Mice deficient in apolipoprotein E but not LDL receptors are resistant to accelerated atherosclerosis associated with obesity


      The aims of this study were to determine whether mice induced to become obese also exhibited accelerated atherosclerosis, and to determine whether obesity itself or dyslipidemia associated with obesity enhanced atherosclerosis. Wild-type (C57BL/6) mice and mice deficient for the low density lipoprotein receptor (LDLR−/−) or apolipoprotein E (apoE−/−) were fed a low fat, rodent chow diet or a high fat, high sucrose (diabetogenic) diet to induce obesity. As compared with wild-type mice, diabetogenic diet-fed LDLR−/− mice became more obese and developed severe dyslipidemia. Consequently, atherosclerotic lesions were increased in the LDLR−/− mice 3.7-fold over chow fed values. ApoE−/− mice showed weight gain profiles similar to those observed for wild-type mice. However, no differences in plasma lipid levels, lipoprotein profiles or atherosclerotic lesion areas were observed between chow-fed and diabetogenic diet-fed apoE−/− mice. These data demonstrate that lipid storage and partitioning as mediated by the low density lipoproteins (LDL) receptor or apoE−/− have profound and opposing consequences for dyslipidemia and atherosclerosis susceptibility associated with obesity.


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      1. National Task Force on the prevention and treatment of obesity. Overweight, obesity, and health risk, Arch Intern Med. 2000; 160: 898–904.

