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

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.