Helwig Ulf, Rubin Diana, Klapper Maja, Li Yin, Nothnagel Michael, Fölsch Ulrich R, Döring Frank, Schreiber Stefan, Schrezenmeir Jürgen
Institute of Physiology and Biochemistry of Nutrition, Federal Research Centre for Nutrition and Food, 24103 Kiel, Germany.
Metabolism. 2007 Jun;56(6):723-31. doi: 10.1016/j.metabol.2006.11.014.
Studies on the association of fatty acid-binding protein 2 (FABP2) A54T and promoter polymorphism, and type 2 diabetes mellitus, insulin, and triglyceride levels are controversial. The aim of this study was to investigate the interfering effect of FABP2 A54T and promoter polymorphism on the postprandial response to a mixed meal and an oral glucose load. Seven hundred men from the Metabolic Intervention Cohort Kiel underwent a standard glucose tolerance test and a standardized mixed meal test and were genotyped by use of the Taqman method. When calculated independently from promoter variability, postprandial triglyceride levels were significantly higher and postprandial insulin sensitivity (homeostasis model assessment index) was lower in homozygous carriers of FABP2 T54T compared with carriers of the FABP2 exon wild-type allele (FABP2 A54A and A54T). This confirms previous findings. The effect of the exon T54T genotype on triglyceride levels and insulin sensitivity, however, was dependent on promoter variability. We found a significant increase in postprandial triglyceride levels and a decrease in insulin sensitivity due to T54T only in the presence of the homozygous B genotype at the promoter polymorphism. Similar results were obtained after oral glucose tolerance test. Reporter gene assays indicated a higher responsiveness to peroxisome proliferator-activating receptor-gamma (PPAR-gamma)/retinoid X receptor (RXR) of FABP2 promoter B vs promoter A. Synergism between a higher inducibility of FABP2 expression and a higher activity of T54 variant may explain higher postprandial triglycerides in case of combined genotype (promoter B + T54). This interference and different linkage disequilibrium between FABP2 exon and promoter polymorphisms may explain the different results obtained in different cohorts.
关于脂肪酸结合蛋白2（FABP2）A54T与启动子多态性、2型糖尿病、胰岛素及甘油三酯水平之间关联的研究存在争议。本研究旨在探讨FABP2 A54T与启动子多态性对混合餐和口服葡萄糖负荷后餐后反应的干扰作用。来自基尔代谢干预队列的700名男性接受了标准葡萄糖耐量试验和标准化混合餐试验，并采用Taqman方法进行基因分型。与FABP2外显子野生型等位基因（FABP2 A54A和A54T）携带者相比，独立于启动子变异性计算时，FABP2 T54T纯合携带者的餐后甘油三酯水平显著更高，餐后胰岛素敏感性（稳态模型评估指数）更低。这证实了先前的研究结果。然而，外显子T54T基因型对甘油三酯水平和胰岛素敏感性的影响取决于启动子变异性。我们发现，仅在启动子多态性为纯合B基因型时，T54T才会导致餐后甘油三酯水平显著升高和胰岛素敏感性降低。口服葡萄糖耐量试验后也得到了类似结果。报告基因分析表明，FABP2启动子B相对于启动子A对过氧化物酶体增殖物激活受体-γ（PPAR-γ）/视黄酸X受体（RXR）的反应性更高。FABP2表达更高的诱导性与T54变体更高的活性之间的协同作用可能解释了联合基因型（启动子B + T54）情况下餐后甘油三酯更高的原因。FABP2外显子与启动子多态性之间的这种干扰和不同的连锁不平衡可能解释了不同队列中得到的不同结果。
