Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver.
Cholestasis induces down-regulation of multidrug resistance protein 2 (Mrp2, symbol Abcc2), which is localized to the canalicular membrane. Given the overlapping substrate specificities of Mrp2 and multidrug resistance protein 3 (Mrp3, symbol Abcc3), we examined the hypothesis of a different subcellular and lobular localization of these members of the Mrp family in rat liver after bile duct ligation. We raised a polyclonal antibody against rat Mrp3 and detected this protein in the basolateral plasma membrane of hepatocytes surrounding the central veins and of cholangiocytes. The Mrp3 protein level was less than 2% of the expression observed after 72 hours of obstructive cholestasis. After 48 hours of bile duct ligation, the Mrp3 protein was increased and was further enhanced after 72 hours. In 72-hour-cholestatic rat liver Mrp3 was expressed, in addition, in periportal hepatocytes. However, there was a preponderance of Mrp3 in the pericentral area of the liver lobule. In Mrp2-deficient mutant rat liver, the Mrp3 protein expression was most enhanced and its zonation was lost. The Mrp3 immunostaining of cholangiocytes was preserved in cholestatic and in Mrp2-deficient mutant liver. Canalicular Mrp2 decreased and amounted to 34% of normal after bile duct ligation for 72 hours. We conclude that the hepatocellular up-regulation of Mrp3 in cholestasis together with cholangiocellular Mrp3 may compensate for the biliary obstruction and impaired canalicular Mrp2 function by clearing cholephilic anionic substances into the blood.
Donner
M G
MG
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany. markus.donner@uni-duesseldorf.de
Keppler
D
D
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002779:Cholestasis / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D015151:Immunoblotting; D007425:Intracellular Membranes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D002352:Carrier Proteins; C095122:multidrug resistance protein 3