Genotypic associations of the hepatic secretion of VLDL apolipoprotein B-100 in obesity

We examined the effect of genetic polymorphisms of proteins regulating intr ahepatic processing of apolipoprotein B-100 (apoB) and the supply of neutra l lipids to the liver on the hepatic secretion of very low density lipoprot ein (VLDL) apoB in obesity, Hepatic secretion of very low density apolipopr otein B-100 (VLDL apoB ) was measured using an infusion of [1-C-13]leucine in 29 obese men. Isotopic enrichment and turnover of VLDL apoB was determin ed using gas chromatography-mass spectrometry and multi-compartmental model ling; respectively. Visceral fat was measured by magnetic resonance imaging Genotypes for the apoB signal peptide (SP27/SP24 alleles), microsomal trig lyceride transfer protein promoter (MTP, -493 G/T alleles), apoE (E2, E3, E 4 alleles), hepatic lipase promoter (-514 C/T alleles), and cholesteryl est er transfer protein (CETP, Taq1B B1/B2 alleles) were determined using polym erase chain reaction. Statistically significant associations were found bet ween hepatic secretion of apoB and allelic combinations of i) apoB SP with apoE (P = 0.02), hepatic lipase (P = 0.02), and CETP (P = 0.006) genes, ii) MTP promoter with CETP genes (P = 0.03); the association with apoBSP/MTP p romoter allelic combinations just failed to reach significance (P = 0.06), however. The CETP/apoBSP allelic combination was the most significant predi ctor of apoB secretion, and this was independent of visceral fat, plasma la thosterol and insulin levels, and dietary fat. SP24 carriers who were homoz ygous for CETP B1 had 60% lower apoB secretion than B2 heterozygotes who we re non-carriers of SP24 (10.5 +/- 1.74 mg/kg fat free mass/day, n = 7 vs. 2 6.1 +/- 3.16, n = 22). The data suggest that variation in both the apoB and CETP genes may be a major genetic determinant of the hepatic secretion of apoB in men with visceral obesity.