Hepatobiliary organic anion transporters are differentially regulated in acute toxic liver injury induced by carbon tetrachloride

J Hepatol. 2002 Aug;37(2):198-205. doi: 10.1016/s0168-8278(02)00108-3.

Abstract

Background/aims: Hepatobiliary transporters are down-regulated in cholestasis, but their expression in acute, non-cholestatic, cytokine-mediated liver injury is unknown. Thus we studied the molecular mechanisms, by which sodium taurocholate cotransporting polypeptide (Ntcp), organic anion transporting polypeptide 1 (Oatp1), Oatp2, Oatp4, multidrug-resistance protein 2 (Mrp2) and bile salt export pump (Bsep) are regulated in liver injury induced by carbon tetrachloride (CCl(4)).

Methods: mRNA and protein levels were determined in rats 24 and 72h after CCl(4) injection. Transporter gene transcription and binding activities of Ntcp and Mrp2 transactivators were assessed by nuclear runoff and electrophoretic mobility shift assays.

Results: mRNA levels significantly declined to 41+/-44% for Ntcp, 65+/-41% for Oatp1 and 64+/-28% for Oatp2, but remained unchanged for Oatp4, canalicular Mrp2 and Bsep. Protein levels declined only for Oatp4 (-50+/-17%) and Ntcp (-23+/-13%) at 24h. Reduced mRNA levels (Ntcp, Oatp1, Oatp2) were associated with decreased transcriptional activities. Binding activity of Ntcp transactivators (hepatocyte nuclear factor 1 alpha (HNF1alpha) and CAAT enhancer binding protein alpha (C/EBPalpha) were reduced by 24h, whereas retinoid X receptor alpha (RXRalpha):retinoid acid receptor alpha (RARalpha) as transactivator of both Ntcp and Mrp2 remained unaltered. Recovery of acute hepatitis and changes in gene expression occurred after 72h.

Conclusions: Acute liver injury results in down-regulation of basolateral organic anion transporters similar to liver regeneration after partial hepatectomy, but in contrast to endotoxin-induced cholestasis. Maintained binding activity of RXRalpha:RARalpha may explain differences in Mrp2 expression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Animals
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Carbon Tetrachloride
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Chemical and Drug Induced Liver Injury
  • Cytokines / genetics
  • DNA-Binding Proteins*
  • Gene Expression / drug effects
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Liver Diseases / metabolism*
  • Liver Diseases / physiopathology*
  • Male
  • Membrane Transport Proteins*
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Nuclear Proteins*
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Dependent
  • Organic Anion Transporters, Sodium-Independent / genetics*
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Symporters
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Carrier Proteins
  • Cytokines
  • DNA-Binding Proteins
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, rat
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Nuclear Proteins
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Dependent
  • Organic Anion Transporters, Sodium-Independent
  • Organic Cation Transport Proteins
  • RNA, Messenger
  • Slco1a1 protein, rat
  • Slco1a4 protein, rat
  • Slco1b2 protein, rat
  • Slco1c1 protein, rat
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Symporters
  • Transcription Factors
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta
  • sodium-bile acid cotransporter
  • multidrug resistance-associated protein 2
  • Carbon Tetrachloride
  • multidrug resistance-associated protein 1