Original Article

Determination of the lower threshold of apolipoprotein E resulting in remnant lipoprotein clearance

Correspondence to: MacRae F. Linton

Correspondence to: Sergio Fazio

Apolipoprotein E (apoE) is the ligand for receptor-mediated clearance of remnant lipoproteins. ApoE at concentrations only 10% of normal, achieved through transplantation of wild-type marrow into apoE(-/-) mice, is sufficient for the maintenance of normal serum lipid and lipoprotein levels. The goal of the present study was to identify the minimal concentration of serum apoE still affecting cholesterol levels, and to determine whether any effects on remnant clearance below this level of apoE were detectable. ApoE(+/+) marrow was mixed with apoE(-/-) marrow in proportions of 1, 5, 10, and 25% to make chimeric mice with serum levels of apoE ranging from 0.005 to 0.46 mg/dl. Analysis of serum cholesterol and apoE levels demonstrated a positive correlation between apoE levels and cholesterol reduction (r = 0.83), with levels of 0.04 mg/dl representing the functional threshold level. There were no differences in lipoprotein profiles and clearance between apoE(-/-) mice and mice with serum apoE of less than 0.04 mg/dl, as assessed by FPLC, non-denaturing gel electrophoresis, and turnover studies. However, electron microscopy of negative stains showed fewer lipoprotein particles with a diameter of <30 nm in the serum of these mice compared to apoE(-/-) mice.

These data demonstrate that the threshold of serum apoE resulting in cholesterol reduction is 0.04 mg/dl, and indicate that apoE below this level affects lipoprotein size distribution possibly by accelerating the clearance of smaller remnants.—Hasty, A. H., M. F. Linton, L. L. Swift, and S. Fazio. Determination of the lower threshold of apolipoprotein E resulting in remnant lipoprotein clearance. J. Lipid Res. 1999. 40: 1529;–1538.

Supplementary key words: apolipoprotein E, remnant lipoproteins, cholesterol, bone marrow transplantation

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

This article has been cited by other articles:

				M. Moerland, H. Samyn, T. van Gent, R. van Haperen, G. Dallinga-Thie, F. Grosveld, A. van Tol, and R. de Crom Acute Elevation of Plasma PLTP Activity Strongly Increases Pre-existing Atherosclerosis Arterioscler. Thromb. Vasc. Biol., July 1, 2008; 28(7): 1277 - 1282. [Abstract] [Full Text] [PDF]

				L. Nelbach, X. Shu, R. J. Konrad, R. O. Ryan, and T. M. Forte Effect of apolipoprotein A-V on plasma triglyceride, lipoprotein size, and composition in genetically engineered mice J. Lipid Res., March 1, 2008; 49(3): 572 - 580. [Abstract] [Full Text] [PDF]

				R. D. Atkinson, K. R. Coenen, M. R. Plummer, M. L. Gruen, and A. H. Hasty Macrophage-derived apolipoprotein E ameliorates dyslipidemia and atherosclerosis in obese apolipoprotein E-deficient mice Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E284 - E290. [Abstract] [Full Text] [PDF]

				P. Rao, Z. H. Huang, and T. Mazzone Angiotensin II Regulates Adipocyte Apolipoprotein E Expression J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4366 - 4372. [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]

				G. Fantuzzi and T. Mazzone Adipose Tissue and Atherosclerosis: Exploring the Connection Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 996 - 1003. [Abstract] [Full Text] [PDF]

				D. Wu, H. Yang, W. Xiang, L. Zhou, M. Shi, G. Julies, J. M. LaPlante, B. R. Ballard, and Z. Guo Heterozygous mutation of ataxia-telangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice J. Lipid Res., July 1, 2005; 46(7): 1380 - 1387. [Abstract] [Full Text] [PDF]

				H. Yang, L. J. Roberts, M. J. Shi, L. C. Zhou, B. R. Ballard, A. Richardson, and Z. M. Guo Retardation of Atherosclerosis by Overexpression of Catalase or Both Cu/Zn-Superoxide Dismutase and Catalase in Mice Lacking Apolipoprotein E Circ. Res., November 26, 2004; 95(11): 1075 - 1081. [Abstract] [Full Text] [PDF]

