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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:1424-1429.)
© 1996 American Heart Association, Inc.

Articles

Transgenic Rabbits Expressing Human Apolipoprotein A-I in the Liver

Nicolas Duverger; Celine Viglietta; Laurence Berthou; Florence Emmanuel; Anne Tailleux; Laurence Parmentier-Nihoul; Bernard Laine; Catherine Fievet; Graciela Castro; Jean Charles Fruchart; Louis Marie Houbebine; Patrice Denefle

Rhone-Poulenc Rorer-Gencell, Cell and Gene Therapy Division, Atherosclerosis Department, Centre de recherche de Vitry-Alfortville, Vitry sur Seine (N.D., L.B., F.E., P.D.); Institut Pasteur, INSERM 325, Lille (A.T., L.P.-N., B.L., C.F., G.C., J.C.F.); and Institut National de la Recherche Agronomique, Jouy en Josas (C.V., L.M.H.), France.

Correspondence to Dr Nicolas Duverger, Atherosclerosis Department, Centre de Recherche de Vitry-Alfortville, 13, Quai Jules Guesde-BP 14, 94403 Vitry sur Seine, Cedex, France. E-mail nicolas.duverger@rp.fr.

Human apolipoprotein A-I (apo A-I) transgenic rabbits were created by use of an 11-kb genomic human apo A-I construct containing a liver-specific promoter. Five independent transgenic lines were obtained in which human apo A-I gene had integrated and was expressed. Plasma levels of human apo A-I ranged from 8 to 100 mg/dL for the founder and up to 175 mg/dL for the progeny. Rabbit apo A-I levels were substantially decreased in the transgenic rabbits. HDL cholesterol (HDL-C) levels were higher in two of the five transgenic rabbit lines than in controls (line 20 versus nontransgenic littermate, HDL-C=80±7 versus 37±6 mg/dL; line 8 versus nontransgenic littermate, HDL-C=54±16 versus 35±6 mg/dL). This resulted in less atherogenic lipoprotein profiles, with very low (VLDL+LDL-C)/HDL-C ratios. HDL size and protein and lipid compositions were similar between transgenic and littermate nontransgenic rabbits. However, a large amount of pre-ß apo A-I–containing lipoproteins was observed in the plasma of the highest human apo A-I expressor. Cell cholesterol efflux was evaluated with the incubation of whole serum from transgenic and control rabbits. Cell cholesterol efflux was highly correlated with HDL cholesterol, with apo A-I, and with the presence of pre-ß apo A-I–containing lipoproteins. These rabbits will be an extremely useful model for the evaluation of the effect of increased hepatic apo A-I expression on atherosclerosis.

Key Words: New Zealand White rabbit • apolipoprotein A-I • transgenic • cholesterol • lipoprotein

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