24-nor-ursodeoxycholic acid as novel therapy for cholangitis

The overall aim of the proposed research project is to identify novel therapeutic strategies for chronic cholangiopathies which are important indications for liver transplantation and causes of liver-related death. A side chain-shortened bile acid such as 24-nor-ursodeoxycholic acid (norUDCA) has been chosen since this biochemical modification results in cholehepatic shunting and targeting to the bile duct epithelium, effects which should provide the distinct pharmacological properties required for the treatment of cholangiopathies such as sclerosing cholangitis. The effects of norUDCA on biochemical, histological and molecular markers of liver and bile duct injury and biliary fibrosis will be tested in the recently established Mdr2-/- cholangiopathy model with features of sclerosing cholangitis. The effects of norUDCA will be compared with UDCA (as current standard treatment of cholangiopathies in humans) and sulindac (a non-steroidal anti-inflamatory drug also undergoing cholehepatic shunting and targeting to the bile duct epithelium). Potential therapeutic (anti-cholestatic and anti-fibrotic) mechanisms will be addressed both in in vivo (animal model) and in vitro (hepatocytes, cholangiocytes). To allow mechanistic insights across species differences, both human and mouse liver tissue/cells will be investigated. A major innovative aspect of this project lies in the attempt to link the research areas of hepatobiliary transport/cholestasis and hepatic fibrogenesis/biliary fibrosis. Current medical treatment options for cholestatic liver diseases and cholangiopathies ultimately resulting in biliary fibrosis and cirrhosis are unsatisfactory and of limited efficacy. The results of this study should contribute to novel therapeutic strategies against cholestatic liver diseases and biliary fibrosis. Moreover, the expected finding should have major general implications for hepatic fibrogenesis beyond the area of cholestasis.

The overall aim of this research project was to identify novel treatment strategies for chronic inflammatory bile duct diseases (cholangiopathies) such as primary sclerosing cholangitis (PSC) as important indication for liver transplantation and cause of liver-related death. Currently available medical therapy of these disorders is of limited efficacy. 24-nor-ursodeoxycholic acid (norUDCA) is a side chain-shortened derivative of ursodeoxycholic acid (UDCA) as the current medical standard therapy. These biochemical modifications result in cholehepatic shunting and thereby improve targeting to the diseased bile duct epithelium. We tested the therapeutic effects and underlying cellular and molecular mechanisms of norUDCA on biochemical, histological and molecular markers of liver and bile duct injury as well as biliary fibrosis in an animal model for sclerosing cholangitis (Mdr2 knockout mouse). In this model system norUDCA (but not "conventional" UDCA) reversed sclerosing cholangitis by improvement of bile acid and lipid homeostasis as well as direct anti-inflammatory, anti-proliferative and anti-fibrotic properties. Moreover we could demonstrate that norUDCA also improves non-alcoholic fatty liver and associated atherosclerosis via similar mechanisms impacting on bile acid / lipid metabolism and inflammation. The results of this project had major implications for the therapy of cholestatic and metabolic diseases. As such, norUDCA is currently undergoing phase II clinical trials for PSC in a multicenter European study.