[Frontiers in Bioscience 16, 2988-3003, June 1, 2011]

Nuclear Receptors CAR and PXR; therapeutic targets for cholestatic liver disease

Satoru Kakizaki1, Daichi Takizawa1, Hiroki Tojima1, Norio Horiguchi1, Yuichi Yamazaki1, Masatomo Mori1

1Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The overall view of the nuclear receptors: CAR and PXR
3.1. CAR (Constitutive Active/androstane Receptor, NR1I3)
3.2. PXR (Pregnane X Receptor, NR1I2)
4. Bile formation and cholestasis
4.1. Bile formation
4.2. Cholestasis
4.3. Drug metabolizing enzymes and transporters in bile homeostasis
5. CAR and PXR in the bile acid homeostasis
5.1. CAR and PXR in the bile acid homeostasis
6. CAR and PXR in cholestatic liver diseases
6.1. Intrahepatic cholestasis
6.2. Intrahepatic cholestasis of pregnancy
6.3. Constitutional hyperbilirubinemia
6.4. Primary biliary cirrhosis and primary sclerosing cholangitis
7. CAR and PXR as therapeutic targets for cholestatic liver diseases
7.1. Treatment for cholestatic liver disease
7.2. CAR and PXR as therapeutic targets for cholestatic liver disease
8. The nuclear receptors FXR and VDR in cholestatic liver disease
8.1. FXR (Farnesoid X Receptor, NR1H4)
8.2. VDR (Vitamin D Receptor, NR1I1)
9. Concluding remarks and future directions
10. References

1. ABSTRACT

Cholestasis results in the intrahepatic retention of cytotoxic bile acids (BA) and it can thus lead to liver injury. Hydrophilic BA ursodeoxycholic acid (UDCA) is currently used to treat cholestasis but its efficacy is limited. Nuclear receptors are key regulators of various processes including metabolism of xeno- and endobiotics such as BA and drugs. Recent studies have made significant progress in elucidating the mechanisms which regulate the BA metabolism by nuclear receptors. The nuclear receptor FXR plays the role of master regulator of BA homeostasis and is a promising drug target for cholestatic liver disease. In addition to FXR, the nuclear receptors CAR and PXR function as sensors of toxic byproducts and regulator of BA homeostasis. Ligands for both receptors including phenobarbital have been used to treat cholestatic liver diseases before the mechanisms of these receptors were revealed. Novel compounds targeting CAR and PXR with specific effects and fewer side effects will therefore be useful for the treatment of cholestatic liver diseases. This article will review the current knowledge of the xenobiotic-sensing nuclear receptors CAR and PXR, while also discussing their potential role in the treatment of cholestatic liver diseases.