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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2267.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Expression of Human Apolipoprotein A-I/C-III/A-IV Gene Cluster in Mice Induces Hyperlipidemia but Reduces Atherogenesis

Laurent Vergnes; Nadine Baroukh; Maria A. Ostos; Graciela Castro; Nicolas Duverger; M. Nazeem Nanjee; Jamila Najib; Jean-Charles Fruchart; Norman E. Miller; Mario M. Zakin; Alberto Ochoa

From the Unité d’Expression des Gènes Eucaryotes, Institut Pasteur (L.V., N.B., M.A.O., M.M.Z., A.O.), Paris, France; U 325 Inserm Institut Pasteur (G.C., J.N., J.-C.F.), Lille, France; Rhone-Poulenc Rorer (N.D.), Vitry sur Seine, France; Institut National de la Recherche Agronomique (A.O.) Jouy-en-Josas, France; and St. Bartholomew’s and the Royal London School of Medicine and Dentistry (M.N.N., N.E.M.), London, UK.

Correspondence to Alberto Ochoa, Unité d’Expression des Gènes Eucaryotes, Institut Pasteur, 28 rue du Dr. Roux, 75724, Paris cedex 15, France. E-mail aochoa{at}pasteur.fr

Abstract—The apolipoprotein (apo)A-I/C-III/A-IV gene cluster is involved in lipid metabolism and atherosclerosis. Overexpression of apoC-III in mice causes hypertriglyceridemia and induces atherogenesis, whereas overexpression of apoA-I or apoA-IV increases cholesterol in plasma high density lipoprotein (HDL) and protects against atherosclerosis. Each gene has been studied alone in transgenic mice but not in combination as the entire cluster. To determine which phenotype is produced by the expression of the entire gene cluster, transgenic mice were generated with a 33-kb human DNA fragment. The results showed that the transgene contained the necessary elements to direct hepatic and intestinal expression of the 3 genes. In the pooled data, plasma concentrations were 257±9, 7.1±0.5, and 1.0±0.2 mg/dL for human apoA-I, apoC-III, and apoA-IV, respectively (mean±SEM). Concentrations of these apolipoproteins were higher in males than in females. Human apoA-I and apoC-III concentrations were positively correlated, suggesting that they are coregulated. Transgenic mice exhibited gross hypertriglyceridemia and accumulation of apoB₄₈–containing triglyceride-rich lipoproteins. Plasma triglyceride and cholesterol concentrations were correlated positively with human apoC-III concentration, and HDL cholesterol was correlated with apoA-I concentration. In an apoE-deficient background, despite being markedly hypertriglyceridemic, cluster transgenic animals compared with nontransgenic animals showed a 61% reduction in atherosclerosis. This suggests that apoA-I and/or apoA-IV can protect against atherosclerosis even in the presence of severe hyperlipidemia. These mice provide a new model for studies of the regulation of the 3 human genes in combination.

Key Words: transgenic mice • hypertriglyceridemia • cholesterol • lipoproteins • atherosclerosis

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