Transgenic rabbits expressing human apolipoprotein A-I in the liver.
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-beta 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-beta 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.
Duverger
N
N
Rhône-Poulenc Rorer-Gencell, Atherosclerosis Department, Centre de recherche de Vitry-Alfortville, Vitry sur Seine, France. nicolas.duverger@rp.fr
Viglietta
C
C
Berthou
L
L
Emmanuel
F
F
Tailleux
A
A
Parmentier-Nihoul
L
L
Laine
B
B
Fievet
C
C
Castro
G
G
Fruchart
J C
JC
Houbebine
L M
LM
Denèfie
P
P
D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000235:genetics*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism*; D011817:Rabbits
D016632:Apolipoprotein A-I; D002784:Cholesterol