We aimed to examine the effect of genetic polymorphisms of apolipoprotein B-100 (apoB) signal peptide and apolipoprotein E (apoE) on the hepatic secretion of very low density lipoprotein (VLDL) apoB in 29 men with visceral obesity. We studied apoB secretion using a primed (1 mg/kg), constant (1 mg/kg/h) intravenous infusion of [1-(13)C]leucine. The isotopic enrichment of VLDL apoB was determined using gas chromatography-mass spectrometry (GCMS). A multi-compartmental model was used to estimate the fractional turnover rate of VLDL apoB. Genotypes for the apoB signal peptide length polymorphism, 27 amino acid (SP27) and 24 amino acid (SP24), and apoE genotypes were determined using polymerase chain reaction. In subjects who were not apoE2 carriers and were homozygous for the SP27 of the apoB signal peptide, the hepatic secretion of VLDL apoB was significantly higher than in subjects who were not apoE2 carriers and were either heterozygous or homozygous for the SP24 allele (31.3 +/- 11.8 mg/kg fat-free mass/day, n = 8 vs. 16.9 +/- 12.2 mg/kg fat-free mass/day, n = 13, P = 0.01). In subjects who were not apoE4 carriers and were either heterozygous or homozygous for the apoB SP24 allele, the hepatic secretion of VLDL apoB was significantly lower than in subjects who were not apoE4 carriers and were homozygous for the SP27 allele (15.8 +/- 12.9 mg/kg fat-free mass/day, n = 13 vs. 27.4 +/- 11.5 mg/kg fat-free mass/day, n = 7, P = 0.03). The data suggest that in men with visceral obesity, the apoB signal peptide and apoE genotypes appear to be involved in the hepatic secretion of apoB.