        • Rabkin S.W.
        • Mathewson F.A.
        • Hsu P.H.
        Relation of body weight to development of ischemic heart disease in a cohort of young North American men after a 26 years observation period: the Manitoba study.
        Am. J. Cardiol. 1977; 39: 452-458
        • Rimm E.B.
        • Sampfer M.J.
        • Giovannucci E.
        • Ascherio A.
        • Spiegelman D.
        • Colditz G.A.
        • et al.
        Body size and fat distribution as predictors of coronary heart disease among middle aged and older US men.
        Am. J. Epidemiol. 1995; 141: 1117-1127
        • Lamarche B.
        Abdominal obesity and its metabolic complications: implications for the risk of ischemic heart disease.
        Coron. Artery Dis. 1998; 9: 473-481
        • Garg A.
        Treatment of diabetic dyslipidemia.
        Am. J. Cardiol. 1998; 81: 47B-51B
        • Rackley C.E.
        Cardiovascular basis for cholesterol therapy.
        Cardiol Rev. 2000; 8: 24-131
        • Alexander J.K.
        Obesity and coronary heart disease.
        Am. J. Med. Sci. 2001; 321: 215-224
        • Chua Jr., S.C.
        • Chung W.K.
        • Wu-Peng X.S.
        • Zhang Y.
        • Liu S.M.
        • Tartaglia L.
        Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor.
        Science. 1996; 271: 994-996
        • Noben-Trauth K.
        • Naggert J.K.
        • North M.A.
        • Nishina P.M.
        A candidate gene for the mouse mutation tubby.
        Nature. 1996; 380: 534-538
        • Masuzaki H.
        • Paterson J.
        • Shinyama H.
        • Morton N.M.
        • Mullins J.J.
        • Seckl J.R.
        • et al.
        A transgenic model of visceral obesity and the metabolic syndrome.
        Science. 2001; 294: 2166-2170
        • Oberbauer A.M.
        • Runstadler J.A.
        • Murray J.D.
        • Havel P.J.
        Obesity and elevated plasma leptin concentration in oMT1A-o growth hormone transgenic mice.
        Obes. Res. 2001; 9: 51-58
        • Nishina P.M.
        • Naggert J.K.
        • Verstuyft J.
        • Paigen B.
        Atherosclerosis in genetically obese mice: the mutants obese diabetes, fat, tubby, and lethal yellow.
        Metabolism. 1994; 43: 554-558
        • Zhang S.H.
        • Reddick R.L.
        • Piedrahita J.A.
        • Maeda N.
        Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.
        Science. 1992; 258: 468-471
        • Nakashima Y.
        • Plump A.S.
        • Raines E.W.
        • Breslow J.L.
        • Ross R.
        ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree.
        Arterioscler Thromb. 1994; 14: 133-140
        • Ishibashi S.
        • Goldstein J.L.
        • Brown M.S.
        • Herz J.
        • Burns D.K.
        Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice.
        J. Clin. Invest. 1994; 93: 1885-1893
        • Surwit R.S.
        • Seldin M.F.
        • Kuhn C.M.
        • Cochrane C.
        • Feinglos M.N.
        Control of expression of insulin resistance and hyperglycemia by different genetic factors in diabetic C57BL/6J mice.
        Diabetes. 1991; 40: 82-87
        • Rebuffe-Scrive M.
        • Surwit R.
        • Feinglos M.
        • Kuhn C.
        • Rodin J.
        Regional fat distribution and metabolism in a new mouse model (C57BL/6J) of non-insulin-dependent diabetes mellitus.
        Metabolism. 1993; 42: 1405-1409
        • Schreyer S.A.
        • Chua Jr., S.C.
        • LeBoeuf R.C.
        Obesity and Diabetes in TNF-α receptor-deficient mice.
        J. Clin. Invest. 1998; 102: 402-411
        • Schreyer S.A.
        • Vick C.
        • Lystig T.C.
        • Mystkowski P.
        • LeBoeuf R.C.
        LDL receptor but not apolipoprotein E deficiency increases diet-induced obesity and diabetes in mice.
        Am. J. Physiol. Endocrinol. Metab. 2002; 282: E207-E214
        • LeBoeuf R.J.
        • Caldwell M.
        • Kirk E.
        Regulation by nutritional status of lipids and apolipoproteins A-I, -II, and -IV in inbred mice.
        J. Lipid Res. 1994; 35: 121-133
        • Schreyer S.A.
        • Wilson D.L.
        • LeBoeuf R.C.
        C57BL/6 mice fed high fat diets as models for diabetes-accelerated atherosclerosis.
        Atherosclerosis. 1998; 136: 17-24
        • Kunjathoor V.V.
        • Wilson D.L.
        • LeBoeuf R.C.
        Increased atherosclerosis in streptozotocin-induced diabetic mice.
        J. Clin. Invest. 1996; 97: 1767-1773
        • Yagyu H.
        • Ishibashi S.
        • Chen Z.
        • Osuga J.-I.
        • Okazaki M.
        • Perrey S.
        • et al.
        Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice.
        J. Lipid Res. 1999; 40: 1677-1685
        • Zsigmond E.
        • Kobayashi K.
        • Tzung K.W.
        • Li L.
        • Fuke Y.
        • Chan L.
        Adenovirus-mediated gene transfer of human lipoprotein lipase ameliorates the hyperlipidemias associated with apolipoprotein E and LDL receptor deficiencies in mice.
        Hum. Gene Ther. 1997; 8: 1921-1933
        • Anderson K.M.
        • Castelli W.P.
        • Levy D.
        Cholesterol and mortality. 30 years of follow-up from the Framingham study.
        JAMA. 1987; 257: 2176-2180
        • Kobayashi K.
        • Forte T.M.
        • Taniguchi S.
        • Ishida B.Y.
        • Oka K.
        • Chan L.
        The db/db mouse, a model for diabetic dyslipidemia: molecular characterization and effects of Western diet feeding.
        Metabolism. 2000; 49: 22-31
        • Merat S.
        • Casanada F.
        • Sutphin M.
        • Palinski W.
        • Reaven P.D.
        Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet.
        Arterioscler Thromb. Vasc. Biol. 1999; 19: 1223-1230
        • Towler D.A.
        • Bidder M.
        • Latifi T.
        • Coleman T.
        • Semenkovich C.F.
        Diet-induced diabetes activates an osteogenic gene regulator program in the aortas of low density lipoprotein receptor-deficient mice.
        J. Biol. Chem. 1998; 273: 30427-30434
        • Merkel M.
        • Velez-Carrasco W.
        • Hudgins L.C.
        • Breslow J.L.
        Compared with saturated fatty acids, dietary monounsaturated fatty acids, and carbohydrates increae atherosclerosis and VLDL cholesterol levels in LDL receptor-deficient, but not apolipoprotein E-deficient, mice.
        Proc. Natl. Acad. Sci. USA. 2001; 98: 13294-13299
        • Zhang S.H.
        • Reddick R.L.
        • Burkey B.
        • Maeda N.
        Diet-induced atherosclerosis in mice heterozygous and homozygous for apoliprotein E gene disruption.
        J. Clin. Invest. 1994; 94: 937-945