Differential effects of streptozotocin-induced diabetes on expression of hepatic ABC-transporters in rats.
OBJECTIVE
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.
van Waarde
Willie M
WM
Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Hospital Groningen, Groningen, The Netherlands. w.m.van.waarde@bkk.azg.nl
Verkade
Henkjan J
HJ
Wolters
Henk
H
Havinga
Rick
R
Baller
Juul
J
Bloks
Vincent
V
Müller
Michael
M
Sauer
Pieter J J
PJ
Kuipers
Folkert
F
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D013656:Taurocholic Acid