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Papers In Press, published online ahead of print April 1, 2007
J. Lipid Res., doi:10.1194/jlr.M600201-JLR200

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Journal of Lipid Research, Vol. 48, 806-815, April 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

High-fat/high-cholesterol diet promotes a S1P receptor-mediated antiapoptotic activity for VLDL

Mirta Mihovilovic^1,*,, Jennifer B. Robinette^*,, Robert M. DeKroon^*,, Patrick M. Sullivan and Warren J. Strittmatter^*,,

^* Deane Laboratory, Duke University Medical Center, Durham, NC 27710
Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC 27710
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of 3 figures.

Published, JLR Papers in Press, January 30, 2007.

¹ To whom correspondence should be addressed. e-mail: mihov001{at}mc.duke.edu

Withdrawing growth factors or serum from endothelial cells leads to the activation of effector caspases 3 and 7, resulting in apoptotic cell death. HDL protects against caspase induction through sphingosine-1-phosphate (S1P) receptors. This anti-caspase activity of HDL is antagonized by VLDL from apolipoprotein E4 (apoE4) (genotype, APOE4/4; apolipoprotein, apoE) targeted replacement (TR) mice, but not by VLDL from TR APOE3/3 mice, and requires the binding of apoE4-VLDL to an LDL receptor family member. In the absence of HDL, apoE4-VLDL and apoE3-VLDL from TR mice have limited antiapoptotic activity. In contrast, we show here that a high-fat/high-cholesterol/cholate diet (HFD) radically alters this biological activity of VLDL. On HFD, both apoE3-VLDL and apoE4-VLDL (HFD VLDL) inhibit caspase 3/7 activation initiated by serum withdrawal. This activity of HFD VLDL is independent of an LDL receptor family member but requires the activation of S1P₃ receptors, as shown by the ability of pharmacological block of S1P receptors by VPC 23019 and by small interfering RNA-mediated downregulation of S1P₃ receptors to inhibit HFD VLDL anticaspase activity.

Supplementary key words apolipoprotein E • high density lipoprotein • sphingosine-1-phosphate • atherosclerosis • endothelial cells • very low density lipoprotein

Abbreviations: apoE, apolipoprotein E; EDG, endothelial differentiation gene; FCS, fetal calf serum; HFD, high-fat/high-cholesterol/cholate diet; HUVEC, human umbilical vein endothelial cell; RAP, receptor-associated protein; SFM, serum-free medium; siRNA, small interfering RNA; S1P, sphingosine-1-phosphate; SR-BI, scavenger receptor class B type I; TR, targeted replacement

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