[Frontiers in Bioscience 14, 2599-2630, January 1, 2009]

Nuclear receptors: mediators and modifiers of inflammation-induced cholestasis

Jaap Mulder1, Saul J. Karpen3, Uwe J.F. Tietge1, Folkert Kuipers1,2

1Department of Pediatrics Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, 2Department of Laboratory Medicine, Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, 3Texas Children's Liver Center, Department of Pediatrics/GI, Hepatology & Nutrition, Baylor College of Medicine, Houston, TX

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Clinical aspects of inflammation-induced cholestasis (IIC)
2.2. Experimental models of IIC
3. Nuclear receptor (NR) biology
3.1. Classes and structures of NRs
3.2. Mechanisms of genomic actions
3.3. Non-genomic actions of NRs
3.4. Clinical relevance of NR ligands
3.5. NRs of specific relevance to IIC
4. Mechanisms underlying IIC
4.1. Physiology of bile formation
4.2. Impaired bile formation during inflammation
4.3. Inflammatory cascade and Kupffer cells
4.4. Inflammatory signaling in hepatocytes
4.5. Hepatobiliary transporters
4.6. NR expression and function during inflammation
4.6.1. RXR-alpha
4.6.2. RAR-alpha
4.6.3. FXR
4.6.4. CAR and PXR
4.6.5. LXR
4.6.6. PPAR-gamma
4.6.7. HNF4-alpha
4.6.8. LRH-1
4.6.9. SHP
4.7. Effects of inflammation on co-factor expression and function
5. Pharmacological/experimental interventions in models of IIC
6. Different roles of NRs in IIC: mediators and modifiers
6.1. Modifier function 1: adaptive responses
6.2. Modifier function 2: anti-inflammatory actions
6.2.1. GR
6.2.2. PPAR-gamma
6.2.3. LXR
6.2.4. RXR-alpha and RAR-alpha
6.2.5. Anti-inflammatory effects of other NRs
6.2.6. General considerations regarding the anti-inflammatory effects of NRs
7. Design of optimal NR ligands for intervention in IIC
7.1. Other approaches
8. Summary and perspective
9. Acknowledgement
10. References

1. ABSTRACT

Inflammation-induced cholestasis (IIC) is a frequently occurring phenomenon. A central role in its pathogenesis is played by nuclear receptors (NRs). These ligand-activated transcription factors not only regulate basal expression of hepatobiliary transport systems, but also mediate adaptive responses to inflammation and possess anti-inflammatory characteristics. The latter two functions may be exploited in the search for new treatments for IIC as well as for cholestasis in general. Current knowledge of the pathogenesis of IIC and the dual role NRs in this process are reviewed. Special interest is given to the use of NRs as potential targets for intervention.