Therapeutic Opportunities of GPBAR1 in Cholestatic Diseases

Abstract

GPBAR1, a transmembrane G protein-coupled receptor for bile acids, is widely expressed in multiple tissues in humans and rodents. In recent years, GPBAR1 has been thought to play an important role in bile homeostasis, metabolism and inflammation. This review specifically focuses on the function of GPBAR1 in cholestatic liver disease and summarizes the various pathways through which GPBAR1 acts in cholestatic models. GPBAR1 mainly regulates cholestasis in a holistic system of liver-gallbladder-gut formation. In the state of cholestasis, the activation of GPBAR1 could regulate liver inflammation, induce cholangiocyte regeneration to maintain the integrity of the biliary tree, control the hydrophobicity of the bile acid pool and promote the secretion of bile HCO3−. All these functions of GPBAR1 might be clear ways to protect against cholestatic diseases and liver injury. However, the characteristic of GPBAR1-mediated proliferation increases the risk of proliferation of cholangiocarcinoma in malignant transformed cholangiocytes. This dichotomous function of GPBAR1 limits its use in cholestasis. During disease treatment, simultaneous activation of GPBAR1 and FXR receptors often results in improved outcomes, and this strategy may become a crucial direction in the development of bile acid-activated receptors in the future.

Bile acid-mediated signaling in cholestatic liver diseases

“…GPCRs represent the most important drug targets, and more than 700 FDA-approved drugs target GPCRs [ 130 ]. Understanding BA-mediated activation of GPCRs will provide critical information for developing novel therapeutic agents for cholestatic liver disease [ 131 ].…”

“…However, TGR5 agonists alone did not improve liver fibrosis in Mdr2 −/− mice, and the dual TGR5/FXR agonist (INT-767) reduced liver inflammation and fibrosis, possibly by lowering BA synthesis in an FXR-dependent manner [ 145 ]. Simultaneous activation of TGR5 and FXR receptors improves prognosis, which may represent a better therapeutic strategy [ 131 ]. Considering the broad expression of TGR5, activation of TGR5 in cholangiocytes and macrophages may be beneficial to reduce cholestatic liver injury and inflammation.…”

The discovery of 12β-methyl-17-epi-18-nor-bile acids as potent and selective TGR5 agonists

“…Extracellular ligand-binding to TGR5 promotes the upregulation of secondary messenger cyclic AMP (cAMP) and subsequent activation of downstream effectors in target cells [e.g. protein kinase A (PKA) and B (PKB/AKT)] [1,2,4,9]. In muscle and brown adipose tissue, TGR5 agonism leads to enhanced energy expenditure and oxygen consumption via increased activity of the cAMP-dependent thyroid hormone-activating enzyme, iodothyronine deiodinase 2 (D2), and uncoupling protein (UCP)-1 [10,11].…”

“…In cholangiocytes and gallbladder epithelial cells, TGR5 activation promotes cytoprotective regulations. These effects include the secretion of bicarbonate, which prevents excessive cell entry of hydrophobic BAs, reduction of bile salt-and CD95-mediated apoptosis, and increased proliferation of cholangiocytes via ROS/EGFR to maintain the integrity of the biliary tree [9,19]. TGR5 is also expressed in neurons, microglia and astrocytes and here, TGR5 activation exerts anti-inflammatory effects by downregulating the production of proinflammatory cytokines and decreasing CCL2 chemokine discharge and the associated microglia activation and proliferation [20,21].…”

“…Direct modulation of neuronal TGR5 mediates anorexigenic effects and additionally, in a murine model of Parkinson's disease, TGR5 activation decreased the release of TNF-α and other secondary chemokines (CCL3 and 6), preventing microglia polarization and neurodegeneration [22,23]. Considering all these factors, TGR5 agonists offer intriguing therapeutic potential for the treatment of metabolic, inflammatory immune, liver and neurological diseases including diabetes, obesity, metabolic syndrome, atherosclerosis, colitis, non-alcoholic steatohepatitis (NASH) and associated comorbidities [9,14,[20][21][22][23][24][25][26][27][28][29]. However, systemic stimulation of TGR5 can produce adverse side effects including excessive filling and inadequate emptying of the gallbladder with an elevated risk for gallstone formation, pruritus and changes to heart rate and blood pressure [30][31][32].…”