title: Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis.
abstract: OBJECTIVE
  Organic anion-transporting polypeptides OATP1B1 and OATP1B3 are sinusoidal membrane transporters mediating liver uptake of a wide range of substrates including conjugated and unconjugated bilirubin, xenobiotics and drugs. Absence of OATP1Bs in the liver causes Rotor syndrome. Our aim was to correlate OATP1B expression with hyperbilirubinemia in common liver diseases.
  
  
  METHODS
  Immunoreactivity of five antibodies against human OATP1Bs was tested on frozen and formalin-fixed paraffin-embedded liver tissue of mouse strains transgenic for SLCO1B1 or SLCO1B3 and on human specimens. The proportion of hepatocytes expressing OATP1Bs was then assessed immunohistologically in formalin-fixed paraffin-embedded liver samples obtained from patients with hepatocellular and primary biliary liver diseases. UGT1A1 promoter TATA-box and SLCO1B1 rs4149056 genotyping was performed to rule out individuals predisposed to hyperbilirubinemia.
  
  
  RESULTS
  The most specific detection of OATP1B3 was achieved with the H-52 (sc-98981) antibody. OATP1B1 was specifically recognized with the ESL (ab15441) anti-OATP1B1 antibody, but only in frozen sections. The MDQ (ab15442) anti-OATP1B1 antibody cross-reacted with both OATP1B proteins in liver tissue of the transgenic mouse strains. Expression of the OATP1B proteins was decreased in advanced liver diseases and inversely correlated with serum bilirubin levels. The reduction was more pronounced in advanced primary biliary diseases (1.9±1.1 vs. 2.7±0.6; P=0.009).
  
  
  CONCLUSIONS
  Down-regulation of OATP1B proteins may contribute to pathogenesis of jaundice accompanying advanced cholestatic liver diseases.
authors.affiliation: Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine 14021 Prague 4, Czech Republic ; Third Faculty of Medicine, Charles University 10000 Prague 10, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Sticova
authors.affiliation: Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine 14021 Prague 4, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Lodererova
authors.affiliation: The Netherlands Cancer Institute Amsterdam, The Netherlands ; TNO Zeist, The Netherlands.
authors.forename: Evita
authors.initials: E
authors.lastname: van de Steeg
authors.affiliation: Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine 14021 Prague 4, Czech Republic.
authors.forename: Sona
authors.initials: S
authors.lastname: Frankova
authors.affiliation: Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine 14021 Prague 4, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Kollar
authors.affiliation: Medical Statistics Unit, Institute for Clinical and Experimental Medicine 14021 Prague 4, Czech Republic.
authors.forename: Vera
authors.initials: V
authors.lastname: Lanska
authors.affiliation: 2nd Department of Pediatrics of The 2nd Medical School, Charles University Prague, Czech Republic.
authors.forename: Radana
authors.initials: R
authors.lastname: Kotalova
authors.affiliation: 2nd Department of Pediatrics of The 2nd Medical School, Charles University Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Dedic
authors.affiliation: The Netherlands Cancer Institute Amsterdam, The Netherlands.
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
authors.affiliation: Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine 14021 Prague 4, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Jirsa
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002779:Cholestasis / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005404:Fixatives; D005557:Formaldehyde; D005629:Frozen Sections; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006932:Hyperbilirubinemia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D027381:Liver-Specific Organic Anion Transporter 1; D008822:Mice, Transgenic; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D016612:Paraffin Embedding; D012189:Retrospective Studies; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016707:Tissue Fixation / Q000379:methods
chemical_list: D015415:Biomarkers; D005404:Fixatives; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D005557:Formaldehyde; D001663:Bilirubin
keywords: Bilirubin; cholestasis; immunohistochemistry; liver disease; organic anion transporter