Cholestasis: Genetic and Acquired

This issue of Seminars in Liver Disease presents a comprehensive review of recent progress in understanding the cellular and molecular basis of cholestatic liver disease. These advances have been built on a background of more than four decades of research into the fundamental mechanisms by which bile is formed, a process that has involved the efforts of an international group of experts as reflected in this issue. Progress in this field has truly been remarkable. Indeed, when my own laboratory began work in this area in the late 1960s, all that was known about bile formation was that it was not due to hydrostatic filtration, like urine, but the result of energydependent excretion of osmotically active substances, particularly bile acids. As in most fields, advances occurred as new techniques were developed. Initial insights came from studies in bile duct cannulated animals and man that measured the clearance of radiolabeled solutes such as erythritol or mannitol and enabled measurements of bile salt dependent and bile salt independent canalicular bile flow. Studies in animal models utilized isolated perfused liver preparations and isolated hepatocytes to begin to understand hepatic transport mechanisms for bile acids, bilirubin, and other solutes. The development of isolated hepatocyte couplets and bile duct units permitted electrophysiologic and fluorescent imaging applications as well as the definition and separation of secretory events between these two different cell types. At the same time, the recognition that the sodium pump was localized to the basolateral membranes of the hepatocyte served as a marker to enable purification of the apical canalicular domain away from basolateral membranes whose vesicles could now be used to more accurately define the nature of the transport mechanisms in each of these regions of the hepatocyte. These approaches first revealed the presence of adenosine-50triphosphate (ATP-) dependent transporters for bile acids in the canalicular membrane. However, the major paradigm-changing events in this field were the advent of molecular cloning and the completion of the human genome. The former facilitated the cloning of rare proteins, initially using frog oocyte expression systems; the latter rapidly led to knowledge of essentially all of the major determinants of the bile secretory process in hepatocytes and cholangiocytes. The cellular locations of the major bile acid and organic solute transporters in the liver, kidney, and intestine that are discussed in this issue of Seminars in Liver Disease are illustrated in Fig. 1. Genetic studies in man ultimately revealed that mutations in several canalicular transporters, familial intrahepatic cholestasis-1 (FIC1 or ATP8B1), bile salt export pump (BSEP), and multidrug resistance protein-3 (MDR3) were responsible for various clinical forms of neonatal, pediatric, and even some adult forms of cholestatic liver diseases. Not only did these human mutations begin to explain the pathophysiology of these disorders, but they were the final ‘‘proof of principle’’ for the critical role that these proteins played in the bile secretory process. How mutations in FIC1 (ATP8B1), BSEP, and MDR3 result in a spectrum of acquired cholestatic disorders is reviewed by the authors of the first three articles. The first section of the fourth article by PauliMagnus, Meier, and Stieger, provides a summary of the molecular basis of bile salt transport and canalicular bile formation. The reader who is unfamiliar with the field is encouraged to start there for background information on this area. Alternatively, several recent reviews provide excellent introductory summaries; a few are referenced here. Pauli-Magnus et al then focus on the role that mutations and polymorphisms in BSEP, MDR3, and farnesoid X receptor (FXR) play in druginduced cholestasis and intrahepatic cholestasis of pregnancy. Wagner, Zollner, and Trauner review the adaptive responses that bile salt transporters in the liver and extrahepatic tissues make in response to cholestatic liver injury and the critical role that nuclear receptors and their ligands play in this increasingly complex process. Progress in this area has important therapeutic significance for future drug development for cholestatic liver diseases. Soroka, Ballatori, and Boyer summarize the current knowledge of the role that the recently discovered organic solute transporter a and b plays in