Regulation of hepatic transport systems involved in bile secretion during liver regeneration in rats.
We investigated the expression of hepatic transport systems involved in bile secretion during liver regeneration after partial hepatectomy (PH) in rats. Initial studies showed maximal BrdU incorporation 24 hours after PH. Therefore, transporter expression and bile secretion were analyzed in detail at this time. The mRNA levels of the multidrug resistance genes mdr1a and mrp1 slightly increased, whereas mdr1b mRNA levels showed an extensive increase after PH. The mRNA levels of the conjugate transporter, mrp2, decreased slightly, whereas mrp2 protein levels did not change. Bilirubin secretion did not change, but the biliary glutathione secretion markedly decreased and the hepatic GSH content increased. The messenger RNA levels of the bile salt uptake transporters ntcp, oatp1, and oatp2 and the bile salt exporter, bsep/spgp, all decreased with ntcp showing the most prominent decrease. Protein levels of ntcp dramatically decreased whereas oatp2 only slightly decreased. Oatp1 protein expression slightly increased and bsep/spgp protein levels did not change. Decreased levels of bile salt uptake systems were associated with a 10-fold increase in the plasma bile salt concentration, yet, bile flow and bile salt secretion were increased when expressed per gram liver and unaffected when expressed on the basis of body weight. In conclusion, during the initial phase of rat liver regeneration ntcp is down-regulated whereas other transporter proteins involved in bile secretion are only slightly affected. Despite increased serum bile salt levels the remnant liver is not cholestatic: bile flow is maintained by uptake of bile salts probably via oatp isoforms and their secretion via bsep/spgp.
Vos
T A
TA
Groningen Institute for Drug Studies, University Hospital Groningen, The Netherlands.
Ros
J E
JE
Havinga
R
R
Moshage
H
H
Kuipers
F
F
Jansen
P L
PL
Müller
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D027321:Anion Transport Proteins; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism; D001663:Bilirubin / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005786:Gene Expression Regulation; D006498:Hepatectomy; D006706:Homeostasis; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D010743:Phospholipids / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027321:Anion Transport Proteins; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D010743:Phospholipids; D012333:RNA, Messenger; D002784:Cholesterol; D001663:Bilirubin