Science and Technology Production
Congress
Authorship
BOAGLIO, ANDREA CAROLINA
;
Zucchetti A. E.
;
Sanchez Pozzi E. J.
;
Mottino A. D.
;
Crocenzi F. A.
;
Roma M. G.
Date
2009
Publishing House and Editing Place
Elsevier
Summary
Information provided by the agent in
SIGEVA
E17G is an endogenous, cholestatic metabolite that induces endocytic internalization of the canalicular transporters relevant to bile secretion Bsep and Mrp2; this may justify its casual association with pregnancy-induced cholestasis.PI3K mediates cholestatic events, e.g. taurolithocolate-induce cholestasis (JBC 278: 17810, 2003). Since common phatomechanisms exist between both kinds of cholestasis, we assessed here wheter PI3K is involved in E17G cholestatic effects. E17G (200uM) activated PI3...
E17G is an endogenous, cholestatic metabolite that induces endocytic internalization of the canalicular transporters relevant to bile secretion Bsep and Mrp2; this may justify its casual association with pregnancy-induced cholestasis.PI3K mediates cholestatic events, e.g. taurolithocolate-induce cholestasis (JBC 278: 17810, 2003). Since common phatomechanisms exist between both kinds of cholestasis, we assessed here wheter PI3K is involved in E17G cholestatic effects. E17G (200uM) activated PI3K from 20 min onwards, as assessed by the phosphorylation of the final PI3K effector Akt in primary cultured hepatocytes.When preadministered to isolated rat hepatocyte couplets(IRHCs), the PI3K inhibitor wortmannin (WM; 100nM) prevented partially the reduction induced by E17G (12.5-800uM) in the proportion of IRHCs accumulating apically the fluorescent Bsep and Mrp2 substrates cholyllysylfluorescein and glutathionylmethylfluorescein, respectively.The alternative PI3K inbibitor LY294002 (50uM) and the "Akt inhibitor" (Calbiochem #124005; 20uM ) showed similar protective effects.Immunostaining of Bsep and Mrp2 in IRHC followed by confocal microscopy and image analysis revealed that E17G induces endocytic internalization of transporters.The redistribution was extensively prevented by WM.To evaluate this phenomenon in a more physiological model, we assessed the anticholestatic effect of WM in perfused rat livers.A bolus, intraportal injection of E17G (2 umol) induced an acute decrease in bile flow within 10 min, which did not recover during the remaining perfusion period (fig. 1). WM (100nM) did not prevent this initial decay, but greatly accelerated the recovery to normality of bile flow. A similar behaviour was observed for the biliary excretion of the Bsep and Mrp2 substrates[3H]-taurocholate and glutathione, respectively.
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Key Words
CHOLESTASISPI3K/AKTE17GBSEP/MRP2