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SHR Neuro Cancer Cardio Metab Microb Lipid

Molecular Regulation of Alternative Bile Acid Transport and Detoxification Mechanisms by Nuclear Receptor (PXR, CAR, VDR) Ligands in the Treatment of Cholestasis

Abstract: 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 and biliary fibrosis. 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 predected to detoxify and eliminate bile acids and other potentially toxic biliary constituents. Targeting nuclear receptors "beyound the classic bile acid receptro FXR" (in particular the "xenobiotic sensors" CAR and VDR) for the treatment of cholestatic liver diseases is novel. This project attempts to provide potential links between the research area of hepatobiliary transport/cholestasis and liver injyry/biliary fibrosis, the latter being the prognostically most relevant consequence of cholestasis. Moreover, biliary fibrosis is an early and important feature of chronic bile duct disorders such as primary sclerosing cholangitis. The combined approach in animal models of cholestasis and human liver tisue form patients with cholestatic disorders both treated with respective nuclear receptor agonists which will provede major mechanistic insights into the therapeutic effects across species diferences. 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 should also impact on other research areas beyound the field of hepatology (e.g., atherosclerosis, colon cancer, hepatic drug metabolism and multidrug resistance).

Keywords: ABC transporters; Bile acids; Bilirubin; Cholestasis; Jaundice; Nuclear (orphan) receptors

Local Subprojectlead:: Trauner Michael

Duration:: 01.01.2006-01.01.2010

Programme:: Einzelprojekt

Type of Research: basic research

Staff: Trauner, Michael, Project Leader

MUG Research Units: Diagnostic and Research Institute of Pathology; Division of Gastroenterology and Hepatology

Project partners: Division of Gastroenterology and Hepatology/Karolinska Institute, Sweden; Liver Research Institute/Center of Toxicology/College of Pharmacy, University of Arizona , United States (USA)

Funded by: FWF, Fonds zur Förderung der Wissenschaftlichen Forschung, Wien, Austria

Project results published: > Expression of the nuclear bile acid receptor/farne... Int J Cancer. 2012; 130(10): 2232-2239.; > A new xenobiotic-induced mouse model of sclerosing... Am J Pathol. 2007; 171(2):525-536; > Principles of hepatic organic anion transporter re... Biochim Biophys Acta. 2007; 1773(3): 283-308.; > Hepatobiliary transporter expression in intercellu... Drug Metab Dispos. 2007; 35(9):1694-1699