Hypomorphic Apolipoprotein E Mice

In creating an allelic variant of mouse Apoe designed to resemble human apolipoprotein E4 (apoE4), we generated hypomorphic apoE (hypoE) mice that express only ∼5% of normal apoE mRNA levels in all tissues. Insertion of a neo cassette flanked by loxP sites in the third intron of Apoe reduced expression of the Arg-61 allelic variant in hypoE mice and resulted in plasma apoE levels that were ∼2–5% of normal. Unlike other mouse models with low levels of circulating apoE, hypoE mice had a nearly normal lipoprotein cholesterol profile when fed a chow diet. Further reduction of apoE expression in hypoE/Apoe−/− heterozygous mice led to an increase in remnant lipoprotein-associated cholesterol levels, demonstrating that hypoE mice express close to the threshold level of Arg-61 apoE required for a normal lipoprotein profile. Unlike wild type mice, hypoE mice were susceptible to diet-induced hypercholesterolemia, which was fully reversed within 3 weeks after resumption of a chow diet. In Mx1-Cre transgenic hypoE mice, plasma apoE levels returned to normal within 10 days after gene repair and removal of the neo cassette following induction of Cre recombinase. HypoE mice provide the opportunity for conditional gene repair by crossing with inducible or lineage/cell type-specific Cre transgenic mice, generating new models to dissect the roles of apoE in atherosclerosis regression, immunoregulation, and neurodegeneration. In creating an allelic variant of mouse Apoe designed to resemble human apolipoprotein E4 (apoE4), we generated hypomorphic apoE (hypoE) mice that express only ∼5% of normal apoE mRNA levels in all tissues. Insertion of a neo cassette flanked by loxP sites in the third intron of Apoe reduced expression of the Arg-61 allelic variant in hypoE mice and resulted in plasma apoE levels that were ∼2–5% of normal. Unlike other mouse models with low levels of circulating apoE, hypoE mice had a nearly normal lipoprotein cholesterol profile when fed a chow diet. Further reduction of apoE expression in hypoE/Apoe−/− heterozygous mice led to an increase in remnant lipoprotein-associated cholesterol levels, demonstrating that hypoE mice express close to the threshold level of Arg-61 apoE required for a normal lipoprotein profile. Unlike wild type mice, hypoE mice were susceptible to diet-induced hypercholesterolemia, which was fully reversed within 3 weeks after resumption of a chow diet. In Mx1-Cre transgenic hypoE mice, plasma apoE levels returned to normal within 10 days after gene repair and removal of the neo cassette following induction of Cre recombinase. HypoE mice provide the opportunity for conditional gene repair by crossing with inducible or lineage/cell type-specific Cre transgenic mice, generating new models to dissect the roles of apoE in atherosclerosis regression, immunoregulation, and neurodegeneration. Apolipoprotein E (apoE) 1The abbreviations used are: apoapolipoproteinLDLlow density lipoprotein(s)VLDLvery low density lipoprotein(s)HDLhigh density lipoprotein(s)WTwild typeneoneomycinFPLCfast performance liquid chromatographyhypoEhypomorphic apoEpIpCpolyinosinic-polycytidylic ribonucleic acid is an important structural and functional protein component of lipoproteins that plays a prominent role in lipid metabolism in plasma and in the central nervous system (1.Mahley R.W. Science. 