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The transmembrane G protein-coupled receptor TGR5 binds to and is activated by bile acids.1 ,2 TGR5 is widely distributed, in animals and humans, in the gallbladder, liver, brown adipose tissue, muscle, intestine, kidney, placenta and brain. In the liver, TGR5 appears in sinusoidal endothelial cells, bile duct epithelial cells and Kupffer cells. Interestingly, the ubiquitous TGR5 expression positions previously unsuspected tissues such as muscle, brain and adipose tissue, and cells such as macrophages and endothelial cells, as potential targets of bile acid signalling. Bile acid binding to TGR5 activates multiple signalling routes involved in a multitude of processes thus potentially affecting metabolism, inflammation, fibrosis and carcinogenesis. Lithocholic acid is the strongest natural ligand of TGR5,1 ,2 while INT-777 is a semisynthetic TGR5 agonist.3 Further development of semisynthetic bile acid analogues that target TGR5 or intracellular nuclear receptors, such as the Farnesoid X receptor (FXR), holds great expectations to treat chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. Randomised, placebo controlled clinical trials for the treatment of non-alcoholic steatohepatitis and primary biliary cirrhosis with FXR agonist obeticholic acid are the first initiated trials.
Cholangiocarcinoma (CCA) is the second most common primary liver tumour and accounts for ∼3% of all …
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