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Journal of Lipid Research, Vol. 47, 2422-2432, November 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Pluronic L81 enhances triacylglycerol accumulation in the cytosol and inhibits chylomicron secretion

Sumbul Fatma, Reuven Yakubov, Kamran Anwar and M. Mahmood Hussain¹

Departments of Anatomy & Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, NY 11203

Published, JLR Papers in Press, August 7, 2006.

¹ To whom correspondence should be addressed. e-mail: mahmood.hussain{at}downstate.edu

Pluronic L81 (PL81) inhibits fat absorption, and other Pluronic copolymers help overcome drug resistance in cancer cells. To understand how PL81 acts, we synthesized a radiolabeled analog, [¹⁴C]PL81, and showed that it was structurally similar to PL81 based on ¹H NMR as well as mass spectrometric analysis. [¹⁴C]PL81 inhibited the secretion of chylomicrons (CMs), lipoproteins essential for fat absorption, by differentiated Caco-2 cells similar to PL81. Moreover, PL81 competed with the cellular uptake of [¹⁴C]PL81. Thus, [¹⁴C]PL81 and PL81 behave similarly in these physiologic assays. Uptake of [¹⁴C]PL81 by Caco-2 cells was concentration-, time-, and temperature-dependent and occurred mainly from the apical side. Intracellularly, it was assimilated in the cytosol. Cells excreted PL81 toward the apical side via a pathway partially sensitive to verapamil. Small amounts were secreted toward the basolateral side unassociated with CM, and this secretion was unaffected by the inhibition of CM assembly. Nonetheless, PL81 significantly inhibited the secretion of triacylglycerols (TGs) and phospholipids as part of CM. PL81-treated cells showed decreased activity of microsomal triglyceride transfer protein and accumulated more TGs, but not phospholipids, in their cytosol. We propose that Pluronic copolymers act by interfering with the export of molecules from the cytosol. They inhibit fat absorption by decreasing TG transport to the endoplasmic reticulum and increase drug efficacy against cancer cells by competing for their excretion.

Supplementary key words apolipoprotein B • microsomal triglyceride transfer protein • lipoproteins • phospholipids • enterocytes

Abbreviations: apoB, apolipoprotein B; CM, chylomicron; ER, endoplasmic reticulum; MTP, microsomal triglyceride transfer protein; OA, oleic acid; PL81, Pluronic L81; TC, taurocholate; TG, triacylglycerol

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