Hepatobiliary transport

The alterations of hepatobiliary transport that occur in cholestasis can be divided into primary defects, such as mutations of transporter genes or ac quired dysfunctions of transport systems that cause defective canalicular o r cholangiocellular secretion, and secondary defects, which result from bil iary obstruction. The dysfunction of distinct biliary transport systems as a primary cause of cholestasis is exemplified by the genetic defects in pro gressive familial intrahepatic cholestasis or by the direct inhibition of t ransporter gene expression by cytokines. In both, the hepatocellular accumu lation of toxic cholephilic compounds causes multiple alterations of hepato cellular transporter expression. In addition, lack of specific components o f bile caused by a defective transporter, as in the case of mdr2/MDR3 defic iency unmasks the toxic potential of other components. The production of bi le is critically dependent upon the coordinated regulation and function of sinusoidal and canalicular transporters, for instance of Na+-taurocholate c otransporting polypeptide (NTCP) and bile salt export pump (BSEP). Whereas the downregulation of the unidirectional sinusoidal uptake system NTCP prot ects the hepatocyte from further intracellular accumulation of bile salts, the relative preservation of canalicular BSEP expression serves to uphold b ile salt secretion, even in complete biliary obstruction. Conversely, the s trong downregulation of canalicular MRP2 (MRP, multidrug resistance protein ) in cholestasis forces the hepatocyte to upregulate basolateral efflux sys tems such as MRP3 and MRP1, indicating an inverse regulation of basolateral and apical transporters. The regulation of hepatocellular transporters in cholestasis adheres to the law of parsimony, since many of the cellular mec hanisms are pivotally governed by the effect of bile salts. The discovery t hat bile salts are the natural ligand of the farnesoid X receptor has shown us how the major bile component is able to regulate its own enterohepatic circulation by affecting transcription of the genes critically involved in transport and metabolism.