title: Kupffer cell-mediated downregulation of hepatic transporter expression in rat hepatic ischemia-reperfusion.
abstract: BACKGROUND
  Hepatic ischemia-reperfusion (IR) injury is frequently followed by cholestatic liver disease. Cytokines released by Kupffer cells following hepatic IR injury may subsequently regulate hepatic transporter expression. The purpose of this study was to determine whether hepatic IR injury and the resultant Kupffer cell activation alters hepatic transporter expression.
  
  
  METHODS
  Rats were subjected to 60 minutes of partial hepatic ischemia followed by 0, 3, 6, 24, or 48 hours of reperfusion. After IR surgery, the following were determined: 1) serum bilirubin and bile acid levels; 2) serum levels of cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL6; 3) expression of several hepatic transporters; and 4) nuclear protein levels of hepatocyte nuclear factor (HNF)-1alpha and retinoid X receptor (RXR)-alpha to investigate whether altered expression of hepatic transporters following IR is associated with decreases in these transcription factors.
  
  
  RESULTS
  After reperfusion: 1) serum bilirubin and bile acids increased; 2) levels of all three cytokines increased; 3) mRNA expression of hepatic transporters organic anion transporting polypeptide (Oatp) 1a1, Oatp1a4, Oatp1b2, sodium taurocholate cotransporting polypeptide, multidrug resistance-associated protein (Mdr) 2, and bile salt export pump decreased, whereas Mdr1b expression increased; and 4) nuclear protein levels of HNF1alpha decreased, whereas RXRalpha was not altered. Pretreatment with gadolinium chloride to deplete Kupffer cells before IR: 1) blocked the increase in serum bile acids, 2) attenuated TNFalpha but not IL1beta/IL6 levels, 3) inhibited the altered hepatic transporter expression, and 4) blocked the decrease in HNF1alpha nuclear protein levels.
  
  
  CONCLUSIONS
  These results suggest that alterations in hepatic transporter expression during IR occur through Kupffer cell-mediated events, possibly involving a decrease in nuclear HNF1alpha.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, 66160, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Chuan
authors.initials: C
authors.lastname: Chen
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Maher
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001663:Bilirubin / Q000097:blood; D005682:Gadolinium / Q000494:pharmacology; D007511:Ischemia / Q000503:physiopathology*; D007728:Kupffer Cells / Q000502:physiology*; D008102:Liver Circulation; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology*
chemical_list: D001647:Bile Acids and Salts; D026901:Membrane Transport Proteins; D005682:Gadolinium; D000410:Alanine Transaminase; C038958:gadolinium chloride; D001663:Bilirubin