Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice

• Published in: The Journal of clinical investigation Vol. 93; no. 4; pp. 1403 - 1410
• Main Authors: VAN VLIJMEN, B. J. M, VAN DEN MAAGDENBERG, A. M. J. M, GIJBELS, M. J. J, VAN DER BOOM, H, HOGENESCH, H, FRANTS, R. R, HOFKER, M. H, HAVEKES, L. M
• Format: Journal Article
• Language: English
• Published: Ann Arbor, MI American Society for Clinical Investigation 01-04-1994
• Subjects: Animals; Apolipoprotein E3; Apolipoproteins E - analysis; Apolipoproteins E - genetics; Arteriosclerosis - etiology; Arteriosclerosis - pathology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cholesterol, Dietary - administration & dosage; Female; Hyperlipoproteinemias - etiology; Lipids - blood; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Sex Factors; Animal model; Pathogenesis; Rodentia; Transgenic animal; Cardiovascular disease; Metabolic diseases; Lipids; Hyperlipoproteinemia; Supplemented diet; Lipoprotein; Cholesterol; Vascular disease; Vertebrata; Mammalia; Hypercholesterolemia; Mouse; Animal; Atherosclerosis
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI117117

Apolipoprotein E3-Leiden (APOE*3-Leiden) transgenic mice have been used to study the effect of different cholesterol-containing diets on the remnant lipoprotein levels and composition and on the possible concurrent development of atherosclerotic plaques. On high fat/cholesterol (HFC) diet, the high expressing lines 2 and 181 developed severe hypercholesterolemia (up to 40 and 60 mmol/liter, respectively), whereas triglyceride levels remained almost normal when compared with regular mouse diet. The addition of cholate increased the hypercholesterolemic effect of this diet. In lines 2 and 181, serum levels of apo E3-Leiden also increased dramatically upon cholesterol feeding (up to 107 and 300 mg/dl, respectively). In these high expressing APOE*3-Leiden transgenic mice, the increase in both serum cholesterol and apo E3-Leiden occurred mainly in the VLDL/LDL-sized fractions, whereas a considerable increase in large, apo E-rich HDL particles also occurred. In contrast to the high expressing lines, the low expressing line 195 reacted only mildly upon HFC diet. On HFC diets, the high expresser APOE*3-Leiden mice developed atherosclerotic lesions in the aortic arch, the descending aorta, and the carotid arteries, varying from fatty streaks containing foam cells to severe atherosclerotic plaques containing cholesterol crystals, fibrosis, and necrotic calcified tissue. Quantitative evaluation revealed that the atherogenesis is positively correlated with the serum level of cholesterol-rich VLDL/LDL particles. In conclusion, with APOE*3-Leiden transgenic mice, factors can be studied that influence the metabolism of remnant VLDL and the development of atherosclerosis.