Regulation of organic anion transporters in a new rat model of acute and chronic cholangitis resembling human primary sclerosing cholangitis.
OBJECTIVE
Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiology. Although the primary defect affects cholangiocytes, cholestatic injury of hepatocytes may promote further liver damage. Since down-regulation of hepatocellular organic anion transporters is implicated in the molecular pathogenesis of cholestasis, expression of these transporters was determined in a novel rat model, which closely resembles human PSC.


METHODS
Hepatic protein and mRNA expression of basolateral (Ntcp, Oatp1, 2 and 4) and canalicular (Mrp2, Bsep) organic anion transporters were analyzed 1, 4 and 12 weeks after induction of experimental PSC by 2,4,6-trinitrobenzenesulfonic acid (TNBS).


RESULTS
Specific down-regulation of basolateral and canalicular transport systems except Oatp4 and Bsep proteins occurred during the acute phase of inflammation. In chronic cholangitis 12 weeks after TNBS Mrp2 protein and mRNA remained down-regulated by 40-50% of controls (P<0.05). In addition Oatp1 protein was also reduced by 40+/-13% (P<0.05), whereas all other transporters returned to control values.


CONCLUSIONS
In chronic cholangitis only canalicular Mrp2 expression remained down-regulated. This might represent the first injury to hepatocytes in chronic cholangitis as an extension of liver injury from the level of cholangiocytes to hepatocytes in PSC.
Geier
Andreas
A
Department of Internal Medicine III, University of Technology Aachen, Pauwelsstrasse 30, D-52074, Aachen, Germany.
Dietrich
Christoph G
CG
Lammert
Frank
F
Orth
Thomas
T
Mayet
Werner-Johannes
WJ
Matern
Siegfried
S
Gartung
Carsten
C
D018528:ATP-Binding Cassette Transporters; D000208:Acute Disease; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D015209:Cholangitis, Sclerosing / Q000503:physiopathology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000502:physiology; D008297:Male; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; C421102:Slco1a1 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