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.