Genetics
Blocking apoB mRNA editing doubles plasma apoB-100 and shifts cholesterol from HDL to LDL specifically in CETP transgenic mice (Arterioscler Thromb Vasc Biol 1998)
Original title: Phenotype interaction of apobec-1 and CETP, LDLR, and apoE gene expression in mice: role of apoB mRNA editing in lipoprotein phenotype expression
By cross-breeding apobec-1 knockout mice, which cannot edit apoB mRNA, with CETP transgenic, apoE knockout, and LDL receptor knockout mice, this study tested whether apoB mRNA editing interacts with these genotypes despite apobec-1 knockouts alone having an essentially normal lipoprotein phenotype. In CETP transgenic mice, inactivating apobec-1 doubled plasma apoB-100 concentration (from 3.5 to 8.8 mg/dL, P<.01) and markedly shifted cholesterol from HDL to IDL/LDL, with the non-HDL to HDL cholesterol ratio rising from 0.47 in apobec-1 wild type without CETP to 1.43 in apobec-1 knockout with CETP expression, an effect further exaggerated by a Western-type diet. Similar apobec-1 by genotype interactions were seen in LDL receptor knockout and apoE knockout mice, each with diet-dependent modulation. The authors conclude that apoB mRNA editing has an important gene-gene interaction with CETP, LDL receptor, and apoE loci that is not apparent from apobec-1 inactivation alone.
Original abstract
Apolipoprotein (apo) B mRNA editing determines the amount of apoB-100 and apoB-48 produced. Surprisingly, apobec-1 knockout mice, which do not edit apoB, have an essentially normal lipoprotein phenotype. By selected cross-breeding of mice of different genotypes, we show in this report that inactivation of editing produces profound phenotypic effects in cholesteryl ester transfer protein (CETP) transgenic mice and in apoE and low density lipoprotein receptor (LDLR) knockout mice. Compared with mice with an apobec-1+/+ background, CETP expression in apobec-1-/- mice caused a doubling of the plasma apoB-100 concentration (from 3.5+/-0.6 to 8.8+/-1.9 mg/dL, P<.01) and a much greater shift of plasma cholesterol from HDL to IDL/LDL as assayed by fast protein liquid chromatography analysis; the ratio of non-HDL to HDL cholesterol was 0.47, 0.46, 0.76, and 1.43 in apobec-1(+/+)/CETP-/-, apobec-1(-/-)/CETP-/-, apobec-1(+/+)/CETP+/-, and apobec-1(-/-)/CETP+/- animals, respectively. Feeding of a Western-type diet further exaggerated the shift in this ratio. In LDLR-/- mice, inactivation of apobec-1 caused an approximately 200% rise in plasma apoB-100 concentration, an approximately 60% increase in apoE concentration, and a 70% increase in total plasma cholesterol, which resulted exclusively from an increase in non-HDL cholesterol. The exaggerated hypercholesterolemia involving the VLDL+LDL fractions was further enhanced by a Western-type diet. In contrast, in apoE-/- mice, inactivation of apobec-1 caused a massive increase (from <0.5 to 55.5+/-16.4 mg/dL) in plasma apoB-100 concentration but an approximately 55% reduction in hypercholesterolemia due to partial amelioration of the marked VLDL+IDL elevation. However, the difference in lipid profiles between apobec-1(+/+)/apoE-/- and apobec-1(-/-)/apoE-/- mice was abolished in a time-dependent manner as further increases in total plasma cholesterol were induced by a Western-type diet. Whereas apobec-1 inactivation in wild-type mice produced little or no change in lipoprotein phenotype, giving rise to speculation that apoB mRNA editing does not have significant effect on lipoprotein dynamics, we show herein that there is important gene-gene interaction between apobec-1 and the CETP, LDLR, and apoE loci, which is subject to further substantial modulation by environmental factors such as a Western-type diet in mice.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.