Extrahepatic cholestasis downregulates Oatp1 by TNF-alpha signalling without affecting Oatp2 and Oatp4 expression and sodium-independent bile salt uptake in rat liver

Liver Int. 2007 Oct;27(8):1056-65. doi: 10.1111/j.1478-3231.2007.01523.x.


Hepatic uptake of bile salts is mediated by sodium-dependent and sodium-independent transport systems. During extrahepatic cholestasis, both the function and the expression of the Na(+)/taurocholate cotransporting polypeptide (Ntcp) are downregulated. To test whether sodium-independent organic anion-transporting polypeptides are also affected by extrahepatic cholestasis, the function and expression of all three Oatps have been determined in common bile duct-ligated (CBDL) rats. Oatp1/Oatp1a1 protein mass remained unchanged after CBDL for 1 day, but then declined by 75+/-7% and 90+/-17%, respectively, after 3 and 7 days. In contrast, Oatp2/Oatp1a4 and Oatp4/Oatp1b2 protein expression was not affected by CBDL as compared with controls. After CBDL, Oatp1 mRNA was rapidly downregulated by 68+/-21% of untreated controls (P<0.05) within 24 h, and remained at similar levels at 3 and 7 days. Cytokine-inactivation studies with etanercept pretreatment demonstrated that TNF-alpha-dependent signals mediated the down-regulation of this transporter gene at both protein and mRNA levels during obstructive cholestasis. Sodium-independent uptake of taurocholate and cholate into freshly isolated hepatocyte suspensions showed neither significant differences in K(m) nor V(max) values. These results indicate that sodium-independent transport of bile salts may be mediated by Oatp2 and 4 during biliary obstruction, because its expression remains unaffected and may compensate for loss of Oatp1 expression and function in cholestatic hepatocytes.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholates / metabolism*
  • Cholestasis, Extrahepatic / metabolism*
  • Common Bile Duct / surgery
  • Disease Models, Animal
  • Down-Regulation
  • Etanercept
  • Immunoglobulin G / pharmacology
  • Ligation
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Organic Anion Transporters / metabolism
  • Organic Anion Transporters, Sodium-Independent / genetics
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Tumor Necrosis Factor
  • Signal Transduction* / drug effects
  • Sodium / metabolism*
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Taurocholic Acid / metabolism*
  • Time Factors
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism*


  • Cholates
  • Immunoglobulin G
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Slco1a1 protein, rat
  • Slco1a4 protein, rat
  • Slco1b2 protein, rat
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Tumor Necrosis Factor-alpha
  • Taurocholic Acid
  • Sodium
  • Etanercept