HDL biology
Human apoA-I transgenic mouse HDL lacks the heat-labile inhibitor that normally caps CETP activity at high HDL levels (J Biol Chem 1997)
Original title: Differential interaction of the human cholesteryl ester transfer protein with plasma high density lipoproteins (HDLs) from humans, control mice, and transgenic mice to human HDL apolipoproteins. Lack of lipid transfer inhibitory activity in transgenic mice expressing human apoA-I
The interaction of human CETP with HDL from humans, control mice, and mice transgenic for human apoA-I, apoA-II, or both was studied to characterize an inhibitory activity affecting CETP at high HDL concentrations. Cholesteryl ester transfer rates rose with increasing HDL from all sources up to a point, but beyond that, human, control mouse, and apoA-II transgenic mouse HDL inhibited CETP activity, whereas apoA-I transgenic and apoA-I-plus-apoA-II transgenic mouse HDL maintained a plateau with no inhibition. This inhibition was reproduced by delipidated apolipoproteins from control mouse HDL but abolished by heating at 56 degrees C, and was absent from delipidated apoA-I transgenic mouse HDL protein regardless of heating. The authors conclude that human, control mouse, and apoA-II transgenic mouse HDL contain a heat-labile lipid transfer inhibitory activity specifically absent from apoA-I transgenic mouse HDL, without CETP-lipoprotein binding itself differing.
Original abstract
Plasma high density lipoproteins (HDLs) from humans, from transgenic mice to human apolipoprotein A-I (HuAITg mice), from transgenic mice to human apolipoprotein A-II (HuAIITg mice), from transgenic mice to human apolipoproteins A-I and A-II (HuAIAIITg mice), and from C57BL/6 control mice were isolated, and their ability to interact with the human cholesteryl ester transfer protein (CETP) was studied. Whereas cholesteryl ester transfer rates were gradually enhanced by the addition of moderate amounts of HDL from the different sources, striking differences appeared when HDL levels kept increasing beyond a maximal transfer value. Indeed, while a plateau value corresponding to maximal CETP activity was maintained when raising the concentration of HuAITg HDL and HuAIAIITg HDL, inhibitions could be observed with the highest levels of human, control mouse, and HuAIITg mouse HDL. The concentration-dependent inhibition of CETP activity could be reproduced by the addition of delipidated HDL apolipoproteins from control mice, but it was abolished by a 1-h preheating treatment at 56 degrees C. In contrast, no significant inhibition of CETP activity was observed with the delipidated protein moiety of HuAITg HDL, and cholesteryl ester transfer rates remained unchanged before and after a 1-h, 56 degrees C preheating step. Finally, the CETP-mediated transfer of radiolabeled cholesteryl esters from human low density lipoprotein to human HDL was significantly higher in the presence of lipoprotein-deficient plasma from HuAITg mice than in the presence of lipoprotein-deficient plasma from control mice. Interestingly, cholesteryl ester transfer rates measured with both control and HuAITg lipoprotein-deficient plasmas became remarkably similar following a 1-h, 56 degrees C preheating treatment. It is concluded that human, control mouse, and HuAIITg mouse HDL contain a heat-labile lipid transfer inhibitory activity that is absent from HDL of HuAITg and HuAIAIITg mice. Alterations in CETP-lipoprotein binding did not account for differential lipid transfer inhibitory activities.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.