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Journal of Lipid Research, Vol. 41, 1004-1012, June 2000
Copyright © 2000 by Lipid Research, Inc.

Original Article

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

Correspondence to: Jianglin Fan

In this study, we created LDL receptor (LDLr) defective (WHHL) transgenic rabbits expressing human apo[a] to examine whether LDLr mediates the Lp[a] clearance from the plasma. By crossbreeding WHHL rabbits with human apo[a] transgenic rabbits, we obtained two groups of human apo[a] transgenic rabbits with defective LDLr functions: apo[a]^1/0 WHHL heterozygous (LDLr^+/-) and apo[a]^+/0 WHHL homozygous (LDLr^-/-) rabbits. The lipid and lipoprotein levels of human apo[a] WHHL rabbits were compared to those of human apo[a] transgenic rabbits with normal LDLr functions (LDLr^+/+). The apo[a] production rate was evaluated by analyzing apo[a] mRNA expression in the liver, the major site for apo[a] synthesis in transgenic rabbits. We found that pre-ß lipoproteins were markedly increased accompanied by a 2-fold increase in the plasma Lp[a] in apo[a]^+/0/LDLr^+/- rabbits and a 4.2-fold increase in apo[a]^+/0/LDLr^-/- rabbits compared with that in apo[a]^+/0 rabbits with normal LDLr function. In apo[a]^+/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 apo[a] expression in WHHL transgenic rabbits was similar to that in LDLr^+/+ transgenic rabbits, suggesting the accumulation of plasma Lp[a] in WHHL transgenic rabbits was not due to increased apo[a] synthesis.

In conclusion, absence of a functional LDLr leads to a marked accumulation of plasma Lp[a] in human apo[a] transgenic WHHL rabbits and LDLr may participate in the catabolism of Lp[a] in rabbits.—Fan, J., M. Challah, H. Shimoyamada, M. Shiomi, S. Marcovina, and T. Watanabe. Defects of the LDL receptor in WHHL transgenic rabbits lead to a marked accumulation of plasma lipoprotein[a]. J. Lipid Res. 2000. 41: 1004;–1012.

Supplementary key words: lipoprotein[a], WHHL rabbit, apolipoprotein[a], LDL receptor, transgenic rabbit, metabolism, catabolism, hypercholesterolemia

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