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
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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