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The apolipoprotein (apo) E isoform is an important determinant of the plasma lipoprotein distribution of apoE and of the metabolism of apoE-containing lipoproteins. We have determined the effects of apoE genotype on the plasma lipoprotein response to cholesterol feeding in 30 young normal male subjects (5 E3/2, 11 E3/3, 14 E4/3) under rigorously controlled dietary conditions. Two diets, differing only in cholesterol content (low cholesterol (LC): 80 mg cholesterol/1000 kcal and high cholesterol (HC): 320 mg cholesterol/1000 kcal), were compared using a random crossover design. At the end of the HC as compared to the LC period, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and HDL2-C increased by an average of 15%, 21%, 7%, and 23%, respectively, for the three genotype groups combined (P < 0.001 for each). The LDL-C response to dietary cholesterol did not differ among the apoE genotypes. However, the increase in HDL-C varied significantly according to the apoE genotype (E3/2: 0 change, E3/3: +4%, E4/3: +12%; P < 0.05). The plasma cholesteryl ester transfer protein (CETP) response to cholesterol feeding also differed amongst the three apoE genotype groups (E3/2: +37%, E3/3: +18%, E4/3: +9%) (P < 0.05). ApoE genotype has significant and opposite effects on plasma CETP and HDL-C responses to dietary cholesterol in men.