EXPRESSION OF THE RAT-LIVER NA+ TAUROCHOLATE COTRANSPORTER IS REGULATED IN-VIVO BY RETENTION OF BILIARY CONSTITUENTS BUT NOT THEIR DEPLETION/

Expression and function of the hepatic Na+/taurocholate cotransporter (ntcp) are down-regulated in several models of experimental cholestasi s, To test whether retention and/or depletion of biliary constituents are involved in ntcp regulation, ntcp expression was quantified in sev eral animal models with altered levels of these constituents, In chole dochocaval fistula rats (CCF) (retention model), ntcp mRNA expression specifically declined after 1 and 3 days by 76 +/- 4% (P < .005) and 3 1 +/- 9% (P < .05), respectively, returning to control levels by 7 day s. However, protein expression as assessed by Western blotting remaine d unchanged for up to 7 days of CCF. In rats with bile fistulas (deple tion model) for 0.5, 1, 2, 4, and 7 days, both ntcp protein and mRNA e xpression remained unaltered, Infusion of either taurocholate or taruo chenodeoxycholate for 12 hours also did not effect ntcp mRNA expressio n in intact animals, probably because of its inability to increase ser um and intrahepatic bile acid levels, In rats with selective bile duct ligation (SBDL), ntcp mRNA levels were down-regulated by 40 +/- 10% ( P < .05) only after 12 and 24 hours in ligated lobes, and mRNA levels returned to control values in these lobes after 2 and 4 days, ntcp mRN A expression remained unchanged in the nonobstructed lobes at any time , When data from CCF and SBDL rats were combined, serum bile acids cor related linearly with ntcp mRNA (r = .62, P < .0005) over a 0 to 110-m u mol/L range, Our results indicate that ntcp is constitutively expres sed and remains uneffected by either depletion or increased flux of bi liary constituents, However, retention of biliary constituents results in rapid down-regulation of ntcp mRNA, consistent with the concept th at hepatocytes may be protected from bile acid toxicity during cholest asis by this mechanism.