PHENOTYPE INTERACTION OF APOBEC-1 AND CETP, LDLR, AND APOE GENE-EXPRESSION IN MICE - ROLE OF APO-B MESSENGER-RNA EDITING IN LIPOPROTEIN PHENOTYPE EXPRESSION

Apolipoprotein (apo) B mRNA editing determines the amount of apoB-100 and apoB-48 produced. Surprisingly, apobec-1 knockout mice, which do n ot edit apoB, have an essentially normal lipoprotein phenotype. By sel ected cross-breeding of mice of different genotypes, we show in this r eport that inactivation of editing produces profound phenotypic effect s in cholesteryl ester transfer protein (CETP) transgenic mice and in apoE and low density lipoprotein receptor (LDLR) knockout mice. Compar ed with mice with an apobec-1(+/+) background, CETP expression in apob ec-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 liq uid chromatography analysis; the ratio of non-HDL to HDL cholesterol w as 0.47, 0.46, 0.76, and 1.43 in apobec-1(+/+)/CETP-/-, apobec-1(-/-)/ CETP-/-, apobec-1(+/+)/CETP+/-, and apobec-1(-/-)/CETPC+/- animals, re spectively. Feeding of a Western-type diet further exaggerated the shi ft in this ratio. In LDLR-/- mice, inactivation of apobec-1 caused an approximate to 200% rise in plasma apoB-100 concentration, an approxim ate to 60% increase in apoE concentration, and a 70% increase in total plasma cholesterol, which resulted exclusively from an increase in no n-HDL cholesterol. The exaggerated hypercholesterolemia involving the VLDL+LDL fractions was further enhanced by a Western-type diet. In con trast, in apoE(-/-) mice, inactivation of apabec-1 caused a massive in crease (from <0.5 to 55.5+/-16.4 mg/dL) in plasma apoB-100 concentrati on but an approximate to 55% reduction in hypercholesterolemia due to partial amelioration of the marked VLDL+IDL elevation. However, the di fference in lipid profiles between apobec-1(+/+)/apoE(-/-) and apobec- 1(-/-)/apoE(-/-) mice was abolished in a time-dependent manner as furt her increases in total plasma cholesterol were induced by a Western-ty pe diet. Whereas apobec-1 inactivation in wild-type mice produced litt le or no change in lipoprotein phenotype, giving rise to speculation t hat 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 W estern-type diet in mice.