[Frontiers in Bioscience 14, 4299-4325, January 1, 2009]

Nuclear receptor ligands in therapy of cholestatic liver disease

Ekkehard Sturm1, Martin Wagner2, Michael Trauner2

1Childrenīs Hospital, University of Tuebingen, Germany, 2Division of Gastroenterology and Hepatology, Medical University Graz, Austria

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Nuclear receptors in cholestatic disease
3.1. General mechanisms of adaptation
3.2. Animal models of cholestatic liver disease
3.2.1. Animal model for obstructive cholestasis: bile duct ligation in mice
3.2.2. Cholestasis due to an inflammatory response after lipopolysaccharide exposure
3.2.3. Bile acid induced cholestasis in rodents
3.2.4. Oestradiol induced cholestasis in a mouse model
3.3. Human Disease
3.3.1. Primary biliary cirrhosis
3.3.2. Cholestasis of pregnancy
3.3.3. Biliary atresia
3.3.4. Progressive Familial Intrahepatic Cholestasis
3.3.5. Sepsis associated cholestasis
3.4. The role of nuclear receptors in sequelae of cholestasis
3.4.1. Fibrosis
3.4.2. Inflammation
3.4.3. Cancer
4. Nuclear receptor ligands in therapy of cholestatic liver diseases
4.1. Bile acids and other FXR ligands
4.1.1. Ursodeoxycholic acid
4.1.2. Nor- Ursodeoxycholic acid
4.1.3. Chenodeoxycholic acid
4.1.4. 6-ethyl Chenodeoxycholic acid and other synthetic FXR agonists
4.2. Enzyme inducers
4.3. Glucocorticoids
4.4. Glitazones and Nonsteroidal anti-inflammatory drugs
4.5. Fibrates and Statins
4.6. Others
5. Conclusions and outlook
6. References

1. ABSTRACT

Cholestasis is a clinical syndrome resulting from disturbed bile formation. The etiology includes different diseases ranging from genetic defects in hepatocellular bile formation to inflammatory diseases of the bile ducts. Many cholestatic diseases are progressive and ultimately fatal. Whatever the cause, cholestasis results in intrahepatic accumulation of cytotoxic bile acids which lead to liver injury reflected by disruption of hepatocellular integrity, inflammation, fibrosis, cirrhosis and increased risk for development of cancer. Determinants of bile secretion undergo an adaptive response during cholestasis aiming to minimize hepatic injury. This adaptation occurs by modification of transport and metabolism of bile acids and other organic solutes in liver, kidney and intestine. The underlying molecular mechanisms are mediated mainly at a transcriptional level by a complex network involving ligand-activated nuclear receptors. However, the adaptive response to accumulation of bile acids cannot fully prevent or repair liver injury in cholestasis. Therefore, novel therapeutic strategies have to be developed involving nuclear receptor ligands which may intensify the protection of the hepatobiliary system in cholestatic disease.