Regulation of rat organic anion transporters in bile salt-induced cholestatic hepatitis: effect of ursodeoxycholate.
Hepatic uptake of organic anions, including bile salts, is mediated by members of the organic anion-transporting polypeptide (Oatp) family. In rat liver, Oatp1 (Slc21a1), Oatp2 (Slc21a5), and Oatp4 (Slca10) are expressed at the basolateral membrane of hepatocytes and may be differentially regulated under pathophysiologic conditions such as cholestasis. The aim of this study was to determine the effects of cholic acid (CA) and ursodeoxycholic acid (UDCA) on the expression of Oatp4 compared with Ntcp, Oatp1, and Oatp2. Wistar rats were fed with CA (0.5%) or both CA (0.5%) and UDCA (0.25%) for 3 weeks. Oatp expression was studied by Northern and Western blot analysis as well as immunofluorescence analysis. Transport function was compared measuring biliary secretion of (14)C-CA and (14)C-taurocholic acid (TCA). In CA-fed animals, biliary secretion of (14)C-CA and (14)C-TCA was markedly delayed over 40 minutes compared with controls. Accordingly, Oatp4 protein was significantly down-regulated in CA-fed animals together with Oatp1 and Ntcp. Cofeeding of CA plus UDCA prevented the impairment of (14)C-CA and (14)C-TCA secretion and the down-regulation of Oatp4. Oatp4 messenger RNA (mRNA) levels did not differ significantly between bile salt-fed groups, suggesting a posttranscriptional effect of CA on Oatp4 expression. In contrast to Oatp1 and Oatp4, Oatp2 protein expression was increased by CA feeding, indicating a differential regulation of Oatp transporters. In conclusion, we show that CA feeding may cause cholestasis associated with a posttranscriptional down-regulation of Oatp4. UDCA may prevent impairment of hepatic function by restoring hepatic transporter expression.
Rost
Daniel
D
Department of Gastroenterology, University Hospital, Heidelberg, Germany. Daniel_Rost@med.uni-heidelberg.de
Herrmann
Thomas
T
Sauer
Peter
P
Schmidts
Hans-Ludwig
HL
Stieger
Bruno
B
Meier
Peter J
PJ
Stremmel
Wolfgang
W
Stiehl
Adolf
A
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D002779:Cholestasis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019826:Cholic Acid / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006505:Hepatitis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism*; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002756:Cholagogues and Choleretics; D026901:Membrane Transport Proteins; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; C421043:Slc22a6 protein, rat; C503597:Slco1a4 protein, rat; C421207:Slco1b2 protein, rat; C451262:Slco1c1 protein, rat; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters; C071908:sodium-bile acid cotransporter; D014580:Ursodeoxycholic Acid; D019826:Cholic Acid