Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis.
Hepatobiliary transport systems are responsible for hepatic uptake and excretion of bile salts and other biliary constituents (eg, bilirubin) into bile. Hereditary transport defects can result in progressive familial and benign recurrent intrahepatic cholestasis. Exposure to acquired cholestatic injury (eg, drugs, hormones, proinflammatory cytokines, biliary obstruction or destruction) also results in altered expression and function of hepatic uptake and excretory systems, changes that may maintain and contribute to cholestasis and jaundice. Recruitment of alternative efflux pumps and induction of phase I and II detoxifying enzymes may limit hepatic accumulation of potentially toxic biliary constituents in cholestasis by providing alternative metabolic and escape routes. These molecular changes are mediated by bile salts, proinflammatory cytokines, drugs, and hormones at a transcriptional and posttranscriptional level. Alterations of hepatobiliary transporters and enzymes are not only relevant for a better understanding of the pathophysiology of cholestatic liver diseases, but may also represent important targets for pharmacotherapy. Drugs (eg, ursodeoxycholic acid, rifampicin) used to treat cholestatic liver diseases and pruritus may counteract cholestasis via stimulation of defective transporter expression and function. In addition, therapeutic strategies may be aimed at supporting and stimulating alternative detoxification pathways and elimination routes for bile salts in cholestasis.
Trauner
Michael
M
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University, Graz, Austria. michael.trauner@meduni-graz.at
Wagner
Martin
M
Fickert
Peter
P
Zollner
Gernot
G
D000818:Animals; D001646:Bile; D001647:Bile Acids and Salts / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism*; D001693:Biological Transport, Active; D015209:Cholangitis, Sclerosing / Q000378:metabolism; D002779:Cholestasis / Q000378:metabolism* / Q000628:therapy*; D002780:Cholestasis, Intrahepatic / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism; D051379:Mice; D009154:Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use
D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear; D014580:Ursodeoxycholic Acid