Differential effects of streptozotocin-induced diabetes on expression of hepatic ABC-transporters in rats

Abstract

Background & Aims: Diabetes mellitus is associated with changes in bile formation. The aim of our study was to investigate the molecular basis for these changes in rats with experimentally induced diabetes. Methods: Expression of bile canalicular transporters was studied by reverse-transcription polymerase chain reaction, immunoblotting, and immunohistochemistry in control, streptozotocin-diabetic, and insulin-treated diabetic rats. Bile formation was studied under basal conditions and during stepwise increasing intravenous infusion of taurocholate to determine bile salt secretory rate maximum (SRm). Results: In diabetic rats, hepatic gene and protein expression of the multidrug resistance P-glycoprotein type 2 (Mdr2) were increased by 105% and 530%, respectively, associated with increased biliary phospholipid output (+520%) and phospholipid/bile salt ratio (+77%). Protein levels of the canalicular bile salt export pump (Bsep) were unchanged in diabetic rats, but basal biliary bile salt output and the SRm of taurocholate were increased by 260% and 130%, respectively, compared with controls. Alterations in transporter expression and bile formation were partly reversed by insulin administration. The bile salt SRm was strongly correlated with biliary phospholipid concentration (P < 0.001, R = 0.82). Conclusions: Induction of Mdr2 expression and biliary phospholipid secretion, rather than Bsep expression, appears to be responsible for the enhanced capacity of biliary bile salt secretion in experimentally induced diabetes.