Steady state analysis and experimental validation of a model for hepatic high-density lipoprotein transport

Traffic
Daniel Wüstner

Abstract

Transport of high-density lipoprotein (HDL) in the hepatocyte plays a fundamental role in reverse cholesterol transport and regulation of plasma HDL levels. On the basis of a recently developed kinetic model, the steady state distribution of HDL was analyzed. Fractional fluorescence of labeled HDL in the basolateral membrane, sorting endosomes (SE), the subapical compartment/ apical recycling compartment, the biliary canaliculus and in late endosomes and lysosomes (LE/LYS) including expected standard deviation is predicted. Improved parameter estimation was obtained by including kinetic data of apical endocytosis of fluorescent markers for LE/LYS, asialoorosomucoid and Rhodamine-dextran, in the regression. Predicted values using the refined kinetic parameters are in good agreement with experimental values of compartmental steady state fluorescence of Alexa488-HDL in polarized hepatic HepG2 cells. From calculated steady state fluxes, it is suggested that export of HDL from basolateral SE is the key step for determining the transport of HDL through the hepatocyte. The analysis provides testable predictions for high-throughput fluorescence microscopy screening experiments on potential inhibitors of hepatic HDL processing. By quant...Continue Reading

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Citations

Nov 15, 2012·BMC Bioinformatics·Daniel WüstnerMichael A Lomholt

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