Transgenic rabbits expressing human apolipoprotein A-I in the liver.

Abstract

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.