1988; 240: 622-630Crossref PubMed Scopus (3465) Google Scholar, 2.Weisgraber K.H. Mahley R.W. FASEB J. 1996; 10: 1485-1494Crossref PubMed Scopus (279) Google Scholar). As a high affinity ligand for the low density lipoprotein (LDL) receptor, the LDL receptor-related protein, and heparan sulfate proteoglycans, apoE mediates the uptake of plasma remnant lipoproteins by the liver (3.Mahley R.W. Ji Z.-S. J. Lipid Res. 1999; 40: 1-16Abstract Full Text Full Text PDF PubMed Google Scholar, 4.Cooper A.D. J. Lipid Res. 1997; 38: 2173-2192Abstract Full Text PDF PubMed Google Scholar). In addition, apoE participates in diverse biological processes, such as intracellular cholesterol utilization (5.Reyland M.E. Williams D.L. J. Biol. Chem. 1991; 266: 21099-21104Abstract Full Text PDF PubMed Google Scholar), cell growth (6.Ishigami M. Swertfeger D.K. Granholm N.A. Hui D.Y. J. Biol. Chem. 1998; 273: 20156-20161Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar), immunoregulation (7.Avila E.M. Holdsworth G. Sasaki N. Jackson R.L. Harmony J.A.K. J. Biol. Chem. 1982; 257: 5900-5909Abstract Full Text PDF PubMed Google Scholar, 8.Hui D.Y. Harmony J.A.K. Innerarity T.L. Mahley R.W. J. Biol. Chem. 1980; 255: 11775-11781Abstract Full Text PDF PubMed Google Scholar, 9.Pepe M.G. Curtiss L.K. J. Immunol. 1986; 136: 3716-3723PubMed Google Scholar), and neuronal growth and repair (2.Weisgraber K.H. Mahley R.W. FASEB J. 1996; 10: 1485-1494Crossref PubMed Scopus (279) Google Scholar). apolipoprotein low density lipoprotein(s) very low density lipoprotein(s) high density lipoprotein(s) wild type neomycin fast performance liquid chromatography hypomorphic apoE polyinosinic-polycytidylic ribonucleic acid Tissue-specific control elements in the Apoe gene restrict its expression to hepatocytes (10.Allan C.M. Taylor S. Taylor J.M. J. Biol. Chem. 1997; 272: 29113-29119Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar), astrocytes (11.Grehan S. Tse E. Taylor J.M. J. Neurosci. 2001; 21: 812-822Crossref PubMed Google Scholar), skin fibroblasts (12.Grehan S. Allan C. Tse E. Walker D. Taylor J.M. J. Invest. Dermatol. 2001; 116: 77-84Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar), adipocytes, and macrophages (13.Shih S.-J. Allan C. Grehan S. Tse E. Moran C. Taylor J.M. J. Biol. Chem. 2000; 275: 31567-31572Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Hepatocyte-derived apoE, the major source of plasma apoE (14.Linton M.F. Gish R. Hubl S.T. Bütler E. Esquivel C. Bry W.I. Boyles J.K. Wardell M.R. Young S.G. J. Clin. Invest. 1991; 88: 270-281Crossref PubMed Scopus (301) Google Scholar), is responsible for receptor-mediated uptake of remnant lipoproteins in the liver by the secretion-capture pathway (15.Ji Z.-S. Fazio S. Lee Y.-L. Mahley R.W. J. Biol. Chem. 1994; 269: 2764-2772Abstract Full Text PDF PubMed Google Scholar, 16.Shimano H. Namba Y. Ohsuga J. Kawamura M. Yamamoto K. Shimada M. Gotoda T. Harada K. Yazaki Y. Yamada N. J. Clin. Invest. 1994; 93: 2215-2223Crossref PubMed Scopus (54) Google Scholar). ApoE secreted by hepatocytes into the space of Disse associates with incoming remnant lipoproteins and with heparan sulfate proteoglycans bound to hepatic sinusoidal surfaces. This local enrichment in apoE facilitates remnant clearance through receptor-mediated processes. In the brain, astrocytes are the major source of apoE, which serves in lipid homeostasis in the central nervous system (17.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. Shooter E.M. J. Clin. Invest. 