| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 273, Issue 41, 26388-26393, October 9, 1998
§,,,§¶,
,, and§**
From the The molecular mechanisms of hypertriglyceridemia
(HTG), a common lipid metabolic disorder in humans, often of genetic
origin, are not well understood. In studying the effect of
apolipoprotein (apo) E on the metabolism of triglyceride-rich
lipoproteins, we found that expressing high plasma levels of human
apoE3 in transgenic mice lacking endogenous mouse apoE caused
HTG. These transgenic animals had 3-fold higher plasma
triglyceride levels, higher very low density lipoproteins (VLDL), and
lower high density lipoproteins than did nontransgenics. Removing one
or both low density lipoprotein receptor alleles in the
apoE3-overexpressing mice caused severe HTG (8-11-fold over
nontransgenics) and increased VLDL and decreased low and high density
lipoproteins, and apoE3-enriched VLDL were markedly depleted in
apoC-II. At least two mechanisms could explain HTG associated with
apoE3 overexpression: stimulated VLDL triglyceride production and
impaired VLDL lipolysis. The apoE3 mice with HTG had a 50% increase in
hepatic VLDL triglyceride production. Furthermore, overexpression of
apoE (E2, E3, or E4) in cultured hepatocytes (McA-RH7777 cells)
correlated positively with secretion of VLDL into the medium. However,
apoE3 overexpression-associated HTG was only partially explained by
VLDL overproduction, as lipoprotein lipase-mediated VLDL lipolysis was
also decreased 20-86% depending on apoE3 levels, most likely by
displacing or masking apoC-II on the particles. In human subjects, HTG
correlated positively with increased VLDL triglyceride and plasma and
VLDL apoE levels. However, plasma and VLDL apoE correlated negatively
with VLDL apoC-II levels and lipoprotein lipase-mediated VLDL
lipolysis. Thus, optimal expression of apoE is crucial for normal
metabolism of triglyceride-rich lipoproteins, and overexpression and/or
accumulation of apoE may contribute to HTG by stimulating VLDL
triglyceride production and by impairing VLDL lipolysis. The
apoE3-overexpressing mice will be useful for studying the
pathophysiology of this disorder.
Gladstone Institute of Cardiovascular
Disease, § Cardiovascular Research Institute, and the
Departments of ¶ Physiology, ** Medicine, and
Pathology, University of California, San Francisco,
California 94141-9100 and the Institute of Arteriosclerosis
Research, University of Münster,
Münster D-48129, Germany
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Parini, U. Gustafsson, M. A. Davis, L. Larsson, C. Einarsson, M. Wilson, M. Rudling, H. Tomoda, S. Omura, S. Sahlin, et al. Cholesterol Synthesis Inhibition Elicits an Integrated Molecular Response in Human Livers Including Decreased ACAT2 Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1200 - 1206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. A. Moen, A. P. Tholens, P. J. Voshol, W. de Haan, L. M. Havekes, P. Gargalovic, A. J. Lusis, K. W. van Dyk, R. R. Frants, M. H. Hofker, et al. The Hyplip2 locus causes hypertriglyceridemia by decreased clearance of triglycerides J. Lipid Res., October 1, 2007; 48(10): 2182 - 2192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Drosatos, D. Sanoudou, K. E. Kypreos, D. Kardassis, and V. I. Zannis A Dominant Negative Form of the Transcription Factor c-Jun Affects Genes That Have Opposing Effects on Lipid Homeostasis in Mice J. Biol. Chem., July 6, 2007; 282(27): 19556 - 19564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Gusarova, J. Seo, M. L. Sullivan, S. C. Watkins, J. L. Brodsky, and E. A. Fisher Golgi-associated Maturation of Very Low Density Lipoproteins Involves Conformational Changes in Apolipoprotein B, but Is Not Dependent on Apolipoprotein E J. Biol. Chem., July 6, 2007; 282(27): 19453 - 19462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Westerterp, W. de Haan, J. F. P. Berbee, L. M. Havekes, and P. C. N. Rensen Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL J. Lipid Res., June 1, 2006; 47(6): 1203 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Kypreos and V. I. Zannis LDL receptor deficiency or apoE mutations prevent remnant clearance and induce hypertriglyceridemia in mice J. Lipid Res., March 1, 2006; 47(3): 521 