Nuclear receptors as therapeutic targets in cholestasis

The overall objective of the proposed research project is to identify novel therapeutic strategies for cholestasis aimed at stimulating alternative bile acid transport and detoxification in liver and kidney via nuclear receptor (PXR, CAR and VDR) agonists and to determine whether this approach results in improvement of cholestasis and cholestasis-associated liver injury. This will be addressed in vivo (mouse models of cholestasis, liver tissue from patients with cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis) and in vitro (primary hepatocyte cultures) by administration of established and specific agonistic nuclear receptor ligands and subsequent analysis of liver injury, biliary fibrosis, as well as expression and function of genes involved in bile acid detoxification and elimination. PXR, CAR and VDR have been chosen as therapeutic targets since these nuclear receptors coordinately regulate genes/gene products predicted to detoxify and eliminate bile acids and other potentially toxic biliary constituents. Targeting nuclear receptors such as PXR, CAR and VDR for the treatment of cholestatic liver diseases is novel, since most approaches have so far focused on the "classic" bile acid receptor FXR. This project attempts to provide potential links between the research area of hepatobiliary transport/cholestasis and liver injury/biliary fibrosis, the latter being the prognostically most relevant consequence of cholestasis. The combined approach in animal models of cholestasis and human liver tissue from patients with cholestatic disorders both treated with respective nuclear receptor agonists which will provide major mechanistic insights into the therapeutic effects across species differences. Currently, medical treatment options for cholestatic liver diseases are unsatisfactory and of limited efficacy. The results of this study will have major implications for understanding and developing future therapeutic strategies against cholestatic liver diseases. Based on the results in the human arm of the study, the proposed project should directly contribute to new knowledge in an area of liver research with potential importance to clinical therapeutics. Moreover, the results of this study sould also impact on other research areas beyond the field of hepatology (e.g., atherosclerosis, colon cancer, cancer multidrug resistance) since the investigated nuclear receptors and dependent transport and detoxification systems could be relevant for cholesterol homeostasis, intestinal defense against cancerogenic secondary bile acids and drug metabolism.

The overall objective of the proposed research project is to identify novel therapeutic strategies for cholestasis aimed at stimulating alternative bile acid transport and detoxification in liver and kidney via nuclear receptor (PXR, CAR and VDR) agonists and to determine whether this approach results in improvement of cholestasis and cholestasis-associated liver injury. This will be addressed in vivo (mouse models of cholestasis, liver tissue from patients with cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis) and in vitro (primary hepatocyte cultures) by administration of established and specific agonistic nuclear receptor ligands and subsequent analysis of liver injury, biliary fibrosis, as well as expression and function of genes involved in bile acid detoxification and elimination. PXR, CAR and VDR have been chosen as therapeutic targets since these nuclear receptors coordinately regulate genes/gene products predicted to detoxify and eliminate bile acids and other potentially toxic biliary constituents. Targeting nuclear receptors such as PXR, CAR and VDR for the treatment of cholestatic liver diseases is novel, since most approaches have so far focused on the "classic" bile acid receptor FXR. This project attempts to provide potential links between the research area of hepatobiliary transport/cholestasis and liver injury/biliary fibrosis, the latter being the prognostically most relevant consequence of cholestasis. The combined approach in animal models of cholestasis and human liver tissue from patients with cholestatic disorders both treated with respective nuclear receptor agonists which will provide major mechanistic insights into the therapeutic effects across species differences. Currently, medical treatment options for cholestatic liver diseases are unsatisfactory and of limited efficacy. The results of this study will have major implications for understanding and developing future therapeutic strategies against cholestatic liver diseases. Based on the results in the human arm of the study, the proposed project should directly contribute to new knowledge in an area of liver research with potential importance to clinical therapeutics. Moreover, the results of this study sould also impact on other research areas beyond the field of hepatology (e.g., atherosclerosis, colon cancer, cancer multidrug resistance) since the investigated nuclear receptors and dependent transport and detoxification systems could be relevant for cholesterol homeostasis, intestinal defense against cancerogenic secondary bile acids and drug metabolism.