Watts G F, Riches F M, Humphries S E, Talmud P J, van Bockxmeer F M
University Department of Medicine and Western Australian Heart Research Institute, University of Western Australia, Royal Perth Hospital, Perth, Western Australia.
J Lipid Res. 2000 Mar;41(3):481-8.
We examined the effect of genetic polymorphisms of proteins regulating intrahepatic processing of apolipoprotein B-100 (apoB) and the supply of neutral lipids to the liver on the hepatic secretion of very low density lipoprotein (VLDL) apoB in obesity. Hepatic secretion of very low density apolipoprotein B-100 (VLDL apoB) was measured using an infusion of [1-(13)C]leucine in 29 obese men. Isotopic enrichment and turnover of VLDL apoB was determined using gas chromatography-mass spectrometry and multi-compartmental modelling, respectively. Visceral fat was measured by magnetic resonance imaging. Genotypes for the apoB signal peptide (SP27/SP24 alleles), microsomal triglyceride transfer protein promoter (MTP, -493 G/T alleles), apoE (E2, E3, E4 alleles), hepatic lipase promoter (-514 C/T alleles), and cholesteryl ester transfer protein (CETP, Taq1B B1/B2 alleles) were determined using polymerase chain reaction. Statistically significant associations were found between 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 promoter allelic combinations just failed to reach significance (P = 0.06), however. The CETP/apoBSP allelic combination was the most significant predictor of apoB secretion, and this was independent of visceral fat, plasma lathosterol and insulin levels, and dietary fat. SP24 carriers who were homozygous for CETP B1 had 60% lower apoB secretion than B2 heterozygotes who were non-carriers of SP24 (10.5 +/- 1.74 mg/kg fat free mass/day, n = 7 vs. 26.1 +/- 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.
我们研究了调节载脂蛋白B-100（apoB）肝内加工过程的蛋白质基因多态性以及肝脏中性脂质供应对肥胖个体极低密度脂蛋白（VLDL）apoB肝脏分泌的影响。在29名肥胖男性中，通过输注[1-(13)C]亮氨酸来测量极低密度载脂蛋白B-100（VLDL apoB）的肝脏分泌。分别使用气相色谱-质谱联用和多室模型来测定VLDL apoB的同位素富集和周转率。通过磁共振成像测量内脏脂肪。使用聚合酶链反应确定apoB信号肽（SP27/SP24等位基因）、微粒体甘油三酯转移蛋白启动子（MTP，-493 G/T等位基因）、apoE（E2、E3、E4等位基因）、肝脂肪酶启动子（-514 C/T等位基因）和胆固醇酯转移蛋白（CETP，Taq1B B1/B2等位基因）的基因型。发现apoB的肝脏分泌与以下基因的等位基因组合之间存在统计学显著关联：i）apoB SP与apoE（P = 0.02）、肝脂肪酶（P = 0.02）和CETP（P = 0.006）基因；ii）MTP启动子与CETP基因（P = 0.03）；然而，与apoBSP/MTP启动子等位基因组合的关联刚刚未达到显著水平（P = 0.06）。CETP/apoBSP等位基因组合是apoB分泌的最显著预测因子，且这与内脏脂肪、血浆羊毛甾醇和胰岛素水平以及饮食脂肪无关。对于CETP B1纯合的SP24携带者，其apoB分泌比非SP24携带者的B2杂合子低60%（10.5±1.74毫克/千克去脂体重/天，n = 7 vs. 26.1±3.16，n = 22）。数据表明，apoB和CETP基因的变异可能是内脏肥胖男性中apoB肝脏分泌的主要遗传决定因素。
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