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-S. Ji, K. Mullendorff, I. H. Cheng, R. D. Miranda, Y. Huang, and R. W. Mahley Reactivity of Apolipoprotein E4 and Amyloid beta Peptide: LYSOSOMAL STABILITY AND NEURODEGENERATION J. Biol. Chem., February 3, 2006; 281(5): 2683 - 2692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ramaswamy, Q. Xu, Y. Huang, and K. H. Weisgraber Effect of Domain Interaction on Apolipoprotein E Levels in Mouse Brain J. Neurosci., November 16, 2005; 25(46): 10658 - 10663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Zern and M. L. Fernandez Cardioprotective Effects of Dietary Polyphenols J. Nutr., October 1, 2005; 135(10): 2291 - 2294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Zern, R. J. Wood, C. Greene, K. L. West, Y. Liu, D. Aggarwal, N. S. Shachter, and M. L. Fernandez Grape Polyphenols Exert a Cardioprotective Effect in Pre- and Postmenopausal Women by Lowering Plasma Lipids and Reducing Oxidative Stress J. Nutr., August 1, 2005; 135(8): 1911 - 1917. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gerritsen, P. C. N. Rensen, K. E. Kypreos, V. I. Zannis, L. M. Havekes, and K. Willems van Dijk ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression J. Lipid Res., July 1, 2005; 46(7): 1466 - 1473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Kypreos, K. W. van Dijk, L. M. Havekes, and V. I. Zannis Generation of a Recombinant Apolipoprotein E Variant with Improved Biological Functions: HYDROPHOBIC RESIDUES (LEU-261, TRP-264, PHE-265, LEU-268, VAL-269) OF apoE CAN ACCOUNT FOR THE apoE-INDUCED HYPERTRIGLYCERIDEMIA J. Biol. Chem., February 25, 2005; 280(8): 6276 - 6284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Heeren, T. Grewal, A. Laatsch, N. Becker, F. Rinninger, K.-A. Rye, and U. Beisiegel Impaired Recycling of Apolipoprotein E4 Is Associated with Intracellular Cholesterol Accumulation J. Biol. Chem., December 31, 2004; 279(53): 55483 - 55492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Harris, W. J. Brecht, Q. Xu, R. W. Mahley, and Y. Huang Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase: MODULATION BY ZINC J. Biol. Chem., October 22, 2004; 279(43): 44795 - 44801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Liberopoulos, G. Miltiadous, M. Hatzivassiliou, N. Ayrton, E. Bairaktari, M. Cariolou, and M. Elisaf Apolipoprotein E Polymorphism in Northwestern Greece: Frequency and Effect on Lipid Parameters Ann. Clin. Lab. Sci., July 1, 2004; 34(3): 347 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ikewaki, W. Cain, F. Thomas, R. Shamburek, L. A. Zech, D. Usher, H. B. Brewer Jr., and D. J. Rader Abnormal in vivo metabolism of apoB-containing lipoproteins in human apoE deficiency J. Lipid Res., July 1, 2004; 45(7): 1302 - 1311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xu, W. J. Brecht, K. H. Weisgraber, R. W. Mahley, and Y. Huang Apolipoprotein E4 Domain Interaction Occurs in Living Neuronal Cells as Determined by Fluorescence Resonance Energy Transfer J. Biol. Chem., June 11, 2004; 279(24): 25511 - 25516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Brecht, F. M. Harris, S. Chang, I. Tesseur, G.-Q. Yu, Q. Xu, J. Dee Fish, T. Wyss-Coray, M. Buttini, L. Mucke, et al. Neuron-Specific Apolipoprotein E4 Proteolysis Is Associated with Increased Tau Phosphorylation in Brains of Transgenic Mice J. Neurosci., March 10, 2004; 24(10): 2527 - 2534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Harris, I. Tesseur, W. J. Brecht, Q. Xu, K. Mullendorff, S. Chang, T. Wyss-Coray, R. W. Mahley, and Y. Huang Astroglial Regulation of Apolipoprotein E Expression in Neuronal Cells: IMPLICATIONS FOR ALZHEIMER'S DISEASE J. Biol. Chem., January 30, 2004; 279(5): 3862 - 3868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zabalawi, S. Bhat, T. Loughlin, M. J. Thomas, E. Alexander, M. Cline, B. Bullock, M. Willingham, and M. G. Sorci-Thomas Induction of Fatal Inflammation in LDL Receptor and ApoA-I Double-Knockout Mice Fed Dietary Fat and Cholesterol Am. J. Pathol., September 1, 2003; 163(3): 1201 - 1213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Vu-Dac, P. Gervois, H. Jakel, M. Nowak, E. Bauge, H. Dehondt, B. Staels, L. A. Pennacchio, E. M. Rubin, J. Fruchart-Najib, et al. Apolipoprotein A5, a Crucial Determinant of Plasma Triglyceride Levels, Is Highly Responsive to