Transgenic mouse models to study the role of APOE in hyperlipidemia and atherosclerosis.

Transgenic technologies have provided a series of very useful mouse models to study hyperlipidemia and atherosclerosis. Normally, mice carry cholesterol mainly in the high density lipoprotein (HDL) sized lipoproteins, and have low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol levels. These low LDL and VLDL levels are due to the very rapid metabolism of remnant clearance in mice, which hamper metabolic studies. In addition, due to the lack of atherogenic lipoproteins, mice will not readily develop atherosclerosis. This situation has changed completely, because to date, most known genes in lipoprotein metabolism have been used in transgenesis to obtain mice in which genes have been silenced or overexpressed. These experiments have yielded many mouse strains with high plasma lipid levels and a greater susceptibility for developing atherosclerosis. One of the most widely used strains are knock-out mice deficient for apoE, which is one of the central players in VLDL metabolism. Subsequently, a wide variety of other transgenic studies involving APOE have been performed elucidating the role of apoE and apoE mutants in lipolysis, remnant clearance, cellular cholesterol efflux and atherogenesis. In addition, the APOE mouse models are excellent tools for the development of gene therapy for hyperlipidemias.

[1]  L. Havekes,et al.  Quantitative assessment of aortic atherosclerosis in APOE*3 Leiden transgenic mice and its relationship to serum cholesterol exposure. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[2]  J. Taylor,et al.  In the absence of a downstream element, the apolipoprotein E gene is expressed at high levels in kidneys of transgenic mice. , 1990, The Journal of biological chemistry.

[3]  M. Katsuki,et al.  Overexpression of apolipoprotein E in transgenic mice: marked reduction in plasma lipoproteins except high density lipoprotein and resistance against diet-induced hypercholesterolemia. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[4]  B. Wieringa,et al.  Inactivation of Apoe and Apoc1 by two consecutive rounds of gene targeting: effects on mRNA expression levels of gene cluster members. , 1995, Human molecular genetics.

[5]  J. Qiao,et al.  Immune-deficient mice develop typical atherosclerotic fatty streaks when fed an atherogenic diet. , 1994, The Journal of clinical investigation.

[6]  B. Paigen,et al.  Comparison of atherosclerotic lesions and HDL-lipid levels in male, female, and testosterone-treated female mice from strains C57BL/6, BALB/c, and C3H. , 1987, Atherosclerosis.

[7]  J. Taylor,et al.  Altered lipoprotein metabolism in transgenic mice expressing low levels of a human receptor-binding-defective apolipoprotein E variant. , 1994, Journal of lipid research.

[8]  R. Ross,et al.  ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[9]  L. Curtiss,et al.  Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by bone marrow transplantation. , 1995, The Journal of clinical investigation.

[10]  M. Katsuki,et al.  Plasma lipoprotein metabolism in transgenic mice overexpressing apolipoprotein E. Accelerated clearance of lipoproteins containing apolipoprotein B. , 1992, The Journal of clinical investigation.

[11]  P. de Knijff,et al.  Apolipoprotein E as a risk factor for coronary heart disease: a genetic and molecular biology approach , 1996, Current opinion in lipidology.

[12]  S. Fazio,et al.  Type III hyperlipoproteinemic phenotype in transgenic mice expressing dysfunctional apolipoprotein E. , 1993, The Journal of clinical investigation.

[13]  A. Lusis.  Genetic factors affecting blood lipoproteins: the candidate gene approach. , 1988, Journal of lipid research.

[14]  N. Maeda,et al.  Diet-induced atherosclerosis in mice heterozygous and homozygous for apolipoprotein E gene disruption. , 1994, The Journal of clinical investigation.

[15]  R. Mahley,et al.  Hypolipidemic and Hyperlipidemic Phenotypes in Transgenic Mice Expressing Human Apolipoprotein E2* , 1996, The Journal of Biological Chemistry.

[16]  T. Mazzone.  Apolipoprotein E secretion by macrophages: its potential physiological functions , 1996, Current opinion in lipidology.

[17]  M. Linton,et al.  Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Taylor,et al.  Evolutionary Duplication of a Hepatic Control Region in the Human Apolipoprotein E Gene Locus , 1995, The Journal of Biological Chemistry.

[19]  S. Fazio,et al.  Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation , 1995, Science.

[20]  P. de Knijff,et al.  Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree. , 1991, The Journal of clinical investigation.

