescence, suggestive of a decrease in intracellular chloride concentration. The TGR5 agonist–dependent increase in MQAE‐fluorescence was absent in TGR5 knockout mice or in the presence of a CFTR inhibitor, indicating that TGR5 mediates chloride secretion via activation of CFTR. The presence of the receptor in both the plasma membrane and the recycling endosome indicate that TGR5 can be regulated by translocation. Conclusion: The data suggest a role for TGR5 in bile acid–induced fluid secretion in biliary epithelial cells. (HEPATOLOGY 2009.)
Cholangiocyte cilia are sensory organelles that extend from the apical membrane into the bile duct lumen and detect changes in bile flow and osmolarity. Whether or not cholangiocyte cilia are ...responsive to bile acids is unknown. TGR5 (Gpbar-1) is a membrane-bound bile acid receptor which is expressed in biliary epithelial cells and promotes chloride secretion in gallbladder epithelial cells. As shown in the present study, TGR5 is localized in the primary cilium of mouse and human cholangiocytes. Here the receptor could play an important role in coupling biliary bile acid concentration and composition to ductular bile formation.
Endocrine and paracrine role of bile acids Verena Keitel Ralf Kubitz Dieter Haussinger
World journal of gastroenterology : WJG,
10/2008, Letnik:
14, Številka:
37
Journal Article
Odprti dostop
Bile acids are not only important for the absorption of dietary lipids and fat soluble vitamins but are signalling molecules with diverse endocrine and paracrine functions. Bile acids regulate bile ...acid, lipid and glucose metabolism and modulate temperature and energy homeostasis. Furthermore, bile acids can not only promote cell proliferation and liver regeneration but can also induce programmed cell death. Bile acid functions are mediated through different pathways which comprise the activation of nuclear hormone receptors, of intracefular kinases and of the plasma membranebound, G-protein coupled bile acid receptor TGRS/Gpbar-1.
Bile duct ligation (BDL) is an experimental procedure that mimics obstructive cholestatic disease. One of the early consequences of BDL in rodents is the appearance of so‐called bile infarcts that ...correspond to Charcot‐Gombault necrosis in human cholestasis. The mechanisms causing bile infarcts and their pathophysiological relevance are unclear. Therefore, intravital two photon–based imaging of BDL mice was performed with fluorescent bile salts (BS) and non‐BS organic anion analogues. Key findings were followed up by matrix‐assisted laser desorption ionization imaging, clinical chemistry, immunostaining, and gene expression analyses. In the acute phase, 1‐3 days after BDL, BS concentrations in bile increased and single‐cell bile microinfarcts occurred in dispersed hepatocytes throughout the liver caused by the rupture of the apical hepatocyte membrane. This rupture occurred after loss of mitochondrial membrane potential, followed by entry of bile, cell death, and a “domino effect” of further death events of neighboring hepatocytes. Bile infarcts provided a trans‐epithelial shunt between bile canaliculi and sinusoids by which bile constituents leaked into blood. In the chronic phase, ≥21 days after BDL, uptake of BS tracers at the sinusoidal hepatocyte membrane was reduced. This contributes to elevated concentrations of BS in blood and decreased concentrations in the biliary tract. Conclusion: Bile microinfarcts occur in the acute phase after BDL in a limited number of dispersed hepatocytes followed by larger infarcts involving neighboring hepatocytes, and they allow leakage of bile from the BS‐overloaded biliary tract into blood, thereby protecting the liver from BS toxicity; in the chronic phase after BDL, reduced sinusoidal BS uptake is a dominant protective factor, and the kidney contributes to the elimination of BS until cholemic nephropathy sets in.
Summary Primary sclerosing cholangitis (PSC) is a chronic cholangiopathy characterized by biliary fibrosis, development of cholestasis and end stage liver disease, high risk of malignancy, and ...frequent need for liver transplantation. The poor understanding of its pathogenesis is also reflected in the lack of effective medical treatment. Well-characterized animal models are utterly needed to develop novel pathogenetic concepts and study new treatment strategies. Currently there is no consensus on how to evaluate and characterize potential PSC models, which makes direct comparison of experimental results and effective exchange of study material between research groups difficult. The I nternational P rimary S clerosing C holangitis S tudy G roup (IPSCSG) has therefore summarized these key issues in a position paper proposing standard requirements for the study of animal models of PSC.
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