Peroxisome Proliferator-activated Receptor alpha Activators J. Biol. Chem., May 9, 2003; 278(20): 17982 - 17985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vega-Lopez, H. C. Freake, and M. L. Fernandez Sex and Hormonal Status Modulate the Effects of Psyllium on Plasma Lipids and Monocyte Gene Expression in Humans J. Nutr., January 1, 2003; 133(1): 67 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. R. Hopkins, Y. Huang, J. G. McGuire, and R. E. Pitas Evidence for differential effects of apoE3 and apoE4 on HDL metabolism J. Lipid Res., November 1, 2002; 43(11): 1881 - 1889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Cohn, M. Tremblay, R. Batal, H. Jacques, L. Veilleux, C. Rodriguez, P. H. R. Barrett, D. Dubreuil, M. Roy, L. Bernier, et al. Effect of atorvastatin on plasma apoE metabolism in patients with combined hyperlipidemia J. Lipid Res., September 1, 2002; 43(9): 1464 - 1471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Hinsdale, P. M. Sullivan, H. Mezdour, and N. Maeda ApoB-48 and apoB-100 differentially influence the expression of type-III hyperlipoproteinemia in APOE*2 mice J. Lipid Res., September 1, 2002; 43(9): 1520 - 1528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-S. Ji, R. D. Miranda, Y. M. Newhouse, K. H. Weisgraber, Y. Huang, and R. W. Mahley Apolipoprotein E4 Potentiates Amyloid beta Peptide-induced Lysosomal Leakage and Apoptosis in Neuronal Cells J. Biol. Chem., June 7, 2002; 277(24): 21821 - 21828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Van Eck, I. S. T. Bos, W. E. Kaminski, E. Orso, G. Rothe, J. Twisk, A. Bottcher, E. S. Van Amersfoort, T. A. Christiansen-Weber, W.-P. Fung-Leung, et al. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues PNAS, April 30, 2002; 99(9): 6298 - 6303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Raffai and K. H. Weisgraber Hypomorphic Apolipoprotein E Mice. A NEW MODEL OF CONDITIONAL GENE REPAIR TO EXAMINE APOLIPOPROTEIN E-MEDIATED METABOLISM J. Biol. Chem., March 22, 2002; 277(13): 11064 - 11068. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Eichner, S. T. Dunn, G. Perveen, D. M. Thompson, K. E. Stewart, and B. C. Stroehla Apolipoprotein E Polymorphism and Cardiovascular Disease: A HuGE Review Am. J. Epidemiol., March 15, 2002; 155(6): 487 - 495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Elam, H. G. Wilcox, L. M. Cagen, X. Deng, R. Raghow, P. Kumar, M. Heimberg, and J. C. Russell Increased hepatic VLDL secretion, lipogenesis, and SREBP-1 expression in the corpulent JCR:LA-cp rat J. Lipid Res., December 1, 2001; 42(12): 2039 - 2048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Pennacchio, M. Olivier, J. A. Hubacek, J. C. Cohen, D. R. Cox, J.-C. Fruchart, R. M. Krauss, and E. M. Rubin An Apolipoprotein Influencing Triglycerides in Humans and Mice Revealed by Comparative Sequencing Science, October 5, 2001; 294(5540): 169 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hirano, T. Takahashi, S. Saito, H. Tajima, T. Ebara, and M. Adachi Apoprotein C-III deficiency markedly stimulates triglyceride secretion in vivo: comparison with apoprotein E Am J Physiol Endocrinol Metab, October 1, 2001; 281(4): E665 - E669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Campos, D. Perlov, C. Khoo, and F. M. Sacks Distinct patterns of lipoproteins with apoB defined by presence of apoE or apoC-III in hypercholesterolemia and hypertriglyceridemia J. Lipid Res., August 1, 2001; 42(8): 1239 - 1249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Mensenkamp, B. Teusink, J. F.W. Baller, H. Wolters, R. Havinga, K. W. van Dijk, L. M. Havekes, and F. Kuipers Mice Expressing Only the Mutant APOE3Leiden Gene Show Impaired VLDL Secretion Arterioscler. Thromb. Vasc. Biol., August 1, 2001; 21(8): 1366 - 1372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-a. Kawashiri, Y. Zhang, D. Usher, M. Reilly, E. Puré, and D. J. Rader Effects of coexpression of the LDL receptor and apoE on cholesterol metabolism and atherosclerosis in LDL receptor-deficient mice J. Lipid Res., June 1, 2001; 42(6): 943 - 950. [Abstract] [Full Text]
|
|
|
|
 |
|
