‣ and may progress to liver fibrosis and cirrhosis . UDCA protects injured cholangiocytes against the toxic effects of the more hydrophilic bile acids , stimulates impaired biliary secretion and the detoxification of hydrophobic bile acids , and reduces apoptosis ( programmed cell death ) in hepatocytes . It is now used to treat a number of other liver conditions , including primary sclerosing cholangitis , intrahepatic cholestasis in pregnancy , liver disease in cystic fibrosis , progressive familial intrahepatic cholestasis and nonalcoholic steatohepatitis ( NASH ). In 1999 , the landscape evolved further when bile acids and bile salts were shown to have hormonal activity and were confirmed to be the endogenous ligand of the nuclear receptor ( NR ) Farnesoid X Receptor ( FXR ). FXR is widely expressed in high levels in the intestine and the liver and it regulates bile acid homeostasis and is a critical regulator of lipids and glucose homeostasis . During liver injury , FXR has been shown to play an anti-inflammatory and anti-fibrotic role and so it is a target for conditions such as PBC , PSC and NASH . A novel bile acid analogue of CDCA , obeticholic acid , has been developed and approved for the treatment of PBC for patients who do not respond to UDCA and is currently in phase III clinical development for NASH , where there is a large and growing unmet medical need .
Figure 2 - Signalling actions of bile acids via FXR and TRG5
21st century developments
In 2002 bile acids were discovered be the natural agonist for a G-protein coupled receptor , Takeda G-Protein Coupled Receptor ( TGR5 ). This is seen as a promising target for interventions in metabolic diseases , including Type 2 diabetes , obesity and non-alcoholic steatohepatitis . TGR5 is expressed in many metabolically active tissues and data from preclinical studies show promising effects of targeting TGR5 on outcomes such as weight
24 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981