PI KINASES, CANALICULAR TRANSPORTERS AND CHOLESTASIS

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Mechanisms responsible for intracellular cholestasis and regulation of intracellular trafficking of the ATP-dependent canalicular transporters spgp (taurocholate), mrp2 (nonbile acid organic anions), mdr1 (organic cations), mdr3 (phosphatidylcholine translocase) and newly described mrp3 (glycocholate) are poorly understood. An intact microtubular network and vesicular trafficking originating in the trans-Golgi network and concluding in the bile canalicular membrane are required. Both are associated with PI 3-kinase activity and are blocked by Wortmannin and LY294002, which are PI 3-kinase inhibitors. Activation of PI 3- kinase in intact cells accelerates bile acid secretion. We propose that PI 3-kinase lipid products are essential for vesicular trafficking of the ATP-dependent canalicular transporters as well as for their activity in the canalicular membrane. We also postulate that generation of these phospholipids is defective in certain forms of cholestasis. Using biochemical, molecular and confocal fluorescence microscopic techniques and novel reagents and experimental models, including genetically engineered p85-/- PI 3- kinase mice, the specific trafficking of canalicular transporters and the role of PI 3-kinase and its lipid producers in bile secretion will be determined. These studies should elucidate intracellular mechanisms of cholestasis. Furthermore, activation of specific PI 3-kinase functions may selectively enhance canalicular transport and have therapeutic potential in cholestasis.