Genetics
Human CETP transgene worsens atherosclerosis in apoE- and LDL-receptor-knockout mice, but effect flips with apoA-I overexpression (ATVB 1999)
Original title: Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression
Breeding a human CETP transgene, producing plasma CETP levels 5 to 10 times normal, onto apoE-knockout mice moderately reduced HDL cholesterol by 34% and delayed clearance of radiolabeled HDL cholesteryl ester, and increased mean atherosclerotic lesion area roughly 2-fold at 2 to 4 months and 1.4- to 1.6-fold at 7 months (P less than 0.02) versus apoE-knockout mice alone. In apoE-knockout mice also overexpressing apoA-I, CETP instead accelerated HDL cholesteryl ester clearance, reduced HDL cholesterol by 76%, and produced only an insignificant 1.3- to 1.7-fold rise in lesion area, while apoA-I alone cut lesion area 3-fold (P less than 0.001). On the LDL-receptor-knockout background after 3 months on a Western diet, the CETP transgene increased lesion area 1.8-fold (P less than 0.01), showing CETP's proatherogenic effect depends on impaired remnant or LDL clearance.
Original abstract
The plasma cholesteryl ester transfer protein (CETP) plays a major role in the catabolism of HDL cholesteryl ester (CE). CETP transgenic mice have decreased HDL cholesterol levels and have been reported to have either increased or decreased early atherosclerotic lesions. To evaluate the impact of CETP expression on more advanced forms of atherosclerosis, we have cross-bred the human CETP transgene into the apoE knock-out (apoE0) background with and without concomitant expression of the human apo A-I transgene. In this model the CETP transgene is induced to produce plasma CETP levels 5 to 10 times normal human levels. CETP expression resulted in moderately reduced HDL cholesterol (34%) in apoE0 mice and markedly reduced HDL cholesterol (76%) in apoE0/apoA1 transgenic mice. After injection of radiolabeled HDL CE, the CETP transgene significantly delayed the clearance of CE radioactivity from plasma in apoE0 mice, but accelerated the clearance in apoE0/apoA1 transgenic mice. ApoE0/CETP mice displayed an increase in mean atherosclerotic lesion area on the chow diet (approximately 2-fold after 2 to 4 months, and 1.4- to 1.6-fold after 7 months) compared with apoE0 mice (P<0.02). At 7 months apoA1 transgene expression resulted in a 3-fold reduction in mean lesion area in apoE0 mice (P<0.001). In the apoE0/apoA1 background, CETP produced an insignificant 1.3- to 1.7-fold increase in lesion area. In further studies the CETP transgene was bred onto the LDL receptor knock-out background (LDLR0). After 3 months on the Western diet, the mean lesion area was increased 1.8-fold (P<0.01) in LDLR0/CETP mice, compared with LDLR0 mice. These studies indicate that CETP expression leads to a moderate increase in atherosclerosis in apoE0 and LDLR0 mice, and suggest a proatherogenic effect of CETP activity in metabolic settings in which clearance of remnants or LDL is severely impaired. However, apoA1 overexpression has more dramatic protective effects on atherosclerosis in apoE0 mice, which are not significantly reversed by concomitant expression of CETP.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.