1989; 83: 1015-1031Crossref PubMed Scopus (455) Google Scholar, 18.Pitas R.E. Boyles J.K. Lee S.H. Hui D. Weisgraber K.H. J. Biol. Chem. 1987; 262: 14352-14360Abstract Full Text PDF PubMed Google Scholar, 19.Pitas R.E. Boyles J.K. Lee S.H. Foss D. Mahley R.W. Biochim. Biophys. Acta. 1987; 917: 148-161Crossref PubMed Scopus (584) Google Scholar). Macrophage-derived apoE promotes remnant lipoprotein uptake and retards the development of atherosclerosis in Apoe−/− mice (20.Linton M.F. Atkinson J.B. Fazio S. Science. 1995; 267: 1034-1037Crossref PubMed Scopus (417) Google Scholar, 21.Boisvert W.A. Spangenberg J. Curtiss L.K. J. Clin. Invest. 1995; 96: 1118-1124Crossref PubMed Scopus (188) Google Scholar, 22.Bellosta S. Mahley R.W. Sanan D.A. Murata J. Newland D.L. Taylor J.M. Pitas R.E. J. Clin. Invest. 1995; 96: 2170-2179Crossref PubMed Scopus (253) Google Scholar). ApoE also participates in the regression of atherosclerosis (23.Tsukamoto K. Tangirala R. Chun S.H. Puré E. Rader D.J. Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2162-2170Crossref PubMed Scopus (98) Google Scholar, 24.Desurmont C. Caillaud J.-M. Emmanuel F. Benoit P. Fruchart J.C. Castro G. Branellec D. Heard J.-M. Duverger N. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 435-442Crossref PubMed Scopus (58) Google Scholar), contributes to the production of very low density lipoprotein (VLDL) triglycerides (25.Kuipers F. Jong M.C. Lin Y. van Eck M. Havinga R. Bloks V. Verkade H.J. Hofker M.H. Moshage H. van Berkel T.J.C. Vonk R.J. Havekes L.M. J. Clin. Invest. 1997; 100: 2915-2922Crossref PubMed Scopus (150) Google Scholar,26.Huang Y. Liu X.Q. Rall Jr., S.C. Taylor J.M. von Eckardstein A. Assmann G. Mahley R.W. J. Biol. Chem. 1998; 273: 26388-26393Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar), impairs VLDL-triglyceride lipolysis (27.Huang Y. Ji Z.-S. Brecht W.J. Rall Jr., S.C. Taylor J.M. Mahley R.W. Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2952-2959Crossref PubMed Scopus (78) Google Scholar), and enhances the production of VLDL-apoB (28.Maugeais C. Tietge U.J.F. Tsukamoto K. Glick J.M. Rader D.J. J. Lipid Res. 2000; 41: 1673-1679Abstract Full Text Full Text PDF PubMed Google Scholar). In addition, apoE has been suggested to participate in the regulation of inflammatory immune responses that protect against bacterial infection (29.Mahley R.W. Rall Jr., S.C. Annu. Rev. Genomics Hum. Genet. 2000; 1: 507-537Crossref PubMed Scopus (1367) Google Scholar) and to act as an antioxidant to protect against atherosclerosis (30.Tangirala R.K. Praticó D. FitzGerald G.A. Chun S. Tsukamoto K. Maugeais C. Usher D.C. Puré E. Rader D.J. J. Biol. Chem. 2001; 276: 261-266Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). The transplantation of wild type (WT) bone marrow into Apoe−/− mice as a source of non-liver-derived apoE demonstrated that levels of plasma apoE equivalent to 10% of normal are sufficient to reduce plasma cholesterol levels to a normal range (20.Linton M.F. Atkinson J.B. Fazio S. Science. 1995; 267: 1034-1037Crossref PubMed Scopus (417) Google Scholar, 21.Boisvert W.A. Spangenberg J. Curtiss L.K. J. Clin. Invest. 1995; 96: 1118-1124Crossref PubMed Scopus (188) Google Scholar, 31.Hasty A.H. Linton M.F. Swift L.L. Fazio S. J. Lipid Res. 1999; 40: 1529-1538Abstract Full Text Full Text PDF PubMed Google Scholar). In transgenic Apoe−/− mice expressing WT apoE in the adrenal gland, 3% but not 1% of normal plasma apoE levels substantially reduced plasma cholesterol levels (32.Thorngate F.E. Rudel L.L. Walzem R.L. Williams D.L. