Defects of the LDL receptor in WHHL transgenic rabbits lead to a marked accumulation of plasma lipoproteina

In this study, we created LDL receptor (LDLr) defective (WHHL) transgenic rabbits expressing human apoa to examine whether LDLr mediates the Lpa clearance from the plasma. By crossbreeding WHHL rabbits with human apoa transgenic rabbits, we obtained two groups of human apoa transgenic rabbits with defective LDLr functions: apoa(1/0) WHHL heterozygous (LDLr(+/-) and apoa(+/0) WHHL homozygous (LDLr(-/-) rabbits. The lipid and lipoprotein levels of human apoa WHHL rabbits were compared to those of human apoa transgenic rabbits with normal LDLr functions (LDLr(+/+). The apoa production rate was evaluated by analyzing apoa mRNA expression in the liver, the major site for apoa synthesis in transgenic rabbits. We found that pre-beta lipoproteins were markedly increased accompanied by a 2-fold increase in the plasma Lpa in apoa(+/0)/LDLr(+/-) rabbits and a 4.2-fold increase in apoa(+/0)/LDLr(-/-) rabbits compared with that in apoa(+/0) rabbits with normal LDLr function. In apoa(+/0)/LDLr(-/-) rabbits, there was a marked increase in plasma total cholesterol and triglycerides, as was found in their counterpart non-transgenic WHHL rabbits. Northern blot analysis revealed that hepatic apoa expression in WHHL transgenic rabbits was similar to that in LDLr(+/+) transgenic rabbits, suggesting the accumulation of plasma Lpa in WHHL transgenic rabbits was not due to increased apoa synthesis. In conclusion, absence of a functional LDLr leads to a marked accumulation of plasma Lpa in human apoa transgenic WHHL rabbits and LDLr may participate in the catabolism of Lpa in rabbits.