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

Jianglin Fan,Mireille Challah,Hiroaki Shimoyamada,Masashi Shiomi,Santica Marcovina,Teruo Watanabe

doi:10.1016/s0022-2275(20)32043-5

Jianglin Fan, Mireille Challah + Show 4 more

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https://doi.org/10.1016/s0022-2275(20)32043-5

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Abstract

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]+/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-β 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.

Highlights

In this study, we created low density lipoprotein (LDL) receptor (LDLr) defective (WHHL) transgenic rabbits expressing human apo[a] to examine whether LDL receptor (LDLr) mediates the Lp[a] clearance from the plasma
To examine whether the LDL receptors may contribute to the catabolism of Lp[a], we generated human apo[a] transgenic Watanabe heritable hyperlipidemic (WHHL) rabbits that have defective LDL receptor functions
We found that there was an accumulation of plasma Lp[a] in transgenic rabbits in the setting of LDLr defective functions, leading to 2-fold and 4.2-fold increases of apo[a] levels in heterozygous and homozygous WHHL transgenic rabbits, respectively, compared to the level in normal transgenic rabbits

Summary

Introduction

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. 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؉/؉). This observation was supported by two other clinical studies [20, 21] This notion is further strengthened by a study of transgenic mice overexpressing human LDLr in the Abbreviations: WHHL, Watanabe heritable hyperlipidemic; apo[a], apolipoprotein[a]; Lp[a], lipoprotein[a]; LDL, low density lipoproteins; LDLr, LDL receptor; VLDL, very low density lipoproteins; IDL, intermediate density lipoproteins; HDL, high density lipoproteins; FH, familial hypercholesterolemia; PCR, polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; mAb, monoclonal antibody.

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