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1939-1945Crossref PubMed Scopus (109) Google Scholar). However, in the bone marrow transplantation model, low levels of apoE failed to restore a normal plasma lipoprotein profile. Unlike WT mice, which transport ∼75–80% of their plasma cholesterol in high density lipoproteins (HDL), Apoe−/− mice transplanted with WT bone marrow and expressing 2–5% of plasma apoE transport ∼30%-40% of their plasma cholesterol in HDL (31.Hasty A.H. Linton M.F. Swift L.L. Fazio S. J. Lipid Res. 1999; 40: 1529-1538Abstract Full Text Full Text PDF PubMed Google Scholar). Recently, we generated an allelic variant of murine apoE, Arg-61, by gene targeting (33.Raffaı̈ R.L. Dong L.-M. Farese Jr., R.V. Weisgraber K.H. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 11587-11591Crossref PubMed Scopus (156) Google Scholar). The targeting vector included a floxed neomycin (neo) cassette in the third intron to follow the mutation. Removal of the neo cassette by Cre-mediated recombination resulted in normal apoE expression levels. However, its retention resulted in hypomorphic apoE (hypoE) mice. HypoE mice express reduced levels of apoE mRNA (∼5% of normal) in all tissues examined, giving rise to ∼2–5% of normal apoE levels in plasma. Other examples of hypomorphic genes created in mice by inserting a neo cassette into an intron have been described (34.Carmeliet P. Ferreira V. Breier G. Pollefeyt S. Kieckens L. Gertsenstein M. Fahrig M. Vandenhoeck A. Harpal K. Eberhardt C. Declercq C. Pawling J. Moons L. Collen D. Risau W. Nagy A. Nature. 1996; 380: 435-439Crossref PubMed Scopus (3506) Google Scholar, 35.Jacks T. Shih T.S. Schmitt E.M. Bronson R.T. Bernards A. Weinberg R.A. Nat. Genet. 1994; 7: 353-361Crossref PubMed Scopus (652) Google Scholar, 36.Meyers E.N. Lewandoski M. Martin G.R. Nat. Genet. 1998; 18: 136-141Crossref PubMed Scopus (893) Google Scholar, 37.Nagy A. Moens C. Ivanyi E. Pawling J. Gertsenstein M. Hadjantonakis A.-K. Pirity M. Rossant J. Curr. Biol. 1998; 8: 661-664Abstract Full Text Full Text PDF PubMed Google Scholar, 38.Mohn A.R. Gainetdinov R.R. Caron M.G. Koller B.H. Cell. 1999; 98: 427-436Abstract Full Text Full Text PDF PubMed Scopus (921) Google Scholar). Here we report that the hypoE mice have a nearly normal lipoprotein profile when fed a chow diet, but they are very susceptible to diet-induced hypercholesterolemia. The hypercholesterolemia can be reversed in Mx1-Cre transgenic hypoE mice by removing the neo cassette following induction of Cre recombinase with polyinosinic-polycytidylic ribonucleic acid (pIpC). This induction results in restoration of normal levels of plasma apoE. Thus, hypoE mice are a new model of reduced apoE expression that provide into the roles of apoE. hypoE mice a opportunity to the role of expression of apoE by was used to for the mouse equivalent of human as described (33.Raffaı̈ R.L. Dong L.-M. Farese Jr., R.V. Weisgraber K.H. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 11587-11591Crossref PubMed Scopus (156) Google Scholar). mice a in which intron 3 a neo cassette flanked by loxP were with mice to heterozygous mice were to mice. The mice were days of and in a with a they were fed a chow mice were with inducible Mx1-Cre transgenic mice A. M. R.E. J. J. Clin. Invest. 1998; PubMed Scopus Google Scholar). Cre expression was in Mx1-Cre transgenic mice with a of A. M. R.E. J. J. Clin. Invest. 1998; PubMed Scopus Google Scholar, R. F. M. K. Science. 1995; 269: PubMed Scopus Google Scholar). tissues and with was in a 1% to and to a mouse apoE with in The was in and for and to of the was with a mouse were with a and and lipoproteins were in mice that had been for and by were by fast performance liquid chromatography a and plasma was by and levels in plasma and were with and was with the mouse plasma was to with or and to was with against mouse apoE (33.Raffaı̈ R.L. Dong L.