Abstract 189: Improved Triglyceride-Rich Lipoprotein Clearance In Human Apolipoprotein A-Ii Knockin Rabbits

Abstract

Apolipoprotein A-II (apoA-II) is a second major apolipoprotein in HDL particles, which account for 15-20 % of total HDL protein in human. Compared with apolipoprotein A-I (apoA-I) which is a most major apolipoproteins in HDL, physiological role of apoA-II is not fully understood. We previously reported that overexpression of apoA-II in rabbits significantly suppressed cholesterol-rich diet induced atherosclerosis. Because rabbits are the animal of naturally deficient in apoA-II, so it becomes a good animal model to study the functions of apoA-II. To elucidate the role of apoA-II independent from apoA-I in HDL on lipid metabolism and atherogenesis, we generated a rabbit model in which the human apoA-II was knocked in to rabbit apoA-I locus by TALEN technology. The model was confirmed by genomic PCR, sequencing, RT-PCR and proteomics. With this model, we found that the triglyceride (TG) levels are significantly lower in homozygote than that in wild type control. The results of lipoprotein analysis using ultracentrifugation and FPLC also show that TG-rich lipoproteins were lower in homozygote than that of wild type. TGs were not increased in homozygote even after feeding of food. Small LDL and HDL2 particles were increased in homozygote rabbits. In addition, increased apoE was shown in HDL3 particle from homozygote. These results suggest that apoA-II knock-in has critical roles in the metabolism of TG-rich lipoproteins. Roles of apoA-II only HDLs from homozygote on cholesterol efflux and atherogenesis are under investigation.