VLDL lipolysis products increase VLDL fluidity and convert apolipoprotein E4 into a more expanded conformation

Department of Plant Sciences, School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India.
The Journal of Lipid Research (Impact Factor: 4.42). 12/2009; 51(6):1273-83. DOI: 10.1194/jlr.M000406
Source: PubMed

ABSTRACT Our previous work indicated that apolipoprotein (apo) E4 assumes a more expanded conformation in the postprandial period. The postprandial state is characterized by increased VLDL lipolysis. In this article, we tested the hypothesis that VLDL lipolysis products increase VLDL particle fluidity, which mediates expansion of apoE4 on the VLDL particle. Plasma from healthy subjects was collected before and after a moderately high-fat meal and incubated with nitroxyl-spin labeled apoE. ApoE conformation was examined by electron paramagnetic resonance spectroscopy using targeted spin probes on cysteines introduced in the N-terminal (S76C) and C-terminal (A241C) domains. Further, we synthesized a novel nitroxyl spin-labeled cholesterol analog, which gave insight into lipoprotein particle fluidity. Our data revealed that the order of lipoprotein fluidity was HDL approximately LDL<VLDL<VLDL+lipoprotein lipase. Moreover, the conformation of apoE4 depended on the lipoprotein fraction: VLDL-associated apoE4 had a more linear conformation than apoE4 associated with LDL or HDL. Further, by changing VLDL fluidity, VLDL lipolysis products significantly altered apoE4 into a more expanded conformation. Our studies indicate that after every meal, VLDL fluidity is increased causing apoE4 associated with VLDL to assume a more expanded conformation, potentially enhancing the pathogenicity of apoE4 in vascular tissue.

Download full-text


Available from: Madhu S Budamagunta, Sep 15, 2014
1 Follower
44 Reads
  • Source
    • "Second, lipolysis products from VLDL, such as free fatty acids, could counteract the actions of LPS. We have recently shown that lipolysis of postprandial VLDL generates approximately two-fold more non-esterified fatty acids than lipolysis of fasting VLDL [42], and that these fatty acids alone induce pro-inflammatory gene expression from THP-1 monocytes [43]. Third, VLDL lipolysis products may differ in their composition when released from fasting or postprandial VLDL, yielding a net greater anti-inflammatory effect when monocytes are treated with fasting VLDL lipolysis products and LPS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Postprandial hyperlipemia, characterized by increased circulating very low-density lipoproteins (VLDL) and circulating lipopolysaccharide (LPS), has been proposed as a mechanism of vascular injury. Our goal was to examine the interactions between postprandial lipoproteins, LPS, and apoE3 and apoE4 on monocyte activation. We showed that apoE3 complexed to phospholipid vesicles attenuates LPS-induced THP-1 monocyte cytokine expression, while apoE4 increases expression. ELISA revealed that apoE3 binds to LPS with higher affinity than apoE4. Electron paramagnetic resonance (EPR) spectroscopy of site-directed spin labels placed on specific amino acids of apoE3 showed that LPS interferes with conformational changes normally associated with lipid binding. Specifically, compared to apoE4, apoE bearing the E3-like R112→Ser mutation displays increased self association when exposed to LPS, consistent with a stronger apoE3-LPS interaction. Additionally, lipolysis of fasting VLDL from normal human donors attenuated LPS-induced TNFα secretion from monocytes to a greater extent than postprandial VLDL, an effect partially reversed by blocking apoE. This effect was reproduced using fasting VLDL lipolysis products from e3/e3 donors, but not from e4/e4 subjects, suggesting that apoE3 on fasting VLDL prevents LPS-induced inflammation more readily than apoE4. Postprandial apoE isoform and conformational changes associated with VLDL dramatically modulate vascular inflammation.
    PLoS ONE 11/2012; 7(11):e50513. DOI:10.1371/journal.pone.0050513 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Many applications today need compact, low-profile, small, lightweight and low-cost antennas. Microstrip patch antennas meet these requirements which made them very popular. Two main techniques exist to achieve circular polarization in patch antennas. The first consists in creating an asymmetry in the patch shape in order to excite two orthogonal linear modes. The second technique consists in exciting two orthogonal linear modes using two separate feeds. Single fed asymmetrically shaped patch antennas have poor axial ratio bandwidths (ARB) typically smaller than 1% (AR < 3 dB). The disadvantage of the double fed antennas is the relatively large size of the feed network. We present a new concept for single fed circularly polarized microstrip patch antennas with an improved ARB
    Antennas and Propagation Society International Symposium, 2001. IEEE; 02/2001
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: AD (Alzheimer's disease) is a progressive neurodegenerative disease of unknown origin. Despite questions as to the underlying cause(s) of this disease, shared risk factors for both AD and atherosclerotic cardiovascular disease indicate that vascular mechanisms may critically contribute to the development and progression of both AD and atherosclerosis. An increased risk of developing AD is linked to the presence of the apoE4 (apolipoprotein E4) allele, which is also strongly associated with increased risk of developing atherosclerotic cardiovascular disease. Recent studies also indicate that cardiovascular risk factors, including elevated blood cholesterol and triacylglycerol (triglyceride), increase the likelihood of AD and vascular dementia. Lipids and lipoproteins in the circulation interact intimately with the cerebrovasculature, and may have important effects on its constituent brain microvascular endothelial cells and the adjoining astrocytes, which are components of the neurovascular unit. The present review will examine the potential mechanisms for understanding the contributions of vascular factors, including lipids, lipoproteins and cerebrovascular Abeta (amyloid beta), to AD, and suggest therapeutic strategies for the attenuation of this devastating disease process. Specifically, we will focus on the actions of apoE, TGRLs (triacylglycerol-rich lipoproteins) and TGRL lipolysis products on injury of the neurovascular unit and increases in blood-brain barrier permeability.
    Clinical Science 11/2010; 119(10):407-21. DOI:10.1042/CS20100094 · 5.60 Impact Factor
Show more