				L. Yue, N. Rasouli, G. Ranganathan, P. A. Kern, and T. Mazzone Divergent Effects of Peroxisome Proliferator-activated Receptor {gamma} Agonists and Tumor Necrosis Factor {alpha} on Adipocyte ApoE Expression J. Biol. Chem., November 12, 2004; 279(46): 47626 - 47632. [Abstract] [Full Text] [PDF]

				H. Wientgen, F. E. Thorngate, S. Omerhodzic, L. Rolnitzky, J. T. Fallon, D. L. Williams, and E. A. Fisher Subphysiologic Apolipoprotein E (ApoE) Plasma Levels Inhibit Neointimal Formation After Arterial Injury in ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1460 - 1465. [Abstract] [Full Text] [PDF]

				R. L. Raffai, A. H. Hasty, Y. Wang, S. E. Mettler, D. A. Sanan, M. F. Linton, S. Fazio, and K. H. Weisgraber Hepatocyte-derived ApoE Is More Effective than Non-hepatocyte-derived ApoE in Remnant Lipoprotein Clearance J. Biol. Chem., March 21, 2003; 278(13): 11670 - 11675. [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]

				G. PERLEMUTER, A. SABILE, P. LETTERON, G. VONA, A. TOPILCO, Y. CHRETIEN, K. KOIKE, D. PESSAYRE, J. CHAPMAN, G. BARBA, et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis FASEB J, February 1, 2002; 16(2): 185 - 194. [Abstract] [Full Text] [PDF]

				J. D. Harris, I. R. Graham, S. Schepelmann, A. K. Stannard, M. L. Roberts, B. L. Hodges, V. Hill, A. Amalfitano, D. G. Hassall, J. S. Owen, et al. Acute regression of advanced and retardation of early aortic atheroma in immunocompetent apolipoprotein-E (apoE) deficient mice by administration of a second generation [E1-, E3-, polymerase-] adenovirus vector expressing human apoE Hum. Mol. Genet., January 1, 2002; 11(1): 43 - 58. [Abstract] [Full Text] [PDF]

				I.-H. Kim, A. Jozkowicz, P. A. Piedra, K. Oka, and L. Chan Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector PNAS, October 25, 2001; (2001) 241506298. [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]

				N. Ishimori, K. Iwabuchi, S. Fujii, K. Watano, C. Iwabuchi, M. Ato, H. Chiba, S. Tanaka, A. Kitabatake, and K. Onoé Mixed allogeneic chimerism with wild-type strains ameliorates atherosclerosis in apolipoprotein E-deficient mice J. Leukoc. Biol., May 1, 2001; 69(5): 732 - 740. [Abstract] [Full Text]

				T. Athanasopoulos, J. S. Owen, D. Hassall, M. G. Dunckley, J. Drew, J. Goodman, A. D. Tagalakis, D. R. Riddell, and G. Dickson Intramuscular injection of a plasmid vector expressing human apolipoprotein E limits progression of xanthoma and aortic atheroma in apoE-deficient mice Hum. Mol. Genet., October 1, 2000; 9(17): 2545 - 2551. [Abstract] [Full Text] [PDF]

				L. K. Curtiss ApoE in Atherosclerosis : A Protein With Multiple Hats Arterioscler. Thromb. Vasc. Biol., August 1, 2000; 20(8): 1852 - 1853. [Full Text] [PDF]

				F. E. Thorngate, L. L. Rudel, R. L. Walzem, and D. L. Williams Low Levels of Extrahepatic Nonmacrophage ApoE Inhibit Atherosclerosis Without Correcting Hypercholesterolemia in ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2000; 20(8): 1939 - 1945. [Abstract] [Full Text] [PDF]

				I.-H. Kim, A. Jozkowicz, P. A. Piedra, K. Oka, and L. Chan Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector PNAS, November 6, 2001; 98(23): 13282 - 13287. [Abstract] [Full Text] [PDF]