-M. Farese Jr., R.V. Weisgraber K.H. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 11587-11591Crossref PubMed Scopus (156) Google Scholar) and against mouse and were mouse LDL mouse plasma by density were with of mouse LDL in were with in were with a of and bound was by a were generated by with and to were with a and hypercholesterolemia, mice were fed a high or the for 3 The hypoE mice expressing reduced levels of apoE were generated by recombination in neo cassette flanked by loxP sites was into 3 to follow the of the human equivalent of by an (33.Raffaı̈ R.L. Dong L.-M. Farese Jr., R.V. Weisgraber K.H. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 11587-11591Crossref PubMed Scopus (156) Google Scholar). cell were into and mice were with mice to mice that were heterozygous for the neo cassette mice were to hypoE mice The apoE mRNA levels in the brain, and in hypoE mice were ∼5% of in WT mice, a for the reduced expression of the Other and tissues that express low levels of apoE The plasma apoE levels in hypoE mice were ∼2–5% of in WT mice mice levels, and hypoE mice were used to the lipoprotein In mice, the plasma cholesterol and levels were in hypoE mice in WT mice However, the lipoprotein cholesterol were in and Arg-61 mice HypoE mice had cholesterol in the density and LDL lipoprotein the WT mice. of the plasma cholesterol in the hypoE mice was with as in WT mice in WT This is in to Apoe−/− mice to express levels of apoE ∼2–5% of WT (31.Hasty A.H. Linton M.F. Swift L.L. Fazio S. J. Lipid Res. 1999; 40: 1529-1538Abstract Full Text Full Text PDF PubMed Google Scholar). In mice, a of plasma cholesterol is with and LDL and only of plasma cholesterol is with HDL (31.Hasty A.H. Linton M.F. Swift L.L. Fazio S. J. Lipid Res. 1999; 40: 1529-1538Abstract Full Text Full Text PDF PubMed Google Scholar). the nearly normal lipoprotein profile in hypoE mice by plasma lipoprotein wild type and hypoE mice fed a chow density density in a new As by hypoE mice had levels of and levels of in plasma WT mice The hypoE mice and Apoe−/− mice had very levels of in WT mice as by In hypoE mice had WT mice. The of a reduction in apoE expression lipoprotein metabolism was by crossing hypoE and Apoe−/− mice. mice not have plasma cholesterol and levels hypoE mice and However, plasma cholesterol as remnant lipoproteins hypoE mice results that hypoE mice express close to the of apoE required to a nearly normal lipoprotein profile. the of hypoE mice to diet-induced hypercholesterolemia was a high hypoE mice had plasma levels of cholesterol and WT mice. an increase of in the HDL and in hypoE mice In the the of all of remnant lipoproteins in hypoE mice, and their plasma cholesterol and levels were of WT mice and responses to have been in other mouse models of low level apoE expression (20.Linton M.F. Atkinson J.B. Fazio S. Science. 1995; 267: 1034-1037Crossref PubMed Scopus (417) Google Scholar, 21.Boisvert W.A. Spangenberg J. Curtiss L.K. J. Clin. Invest. 1995; 96: 1118-1124Crossref PubMed Scopus (188) Google Scholar). The hypercholesterolemia in hypoE mice was fully reversed 3 weeks after resumption of a chow results that hypoE mice are susceptible to diet-induced hypercholesterolemia WT mice and that very lipoprotein and plasma lipid levels can be of diet-induced hypercholesterolemia in mice. were the for 3 mice was and by mice were returned to a chow for 3 and plasma mice was by to the lipoprotein are have demonstrated that removal of the neo cassette the Apoe by crossing hypoE mice with transgenic mice resulted in of the hypomorphic (33.Raffaı̈ R.L. Dong L.