 F. M. Sacks, P. Alaupovic, L. A. Moye, T. G. Cole, B. Sussex, M. J. Stampfer, M. A. Pfeffer, and E. Braunwald VLDL, Apolipoproteins B, CIII, and E, and Risk of Recurrent Coronary Events in the Cholesterol and Recurrent Events (CARE) Trial Circulation, October 17, 2000; 102(16): 1886 - 1892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Maugeais, U. J. F. Tietge, K. Tsukamoto, J. M. Glick, and D. J. Rader Hepatic apolipoprotein E expression promotes very low density lipoprotein-apolipoprotein B production in vivo in mice J. Lipid Res., October 1, 2000; 41(10): 1673 - 1679. [Abstract] [Full Text]
|
|
|
|
|
|
F. de Beer, K. W. van Dijk, M. C. Jong, L. C. van Vark, A. van der Zee, M. H. Hofker, F. J. Fallaux, R. C. Hoeben, A. H. M. Smelt, and L. M. Havekes Apolipoprotein E2 (Lys146->Gln) Causes Hypertriglyceridemia due to an Apolipoprotein E Variant-Specific Inhibition of Lipolysis of Very Low Density Lipoproteins-Triglycerides Arterioscler. Thromb. Vasc. Biol., July 1, 2000; 20(7): 1800 - 1806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. N. Rensen, M. C. Jong, L. C. van Vark, H. van der Boom, W. L. Hendriks, T. J. C. van Berkel, E. A. L. Biessen, and L. M. Havekes Apolipoprotein E Is Resistant to Intracellular Degradation in Vitro and in Vivo. EVIDENCE FOR RETROENDOCYTOSIS J. Biol. Chem., March 17, 2000; 275(12): 8564 - 8571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tsukamoto, C. Maugeais, J. M. Glick, and D. J. Rader Markedly increased secretion of VLDL triglycerides induced by gene transfer of apolipoprotein E isoforms in apoE-deficient mice J. Lipid Res., February 1, 2000; 41(2): 253 - 259. [Abstract] [Full Text]
|
|
|
|
|
|
A. R Mensenkamp, M. C Jong, H. van Goor, M. J. A. van Luyn, V. Bloks, R. Havinga, P. J. Voshol, M. H. Hofker, K. W. van Dijk, L. M. Havekes, et al. Apolipoprotein E Participates in the Regulation of Very Low Density Lipoprotein-Triglyceride Secretion by the Liver J. Biol. Chem., December 10, 1999; 274(50): 35711 - 35718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kako, L.-S. Huang, J. Yang, T. Katopodis, R. Ramakrishnan, and I. J. Goldberg Streptozotocin-induced diabetes in human apolipoprotein B transgenic mice: effects on lipoproteins and atherosclerosis J. Lipid Res., December 1, 1999; 40(12): 2185 - 2194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. van Dijk, B. J.M. van Vlijmen, M. P.J. de Winther, B. van ’t Hof, A. van der Zee, H. van der Boom, L. M. Havekes, and M. H. Hofker Hyperlipidemia of ApoE2(Arg158-Cys) and ApoE3-Leiden Transgenic Mice Is Modulated Predominantly by LDL Receptor Expression Arterioscler. Thromb. Vasc. Biol., December 1, 1999; 19(12): 2945 - 2951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Huang, Z.-S. Ji, W. J. Brecht, S. C. Rall Jr, J. M. Taylor, and R. W. Mahley Overexpression of Apolipoprotein E3 in Transgenic Rabbits Causes Combined Hyperlipidemia by Stimulating Hepatic VLDL Production and Impairing VLDL Lipolysis Arterioscler. Thromb. Vasc. Biol., December 1, 1999; 19(12): 2952 - 2959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Mahley, Y. Huang, and S. C. Rall , Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes J. Lipid Res., November 1, 1999; 40(11): 1933 - 1949. [Abstract] [Full Text]
|
|
|
|
|
|
D. Rees, T. Sloane, W. Jessup, R. T. Dean, and L. Kritharides Apolipoprotein A-I Stimulates Secretion of Apolipoprotein E by Foam Cell Macrophages J. Biol. Chem., September 24, 1999; 274(39): 27925 - 27933. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Tangirala, D. Pratico, G. A. FitzGerald, S. Chun, K. Tsukamoto, C. Maugeais, D. C. Usher, E. Pure, and D. J. Rader Reduction of Isoprostanes and Regression of Advanced Atherosclerosis by Apolipoprotein E J. Biol. Chem., January 5, 2001; 276(1): 261 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Kypreos, K. W. van Dijk, A. van der Zee, L. M. Havekes, and V. I. Zannis Domains of Apolipoprotein E Contributing to Triglyceride and Cholesterol Homeostasis in Vivo. CARBOXYL-TERMINAL REGION 203-299 PROMOTES HEPATIC VERY LOW DENSITY LIPOPROTEIN-TRIGLYCERIDE SECRETION J. Biol. Chem., June 1, 2001; 276(23): 19778 - 19786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Van Eck, I. S. T. Bos, W. E. Kaminski, E. Orso, G. Rothe, J. Twisk, A. Bottcher, E. S. Van Amersfoort, T. A. Christiansen-Weber, W.-P. Fung-Leung, et al. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues PNAS, April 30, 2002; 99(9): 6298 - 6303. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
