Transcriptional regulation of hepatobiliary transport systems in health and disease: implications for a rationale approach to the treatment of intrahepatic cholestasis.

[benign recurrent intrahepatic cholestasis]

Hepatobiliary transport systems mediate hepatic uptake and biliary excretion of bile acids , bilirubin and other biliary constituents . Hereditary or acquired defects of these transporters may cause or maintain cholestasis and jaundice under various clinical conditions including progressive familial intrahepatic cholestasis (PFIC ) 1 -3 or its milder forms , benign recurrent intrahepatic cholestasis (BRIC ) 1 and 2 , Dubin-Johnson syndrome , drug and inflammation -induced cholestasis and intrahepatic cholestasis of pregnancy . Moreover , induction of alternative efflux pumps for bile acids /bilirubin and phase I /II detoxifying enzymes may counteract hepatic accumulation of potentially toxic biliary constituents in cholestasis by providing alternative escape routes . Transcriptional and post-transcriptional regulation of hepatobiliary transporters in health and disease is mediated by multiple factors such as bile acids , proinflammatory cytokines , drugs and hormones . Ligand-activated nuclear receptors (NR ) and hepatocyte-enriched transcription factors play a critical role in transcriptional transporter regulation . Many hepatobiliary transporter alterations in cholestatic liver disease can now be explained by ligand binding of accumulating cholephiles to NRs . Moreover , NR-mediated actions may be targeted by pharmacological ligands . Understanding the transcriptional mechanisms leading to transporter changes therefore not only represents a key for understanding the pathophysiology of the cholestatic liver disease , but also represents a prerequisite for designing novel therapeutic strategies .