-M. Farese Jr., R.V. Weisgraber K.H. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 11587-11591Crossref PubMed Scopus (156) Google Scholar). of apoE mRNA in mice are to WT in the brain, and and plasma lipid levels and lipoprotein are (33.Raffaı̈ R.L. Dong L.-M. Farese Jr., R.V. Weisgraber K.H. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 11587-11591Crossref PubMed Scopus (156) Google Scholar). the of conditional gene repair plasma lipid we hypoE mice with inducible Mx1-Cre transgenic mice. of mice has been demonstrated to to Cre-mediated recombination in the liver and bone marrow A. M. R.E. J. J. Clin. Invest. 1998; PubMed Scopus Google Scholar, R. F. M. K. Science. 1995; 269: PubMed Scopus Google Scholar). Mx1-Cre transgenic hypoE mice had plasma apoE levels to of hypoE mice, and they were susceptible to diet-induced hypercholesterolemia of of in Mx1-Cre transgenic hypoE mice plasma apoE levels within and normal plasma apoE levels were within 10 days of plasma apoE levels reversed diet-induced hypercholesterolemia, in a plasma cholesterol level of and a WT lipoprotein profile in mice This that a neo cassette flanked by loxP sites into Apoe intron 3 to a human allelic variant results in mice with reduced apoE mRNA expression in all tissues. The of a variant a major of has been as an for the hypomorphic in other models T. Shih T.S. Schmitt E.M. Bronson R.T. Bernards A. Weinberg R.A. Nat. Genet. 1994; 7: 353-361Crossref PubMed Scopus (652) Google Scholar, 36.Meyers E.N. Lewandoski M. Martin G.R. Nat. Genet. 1998; 18: 136-141Crossref PubMed Scopus (893) Google Scholar, 37.Nagy A. Moens C. Ivanyi E. Pawling J. Gertsenstein M. Hadjantonakis A.-K. Pirity M. Rossant J. Curr. Biol. 1998; 8: 661-664Abstract Full Text Full Text PDF PubMed Google Scholar). plasma apoE levels of ∼2–5% of hypoE mice have a lipoprotein cholesterol profile to that of WT mice. of the plasma cholesterol is with as in WT mice. Unlike WT mice, hypoE mice are susceptible to diet-induced hypercholesterolemia, which is reversed when the mice are fed a normal chow diet. The of remnant is with that 2–5% of normal plasma apoE levels can remnant HypoE mice mouse models with reduced plasma apoE levels. of transgenic Apoe−/− mice expressing WT mouse apoE in the adrenal have reduced plasma cholesterol levels with 3% but not with 1% of WT plasma apoE levels (32.Thorngate F.E. Rudel L.L. Walzem R.L. Williams D.L. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1939-1945Crossref PubMed Scopus (109) Google Scholar). The lipoprotein profile of the transgenic Apoe−/− mice expressing 3% of WT apoE was not in the and be with hypoE mice. Apoe−/− mice to express apoE ∼2–5% of normal levels by bone marrow transplantation have reduced plasma cholesterol only of their plasma cholesterol is with HDL (31.Hasty A.H. Linton M.F. Swift L.L. Fazio S. J. Lipid Res. 1999; 40: 1529-1538Abstract Full Text Full Text PDF PubMed Google Scholar) in hypoE mice and in WT mice. that the of apoE in the hypoE mice the in remnant lipoprotein metabolism hypoE mice and mice expressing low levels of plasma apoE The hypoE mouse model that ∼2–5% of normal plasma apoE is close to the threshold level of apoE required for normal lipoprotein metabolism in mice fed a chow diet. to be that the Arg-61 apoE is in remnant clearance WT apoE. However, we have demonstrated that plasma lipid levels and lipoprotein are in WT and mice expressing normal levels of Arg-61 apoE, are they be (33.Raffaı̈ R.L. Dong L.