Changes in the expression and localization of hepatocellular transporters and radixin in primary biliary cirrhosis.
OBJECTIVE
Expression and localization of human hepatocellular transporters and of radixin, cross-linking actin with some membrane transporters, may change in cholestatic liver diseases.


METHODS
We investigated the uptake transporters OATP2 (SLC21A6), OATP8 (SLC21A8), and NTCP (SLC10A1), the export pumps MRP2 (ABCC2), MRP3 (ABCC3), MRP6 (ABCC6), and P-glycoproteins (ABCB1, ABCB4, ABCB11), and radixin, in non-icteric primary biliary cirrhosis (PBC stages I-III) and control human liver needle-biopsies using immunofluorescence microscopy and semi-quantitative RT-PCR.


RESULTS
Expression and localization of all transporters were unchanged in PBC I-II. Immunostaining intensities of uptake transporters decreased in PBC III with a concomitant decrease in mRNA levels. Immunostaining intensities and mRNA levels of export pumps were similar in controls and PBC I-III, however, irregular MRP2 immunostaining suggested redistribution of MRP2 into intracellular structures in PBC III. Areas of irregular MRP2 immunostaining showed largely reduced radixin immunostaining, whereas normal hepatocytes had MRP2 and radixin confined to the canalicular membrane. Disrupted localization of radixin and MRP2 supports the concept that radixin contributes to the canalicular localization of MRP2.


CONCLUSIONS
Down-regulation of uptake transporters may contribute to the impaired hepatobiliary elimination in advanced PBC, and partially altered localization of MRP2 may reflect the onset of changes leading to icteric PBC.
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Hideyuki
H
Kojima
Anne T
AT
Nies
Jörg
J
König
Wolfgang
W
Hagmann
Herbert
H
Spring
Masahito
M
Uemura
Hiroshi
H
Fukui
Dietrich
D
Keppler
D000328:Adult; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013194:Staining and Labeling; D014018:Tissue Distribution
D001798:Blood Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C000715087:ABCC2 protein, human; C071776:radixin