Objective. Apolipoprotein (apo) C1 is a 6.6 kDa protein associated with HDL and VLDL. ApoC1 alters triglyceride clearance by inhibiting lipolysis and VLDL uptake, and it also favors cholesterol accumulation in HDL, especially by inhibiting CETP. Apart from studies in mice, which lack CETP, the impact of apoC1 on atherosclerosis in animal models which express CETP, like in humans, is not known. The objective of this study was to determine the net effect of human apoC1 on atherosclerosis in rabbits, a species with naturally high CETP activity but dysfunctional apoC1.
Approach and Results. Rabbits expressing a human apoC1 transgene (HuApoC1Tg) were generated. Significant amounts of human apoC1 were measured in plasma of the transgenic rabbits. In chow-fed animals, the level of HDL-cholesterol was significantly higher in HuApoC1Tg than in WT animals (0.83±0.11 versus 0.73±0.11 mmol/L, respectively, p<0.05. It was associated with significantly lower CETP activity (cholesteryl ester transfer rate, -10%, p<0.05; specific CETP activity, -14%, p<0.05). In cholesterol-fed HuApoC1 rabbits, HDL displayed a reduced ability to serve as CETP substrates (-25%, p<0.05) compared with HDL from WT rabbits, accounting in part for the rise in plasma HDL cholesterol level and PON-1 activity. Importantly, atherosclerosis lesions after cholesterol feeding were significantly less extensive in HuApoC1Tg rabbits than in WT littermates (-22%, p<0.05).
Conclusion. Expression of fully functional human apoC1 in transgenic rabbit plasma inhibits CETP activity, increases plasma HDL levels and attenuates atherosclerosis.

05 - HUMAN APOLIPOPROTEIN C1 TRANSGENESIS TO INHIBIT CETP AND TO ATTENUATE ATHEROSCLEROSIS IN HYPERCHOLESTEROLEMIC RABBITS