Abstract
Transgenic mice were prepared that expressed a dysfunctional apo E variant, apo E (Arg-112, Cys-142), which is associated with dominant inheritance of type III hyperlipoproteinemia (type III HLP) in humans. Among eight founder mice, plasma apo E (Arg-112, Cys-142) levels varied 100-fold and directly correlated with plasma cholesterol and triglyceride levels. On a normal chow diet, mice expressing high levels (> 70 mg/dl) of the dysfunctional apo E had grossly elevated plasma lipids, with cholesterol levels of up to 410 mg/dl and triglyceride levels of up to 1,210 mg/dl. Upon agarose electrophoresis, plasma from these mice demonstrated beta-very low density lipoproteins (beta-VLDL). Mice expressing low (< 2.5 mg/dl) or intermediate (21 mg/dl) levels of the apo E variant had much less severe hyperlipidemia and did not have beta-VLDL. Although the transgenic mouse beta-VLDL were enriched in cholesteryl esters compared with normal mouse VLDL, they were not as cholesterol enriched as human beta-VLDL from type III HLP subjects. Transgenic mouse beta-VLDL injected into normal mice were cleared from plasma at a significantly slower rate than normal mouse VLDL, demonstrating the impaired catabolism of beta-VLDL. Thus, transgenic mice expressing high levels of the dysfunctional apo E (Arg-112, Cys-142) variant have many characteristics of the human type III HLP phenotype and appear to be a suitable animal model for this disorder.
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- Bilheimer D. W., Eisenberg S., Levy R. I. The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972 Feb 21;260(2):212–221. doi: 10.1016/0005-2760(72)90034-3. [DOI] [PubMed] [Google Scholar]
- Boyles J. K., Zoellner C. D., Anderson L. J., Kosik L. M., Pitas R. E., Weisgraber K. H., Hui D. Y., Mahley R. W., Gebicke-Haerter P. J., Ignatius M. J. A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J Clin Invest. 1989 Mar;83(3):1015–1031. doi: 10.1172/JCI113943. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fazio S., Yao Z., McCarthy B. J., Rall S. C., Jr Synthesis and secretion of apolipoprotein E occur independently of synthesis and secretion of apolipoprotein B-containing lipoproteins in HepG2 cells. J Biol Chem. 1992 Apr 5;267(10):6941–6945. [PubMed] [Google Scholar]
- Gregg R. E., Zech L. A., Schaefer E. J., Stark D., Wilson D., Brewer H. B., Jr Abnormal in vivo metabolism of apolipoprotein E4 in humans. J Clin Invest. 1986 Sep;78(3):815–821. doi: 10.1172/JCI112645. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Havel R. J., Kotite L., Kane J. P., Tun P., Bersot T. Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3. J Clin Invest. 1983 Jul;72(1):379–387. doi: 10.1172/JCI110978. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Horie Y., Fazio S., Westerlund J. R., Weisgraber K. H., Rall S. C., Jr The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia. J Biol Chem. 1992 Jan 25;267(3):1962–1968. [PubMed] [Google Scholar]
- Hussain M. M., Maxfield F. R., Más-Oliva J., Tabas I., Ji Z. S., Innerarity T. L., Mahley R. W. Clearance of chylomicron remnants by the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem. 1991 Jul 25;266(21):13936–13940. [PubMed] [Google Scholar]
- Jiao S., Cole T. G., Kitchens R. T., Pfleger B., Schonfeld G. Genetic heterogeneity of lipoproteins in inbred strains of mice: analysis by gel-permeation chromatography. Metabolism. 1990 Feb;39(2):155–160. doi: 10.1016/0026-0495(90)90069-o. [DOI] [PubMed] [Google Scholar]
- Kane J. P. Apolipoprotein B: structural and metabolic heterogeneity. Annu Rev Physiol. 1983;45:637–650. doi: 10.1146/annurev.ph.45.030183.003225. [DOI] [PubMed] [Google Scholar]
- Kowal R. C., Herz J., Weisgraber K. H., Mahley R. W., Brown M. S., Goldstein J. L. Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein. J Biol Chem. 1990 Jun 25;265(18):10771–10779. [PubMed] [Google Scholar]
- Lusis A. J., Taylor B. A., Quon D., Zollman S., LeBoeuf R. C. Genetic factors controlling structure and expression of apolipoproteins B and E in mice. J Biol Chem. 1987 Jun 5;262(16):7594–7604. [PubMed] [Google Scholar]
