[Frontiers in Bioscience 14, 4904-4920, June 1, 2009]

Hepatobiliary ABC transporters: physiology, regulation and implications for disease

Johan W. Jonker 1, Catherine A.M. Stedman2, Christopher Liddle3, Michael Downes1

1Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 Torrey Pines Road, CA 92037, La Jolla, USA, 2Department of Gastroenterology, Christchurch Hospital and University of Otago, Christchurch, Private Bag 4710 Christchurch, New Zealand, 3Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead NSW 2145, Australia

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Hepatocyte apical ABC transporters in physiology and disease
3.1. ABCB1 (MDR1)
3.2. ABCB4 (MDR2)
3.3. ABCB11 (BSEP/S-PGP)
3.4. ABCC2 (MRP2)
3.5. ABCG2 (BCRP)
3.6. ABCG5/8
4.Regulation of hepatic transport and metabolism by Hepatic Nuclear Receptors
4.1. Nuclear Receptors
4.2. Regulation of bile acid transport and metabolism by FXR
4.3. Regulation of bile acid metabolism through CYP7A1 and CYP3A4
4.4. Regulation of ABCC2, ABCB4 and ABCG5/8
4.5. Regulation of the multidrug transporters ABCB1 and ABCG2
4.6. Implications for cholestatic liver disorders
5. Perspective
6. Acknowledgement
7. References

1. ABSTRACT

The liver plays a key role in the metabolic conversion and elimination of endo- and xenobiotics. Hepatobiliary transport of many of these compounds is mediated by several ATP-binding cassette (ABC) transporters expressed at the canalicular membrane of the hepatocyte. Impaired function of these ABC transporters leads to impaired bile formation or cholestasis and mutations in these genes are associated with a variety of hereditary cholestatic syndromes. At the transcriptional level, these ABC transporters and the metabolizing enzymes involved in processing of their substrates are coordinately regulated by members of the nuclear receptor (NR) family of ligand-modulated transcription factors. In this review we will focus on ABC transporters involved in hepatobiliary excretion and how they are associated with hepatic physiology and disease states. We will also examine how NRs, acting as intracellular sensors for lipophilic molecules, regulate these ABC transporters and maintain metabolic homeostasis.