Differential expression of bile salt and organic anion transporters in developing rat liver.
OBJECTIVE
Differentiated hepatocytes express distinct transport systems at their basolateral and canalicular membrane domains. Here, we investigated the ontogenesis of the polar expression of hepatocellular organic anion and bile salt transport systems in rat liver.


METHODS
mRNA levels (real time PCR) and protein expression (immunofluorescence microscopy) were investigated for the Na(+)-taurocholate cotransport protein (Ntcp), the organic anion transporting polypeptides (Oatp1a1, Oatp1a4, Oatp1b2), the multidrug resistance associated proteins (Mrp2, Mrp6) and the bile salt export pump (Bsep).


RESULTS
Expression of mRNA and protein was detected first for Oatp1b2, Mrp2 and Mrp6 at embryonic day 16 (E16), followed by Ntcp, Oatp1a1 and Bsep at E20 and by Oatp1a4 at postnatal day 5 (P5). Intracellular localization of Oatps (e.g. Oatp1b2) preceded expression at the plasma membrane. Approximate adult phenotypes of polarized expression were achieved for Ntcp by P5, for Bsep, Mrp2 and Mrp6 by P12 and for Oatp1a1, Oatp1a4 and Oatp1b2 by P29.


CONCLUSIONS
The data demonstrate that full maturation of polarized transporter expression in rat liver requires several weeks. The findings provide a molecular explanation for the previously observed chronology of the functional maturation of bile salt-independent and dependent bile formation and of hepatic detoxification functions in developing rat liver.
Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland.
Bo
B
Gao
Marie V
MV
St Pierre
Bruno
B
Stieger
Peter J
PJ
Meier
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000235:genetics / Q000378:metabolism*; D003199:Computer Systems; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D005260:Female; D005455:Fluorescent Antibody Technique; D008099:Liver / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; C490548:Abcb11 protein, rat; C071908:sodium-bile acid cotransporter