-M. Farese Jr., R.V. Weisgraber K.H. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 11587-11591Crossref PubMed Scopus (156) Google Scholar). the the Arg-61 and WT apoE we are generating WT hypoE mice by inserting a neo cassette flanked by loxP sites into intron 3 of the WT Apoe The of hypoE mice to hypercholesterolemia by the used was the of plasma cholesterol in Apoe−/− mice and in Apoe−/− mice expressing low levels of mouse or human apoE (20.Linton M.F. Atkinson J.B. Fazio S. Science. 1995; 267: 1034-1037Crossref PubMed Scopus (417) Google Scholar, 21.Boisvert W.A. Spangenberg J. Curtiss L.K. J. Clin. Invest. 1995; 96: 1118-1124Crossref PubMed Scopus (188) Google Scholar, 22.Bellosta S. Mahley R.W. Sanan D.A. Murata J. Newland D.L. Taylor J.M. Pitas R.E. J. Clin. Invest. 1995; 96: 2170-2179Crossref PubMed Scopus (253) Google Scholar, 31.Hasty A.H. Linton M.F. Swift L.L. Fazio S. J. Lipid Res. 1999; 40: 1529-1538Abstract Full Text Full Text PDF PubMed Google Scholar, F.E. Rudel L.L. Walzem R.L. Williams D.L. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1939-1945Crossref PubMed Scopus (109) Google Scholar, S.H. N. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, T. K. A. E.M. Cell. Full Text PDF PubMed Scopus Google Scholar). However, the hypoE mouse model the opportunity to a of lipoprotein and plasma cholesterol levels by cholesterol levels in hypoE mice by the high and by the diet. As a plasma lipid and lipoprotein levels can be by in hypoE mice in WT mice. of hypoE mice was the of plasma and levels. HypoE mice had levels of and levels of WT mice. In hypoE mice, lipoproteins are the by the LDL receptor, the clearance of which apoE, be (3.Mahley R.W. Ji Z.-S. J. Lipid Res. 1999; 40: 1-16Abstract Full Text Full Text PDF PubMed Google Scholar, Walzem R.L. V. R. D. J. Young S.G. J. Clin. Invest. 1998; PubMed Scopus Google Scholar). The LDL receptor-related protein also to to of circulating apoE, in levels of the reduced levels of in hypoE mice by the hepatic apoE expression has been to (28.Maugeais C. Tietge U.J.F. Tsukamoto K. Glick J.M. Rader D.J. J. Lipid Res. 2000; 41: 1673-1679Abstract Full Text Full Text PDF PubMed Google Scholar). the that to reduced levels of plasma in hypoE mice, be to the production of in and in of hepatocytes hypoE mice. The hypoE mouse model also the of of that in Mx1-Cre transgenic hypoE mice, removal of the neo cassette by Cre-mediated recombination normal plasma apoE levels following induction of Cre recombinase. crossing hypoE mice with Cre transgenic mice, be to restore normal levels of apoE expression in crossing hypoE mice with transgenic mice G. mice in which apoE expression is fully only in mice to the role of apoE in plasma lipoprotein metabolism and in the of normal plasma apoE levels in Mx1-Cre and in and cell Cre transgenic hypoE mice, such as and a to the biological roles of apoE in the and levels of apoE expression after Cre-mediated of the neo cassette an to the of apoE to atherosclerosis regression not in when WT hypoE mice Arg-61 apoE and WT apoE provide the to the of as a and in atherosclerosis In we report the development of mice with reduced apoE expression or hypoE mice. The of the hypomorphic in hypoE mice the opportunity for an of the role of apoE in and inducible Cre transgenic mice A. 2000; PubMed Scopus Google Scholar) and in new as they for with the of for Mx1-Cre transgenic mice, for and for and and for

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.