- Mabuchi H., Itoh H., Takeda M., Kajinami K., Wakasugi T., Koizumi J., Takeda R., Asagami C. A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency. Metabolism. 1989 Feb;38(2):115–119. doi: 10.1016/0026-0495(89)90249-7. [DOI] [PubMed] [Google Scholar]
- Mahley R. W., Innerarity T. L. Lipoprotein receptors and cholesterol homeostasis. Biochim Biophys Acta. 1983 May 24;737(2):197–222. doi: 10.1016/0304-4157(83)90001-1. [DOI] [PubMed] [Google Scholar]
- Marotti K. R., Castle C. K., Murray R. W., Rehberg E. F., Polites H. G., Melchior G. W. The role of cholesteryl ester transfer protein in primate apolipoprotein A-I metabolism. Insights from studies with transgenic mice. Arterioscler Thromb. 1992 Jun;12(6):736–744. doi: 10.1161/01.atv.12.6.736. [DOI] [PubMed] [Google Scholar]
- McLean J. W., Elshourbagy N. A., Chang D. J., Mahley R. W., Taylor J. M. Human apolipoprotein E mRNA. cDNA cloning and nucleotide sequencing of a new variant. J Biol Chem. 1984 May 25;259(10):6498–6504. [PubMed] [Google Scholar]
- Plump A. S., Smith J. D., Hayek T., Aalto-Setälä K., Walsh A., Verstuyft J. G., Rubin E. M., Breslow J. L. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343–353. doi: 10.1016/0092-8674(92)90362-g. [DOI] [PubMed] [Google Scholar]
- Rall S. C., Jr, Mahley R. W. The role of apolipoprotein E genetic variants in lipoprotein disorders. J Intern Med. 1992 Jun;231(6):653–659. doi: 10.1111/j.1365-2796.1992.tb01254.x. [DOI] [PubMed] [Google Scholar]
- Rall S. C., Jr, Newhouse Y. M., Clarke H. R., Weisgraber K. H., McCarthy B. J., Mahley R. W., Bersot T. P. Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3. Structure and genetics of an apolipoprotein E3 variant. J Clin Invest. 1989 Apr;83(4):1095–1101. doi: 10.1172/JCI113988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schaefer E. J., Gregg R. E., Ghiselli G., Forte T. M., Ordovas J. M., Zech L. A., Brewer H. B., Jr Familial apolipoprotein E deficiency. J Clin Invest. 1986 Nov;78(5):1206–1219. doi: 10.1172/JCI112704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shimano H., Yamada N., Katsuki M., Shimada M., Gotoda T., Harada K., Murase T., Fukazawa C., Takaku F., Yazaki Y. Overexpression of apolipoprotein E in transgenic mice: marked reduction in plasma lipoproteins except high density lipoprotein and resistance against diet-induced hypercholesterolemia. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1750–1754. doi: 10.1073/pnas.89.5.1750. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shimano H., Yamada N., Katsuki M., Yamamoto K., Gotoda T., Harada K., Shimada M., Yazaki Y. Plasma lipoprotein metabolism in transgenic mice overexpressing apolipoprotein E. Accelerated clearance of lipoproteins containing apolipoprotein B. J Clin Invest. 1992 Nov;90(5):2084–2091. doi: 10.1172/JCI116091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Simonet W. S., Bucay N., Lauer S. J., Wirak D. O., Stevens M. E., Weisgraber K. H., Pitas R. E., Taylor J. M. In the absence of a downstream element, the apolipoprotein E gene is expressed at high levels in kidneys of transgenic mice. J Biol Chem. 1990 Jul 5;265(19):10809–10812. [PubMed] [Google Scholar]
- Simonet W. S., Bucay N., Pitas R. E., Lauer S. J., Taylor J. M. Multiple tissue-specific elements control the apolipoprotein E/C-I gene locus in transgenic mice. J Biol Chem. 1991 May 15;266(14):8651–8654. [PubMed] [Google Scholar]
- Tall A. R. Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. J Clin Invest. 1990 Aug;86(2):379–384. doi: 10.1172/JCI114722. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weisgraber K. H. Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 112. J Lipid Res. 1990 Aug;31(8):1503–1511. [PubMed] [Google Scholar]
- Weisgraber K. H., Mahley R. W., Kowal R. C., Herz J., Goldstein J. L., Brown M. S. Apolipoprotein C-I modulates the interaction of apolipoprotein E with beta-migrating very low density lipoproteins (beta-VLDL) and inhibits binding of beta-VLDL to low density lipoprotein receptor-related protein. J Biol Chem. 1990 Dec 25;265(36):22453–22459. [PubMed] [Google Scholar]
- Zhang S. H., Reddick R. L., Piedrahita J. A., Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992 Oct 16;258(5081):468–471. doi: 10.1126/science.1411543. [DOI] [PubMed] [Google Scholar]