THE ROLE OF CHOLESTERYL ESTER TRANSFER PROTEIN IN PRIMATE APOLIPOPROTEIN-A-I METABOLISM - INSIGHTS FROM STUDIES WITH TRANSGENIC MICE

To assess the effects of cholesteryl ester transfer protein (CETP) on the primate lipoprotein profile, a transgenic mouse expressing cynomolgus monkey CETP was developed. The C57BL/6 mouse was used, and four lines expressing the primate CETP were established. The level of CETP activity in the plasma of the transgenic mice ranged from values similar to those obtained for the monkey to levels approximately sixfold higher than that in the normal monkey. When all of the lines were taken into consideration, there was a strong (r=-0.81 or higher, p<0.01) negative correlation between plasma CETP activity and total plasma cholesterol, plasma apolipoprotein (apo) A-I levels, and plasma apo A-I to apo B ratio. There was a strong positive correlation (r=0.77) between plasma CETP activity and plasma apo B levels. The size of the apo A-I-containing lipoproteins was significantly reduced in mice with high plasma CETP activity, and that reduction in size was due to the absence of the larger (HDL1 and HDL2) apo A-I-containing particles in the plasma. When the transgenic mice were fed a high-fat, high-cholesterol diet, the effects of the diet on lipoprotein profile were more prominent in the CETP transgenic mice than the controls. The CETP transgenic mice had, for example, substantially higher plasma cholesterol and plasma apo B levels (p<0.01), and the apo B-containing lipoproteins were generally larger than those in the nontransgenic C57BL/6 mice consuming the same diet. These studies show that expression of primate CETP in the C57BL/6 mouse has a marked effect on the mouse's apo B- and apo A-I-containing lipoproteins, and they establish a metabolic basis for the previously reported (Arterioscler Thromb 1991;11:1759-1771) negative correlation between hepatic CETP mRNA levels and plasma apo A-I levels in the cynomolgus monkey. In addition, they suggest that increased CETP activity is associated with an atherogenic shift in the lipoprotein profile.