Differential expression of basolateral and canalicular organic anion transporters during regeneration of rat liver

Background & Aims: Liver regeneration in response to various forms of injur y or surgical resection is a complex process resulting in restoration of th e original liver mass and maintenance of liver-specific functions such as b ile formation. However, liver regeneration is frequently associated with ch olestasis, whose molecular pathogenesis remains unknown, Methods: To study the molecular mechanisms leading to cholestasis, expression of all major he patic organic anion transporters contributing to bile formation was determi ned for up to 2 weeks in rats after 70% partial hepatectomy. Results: Inver sely related to serum bile acid levels, basolateral transporters including the sodium-taurocholate cotransporter (Ntcp) and the organic anion transpor ting polypeptides Oatp1 and Oatp2 were markedly down-regulated at both prot ein and steady-state mRNA levels by 50%-60% of controls (P < 0.05) during e arly replicative stages of regeneration (12 hours to 2 days) with a slightl y delayed time course for Oatp2. Expression of all basolateral transporters returned to control values between 4 and 4 days after partial hepatectomy. In contrast, protein and mRNA expression of both the canalicular ATP-depen dent bile salt export pump (Bsep) and the multiorganic anion transporter Mr p2 remained unchanged or were slightly increased during liver regeneration, but also returned to control values 7-14 days after partial hepatectomy, C onclusions: The data suggest a differential regulation of basolateral and c analicular organic anion transporters in the regenerating liver. Unaltered expression of Bsep and Mrp2 provides a potential molecular mechanism for re generating liver cells to maintain or even increase bile secretion expresse d per weight of remaining liver. However, down-regulation of basolateral or ganic anion transporters might protect replicating liver cells by diminishi ng uptake of potentially hepatotoxic bile salts, because the remaining live r initially cannot cope with the original bile acid pool size.