title: Regulation of organic anion transporters in a new rat model of acute and chronic cholangitis resembling human primary sclerosing cholangitis.
abstract: 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.
authors.affiliation: Department of Internal Medicine III, University of Technology Aachen, Pauwelsstrasse 30, D-52074, Aachen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
authors.forename: Christoph G
authors.initials: CG
authors.lastname: Dietrich
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.forename: Thomas
authors.initials: T
authors.lastname: Orth
authors.forename: Werner-Johannes
authors.initials: WJ
authors.lastname: Mayet
authors.forename: Siegfried
authors.initials: S
authors.lastname: Matern
authors.forename: Carsten
authors.initials: C
authors.lastname: Gartung
mesh_terms: 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
chemical_list: 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