Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis.
OBJECTIVE
Information about alterations of hepatobiliary transporter expression in primary biliary cirrhosis (PBC) could provide important insights into the pathogenesis of cholestasis. This study aimed to determine the expression of hepatobiliary transport systems for bile salts (Na(+)/taurocholate cotransporter, NTCP; bile salt export pump, BSEP), organic anions (organic anion transporting protein, OATP2; canalicular conjugate export pump, MRP2; basolateral MRP homologue, MRP3), organic cations (canalicular multidrug export pump, MDR1), and phospholipids (canalicular phospholipid flippase MDR3) in livers from patients with advanced stages of PBC.


METHODS
Transporter mRNA and protein levels were assessed by reverse transcription polymerase chain reaction and Western blot analysis. Tissue distribution of transporters was investigated by immunohistochemistry and immunofluorescence microscopy. Hepatic bile acids were measured by gas chromatography-mass spectrometry.


RESULTS
Compared to controls, basolateral uptake systems (NTCP, OATP2) were reduced, canalicular export pumps for bile salts and bilirubin (BSEP, MRP2) were preserved, while canalicular MDR P-glycoproteins (MDR1, MDR3) and the basolateral efflux pump MRP3 were increased in PBC. Double immunofluorescence labeling with a canalicular marker (dipeptidyl peptidase IV) demonstrated proper canalicular localization of BSEP and MRP2 in PBC. OATP2 and MRP2 expression correlated inversely with hepatic levels of hydrophobic bile acids, while positively correlating with hepatic enrichment with ursodeoxycholic acid.


CONCLUSIONS
Down-regulation of basolateral uptake systems and maintenance/up-regulation of canalicular and basolateral efflux pumps may represent adaptive mechanisms limiting the accumulation of toxic biliary constituents.
Zollner
Gernot
G
Division of Gastroenterology and Hepatology, Department of Medicine, Karl-Franzens University, Auenbruggerplatz 15, A-8036, Graz, Austria.
Fickert
Peter
P
Silbert
Dagmar
D
Fuchsbichler
Andrea
A
Marschall
Hanns Ulrich
HU
Zatloukal
Kurt
K
Denk
Helmut
H
Trauner
Michael
M
D000222:Adaptation, Physiological; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism; D001648:Bile Canaliculi / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D015854:Up-Regulation
D001647:Bile Acids and Salts; D002352:Carrier Proteins; D012333:RNA, Messenger