[21]  H. Brewer,et al.  Apolipoprotein E deficiency in mice: gene replacement and prevention of atherosclerosis using adenovirus vectors. , 1995, The Journal of clinical investigation.

[22]  R. Frants,et al.  Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice. , 1994, The Journal of clinical investigation.

[23]  Yukiko Kurihara,et al.  A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection , 1997, Nature.

[24]  A. vonEckardstein.  Cholesterol efflux from macrophages and other cells. , 1996 .

[25]  D. Rader,et al.  Liver-directed gene transfer and prolonged expression of three major human ApoE isoforms in ApoE-deficient mice. , 1997, The Journal of clinical investigation.

[26]  C. Luo,et al.  The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution. , 1988, Journal of lipid research.

[27]  R. Frants,et al.  Evolutionary conservation of the mouse apolipoprotein e-c1-c2 gene cluster: structure and genetic variability in inbred mice. , 1993, Genomics.

[28]  J. D. Smith,et al.  T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[29]  E. Rubin,et al.  Effect of human apoE4 on the clearance of chylomicron-like lipid emulsions and atherogenesis in transgenic mice. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[30]  J. Taylor,et al.  Overexpression of human apolipoprotein C-III in transgenic mice results in an accumulation of apolipoprotein B48 remnants that is corrected by excess apolipoprotein E. , 1994, The Journal of biological chemistry.

[31]  N. Maeda,et al.  Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[32]  R. Frants,et al.  The apolipoprotein C2-linked (Acl) gene: a new gene within the mouse apolipoprotein e-c1-c2 gene cluster. , 1994, Genomics.

[33]  L. Havekes,et al.  Atypical xanthomatosis in apolipoprotein E-deficient mice after cholesterol feeding. , 1995, Atherosclerosis.

[34]  J. Taylor,et al.  Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice. , 1995, The Journal of clinical investigation.

[35]  B. Wieringa,et al.  Diet-induced hypercholesterolemia and atherosclerosis in heterozygous apolipoprotein E-deficient mice. , 1994, Atherosclerosis.

[36]  E. Rubin,et al.  Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. , 1994, The Journal of clinical investigation.

[37]  J. Breslow,et al.  Overexpression of apolipoprotein CII causes hypertriglyceridemia in transgenic mice. , 1994, The Journal of clinical investigation.

[38]  J. Breslow,et al.  Accumulation of human apolipoprotein E in the plasma of transgenic mice. , 1990, The Journal of biological chemistry.

[39]  T. V. van Berkel,et al.  Apolipoprotein E Effectively Inhibits Lipoprotein Lipase-mediated Lipolysis of Chylomicron-like Triglyceride-rich Lipid Emulsions in Vitro and in Vivo* , 1996, The Journal of Biological Chemistry.

[40]  J. Breslow,et al.  Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl. , 1996, The Journal of clinical investigation.

[41]  R. Frants,et al.  Modulation of very low density lipoprotein production and clearance contributes to age- and gender- dependent hyperlipoproteinemia in apolipoprotein E3-Leiden transgenic mice. , 1996, The Journal of clinical investigation.

[42]  T. Willnow,et al.  Inhibition of hepatic chylomicron remnant uptake by gene transfer of a receptor antagonist. , 1994, Science.

[43]  N. Maeda,et al.  Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[44]  A. Roberts,et al.  Inbred mice and their hypbrids as an animal model for atherosclerosis research. , 1976, Advances in experimental medicine and biology.

[45]  A. Tall,et al.  A Mouse Model with Features of Familial Combined Hyperlipidemia , 1997, Science.

[46]  A. Lusis,et al.  Genetic factors in lipoprotein metabolism. Analysis of a genetic cross between inbred mouse strains NZB/BINJ and SM/J using a complete linkage map approach. , 1995, The Journal of clinical investigation.

[47]  Michael Ginsberg,et al.  Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[48]  M. Kay,et al.  Assessment of recombinant adenoviral vectors for hepatic gene therapy. , 1993, Human gene therapy.

[49]  R. Frants,et al.  Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia. , 1993, The Journal of biological chemistry.

[50]  E M Rubin,et al.  Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. , 1995, Journal of lipid research.

[51]  R. Mahley,et al.  Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3. Structure and genetics of an apolipoprotein E3 variant. , 1989, The Journal of clinical investigation.

