Pluronic L81 enhances triacylglycerol accumulation in the cytoplasm, diminishes microsomal triglyceride transfer activity and inhibits chylomicron secretion

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

Anatomy and Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203

Corresponding Author: mhussain{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 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 secretion of chylomicrons (CM), 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 mainly occurred 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 and phospholipids as part of CM. PL81 treated cells showed decreased activity of microsomal triglyceride transfer protein and accumulated more triacylglycerols, 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 triacylglycerol transport to the endoplasmic reticulum and increase drug efficacy against cancer cells by competing for their excretion.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

D. Cheng, J. Iqbal, J. Devenny, C.-H. Chu, L. Chen, J. Dong, R. Seethala, W. J. Keim, A. V. Azzara, R. M. Lawrence, et al.
Acylation of Acylglycerols by Acyl Coenzyme A:Diacylglycerol Acyltransferase 1 (DGAT1): FUNCTIONAL IMPORTANCE OF DGAT1 IN THE INTESTINAL FAT ABSORPTION
J. Biol. Chem., October 31, 2008; 283(44): 29802 - 29811.
[Abstract] [Full Text] [PDF]

X. Pan, F. N. Hussain, J. Iqbal, M. H. Feuerman, and M. M. Hussain
Inhibiting Proteasomal Degradation of Microsomal Triglyceride Transfer Protein Prevents CCl4-induced Steatosis
J. Biol. Chem., June 8, 2007; 282(23): 17078 - 17089.
[Abstract] [Full Text] [PDF]

All ASBMB Journals	Journal of Biological Chemistry
Molecular and Cellular Proteomics	ASBMB Today

				X. Pan, F. N. Hussain, J. Iqbal, M. H. Feuerman, and M. M. Hussain Inhibiting Proteasomal Degradation of Microsomal Triglyceride Transfer Protein Prevents CCl4-induced Steatosis J. Biol. Chem., June 8, 2007; 282(23): 17078 - 17089. [Abstract] [Full Text] [PDF]