Adaptive Regulation of the Canalicular Bile Salt Export Pump in Response to Changes of Bile Salt Pool Size

M. Arrese, M. Pizarro, N. Solís, L. Acattino.:

Presentado a: Congreso anual de la American Gastroenterological Association. 20 al 26 de Mayo, 2000. San Diego, California, Estados Unidos.

Background: Adaptive up- and down-regulation of hepatic bile salt transport occurs in response to changes in bile salt (BS) pool size and/or bile salt flux in the liver (Arrese M. et al, J. Hepatol 1997:26:694-702). BS are excreted into the canaliculi by an ATP-dependent carrier named BS export pump (Bsep).

Aim. To assess whether changes in BS pool size are associated to changes in the expression of the Bsep.

Methods: Male Sprague-Dawley rats were subjected to the following experimental conditions: 1) BS Overload using a) exogenous BS feeding (1% w/w of cholic acid) during 4 days, or b) endogenous BS overload through a choledoco-jugular fistula for 1 and 2 days, and 2) depletion of the BS pool by external biliary drainage for 24 hrs. Bile flow, basal BS secretion and maximum taurocholate secretory rate (SRm) were determined. Bsep protein mass in isolated canalicular membranes was estimated by Western blotting. Protein mass of the basolateral sodium taurocholate cotransporting polypeptide (ntcp) was also assessed using a crude liver membrane fraction.

Results: BS overload (groups 1a and 1b) was associated with significantly increased basal BS secretion (222%, 660% and 497%, respectively) and taurocholate SRm (172%, 199% and 148%,respectively). In these groups, a significant increase of membrane Bsep protein mass (533%, 317% and 174%, respectively) was apparent. In contrast, BS pool depletion, which determined a significant decrease of basal BS secretion (to 10%) and taurocholate SRm (to 65%), was associated with a significant decrease of Bsep protein mass (to 80%). Ntcp protein mass was not modified by BS feeding or BS depletion.

Conclusion: these results support the role of Bsep in canalicular transport of BS and indicate that its expression is regulated by changes in BS pool size (Grants FONDECYT 1971124 and 1990519).