[52]  R. Frants,et al.  Both lipolysis and hepatic uptake of VLDL are impaired in transgenic mice coexpressing human apolipoprotein E*3Leiden and human apolipoprotein C1. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[53]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[54]  K. Reue,et al.  Evolution of apolipoprotein E: mouse sequence and evidence for an 11-nucleotide ancestral unit. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[55]  M. Katsuki,et al.  Hepatic and renal expression of rat apolipoprotein E under control of the metallothionein promotor in transgenic mice , 1991 .

[56]  K. V. van Dijk,et al.  In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway. , 1996, The Journal of clinical investigation.

[57]  J. Taylor,et al.  Expression of a novel human apolipoprotein (apoC-IV) causes hypertriglyceridemia in transgenic mice. , 1996, Journal of lipid research.

[58]  S. Young,et al.  Increased autoantibody titers against epitopes of oxidized LDL in LDL receptor-deficient mice with increased atherosclerosis. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[59]  M. Freeman,et al.  Type I macrophage scavenger receptor contains α-helical and collagen-like coiled coils , 1990, Nature.

[60]  R. Mahley,et al.  Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein. , 1990, The Journal of biological chemistry.

[61]  J. Taylor,et al.  A far-downstream hepatocyte-specific control region directs expression of the linked human apolipoprotein E and C-I genes in transgenic mice. , 1993, The Journal of biological chemistry.

[62]  N. Maeda,et al.  Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. , 1992, Science.

[63]  P. Libby,et al.  Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. , 1997, The American journal of pathology.

[64]  K. V. van Dijk,et al.  In the Absence of Endogenous Mouse Apolipoprotein E, Apolipoprotein E*2(Arg-158 → Cys) Transgenic Mice Develop More Severe Hyperlipoproteinemia than Apolipoprotein E*3-Leiden Transgenic Mice* , 1996, The Journal of Biological Chemistry.

[65]  V. Ord,et al.  ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[66]  R. Gerard,et al.  Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[67]  R. Mahley,et al.  Susceptibility to diet-induced atherosclerosis in transgenic mice expressing a dysfunctional human apolipoprotein E(Arg 112,Cys142). , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[68]  J. Taylor,et al.  Identification and characterization of a new human gene (APOC4) in the apolipoprotein E, C-I, and C-II gene locus. , 1995, Genomics.

[69]  L. Havekes,et al.  Uptake by J774 macrophages of very-low-density lipoproteins isolated from apoE-deficient mice is mediated by a distinct receptor and stimulated by lipoprotein lipase. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[70]  M. Katsuki,et al.  Inhibition of diet-induced atheroma formation in transgenic mice expressing apolipoprotein E in the arterial wall. , 1995, The Journal of clinical investigation.

[71]  E. Schaefer,et al.  Type III hyperlipoproteinemia associated with apolipoprotein E deficiency. , 1981, Science.

[72]  B. Paigen,et al.  Synthetic low and high fat diets for the study of atherosclerosis in the mouse. , 1990, Journal of lipid research.

[73]  K. Rajewsky,et al.  Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting , 1993, Cell.

[74]  J. Breslow,et al.  Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. , 1990, Science.

[75]  P. de Knijff,et al.  Apolipoprotein E*3-Leiden allele results from a partial gene duplication in exon 4. , 1989, Biochemical and biophysical research communications.

[76]  N. Maeda,et al.  Targeted Replacement of the Mouse Apolipoprotein E Gene with the Common Human APOE3 Allele Enhances Diet-induced Hypercholesterolemia and Atherosclerosis* , 1997, The Journal of Biological Chemistry.

[77]  Y. Zhu,et al.  Localization of a liver-specific enhancer in the apolipoprotein E/C-I/C-II gene locus. , 1993, Journal of lipid research.

[78]  A. Lusis,et al.  Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[79]  A. Mcclelland,et al.  Phenotypic correction of hypercholesterolemia in apoE-deficient mice by adenovirus-mediated in vivo gene transfer. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[80]  J. Taylor,et al.  Multiple tissue-specific elements control the apolipoprotein E/C-I gene locus in transgenic mice. , 1991, The Journal of biological chemistry.

[81]  P. Elias,et al.  Apolipoprotein E deficiency leads to cutaneous foam cell formation in mice. , 1995, The Journal of investigative dermatology.

[82]  K. Weisgraber,et al.  Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121-127. , 1989, The Journal of biological chemistry.