A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease
A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease
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DOI：
10.1073/pnas.0602178103
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发表时间：
2006-05-02
影响因子：
11.1
通讯作者：
Hotamisligil, GS
中科院分区：
文献类型：
--
作者：
Tuncman, G;Erbay, E;Hotamisligil, GS
肥胖和相关的病理学，包括血脂异常，胰岛素抵抗，2型糖尿病和心血管疾病构成了对全球人类健康的主要威胁。然而，遗传因素的差异，使个人倾向于这一集群的病理尚不清楚。脂肪酸结合蛋白aP 2是在脂肪细胞和巨噬细胞中表达的细胞质脂质伴侣。aP 2缺乏的小鼠部分抵抗肥胖诱导的胰岛素抵抗和2型糖尿病，具有较低的循环甘油三酯，并表现出对动脉粥样硬化的显著保护。在这里，我们证明了在人类的aP 2基因座的功能显着的遗传变异，导致减少脂肪组织aP 2的表达，由于改变CAAT盒/增强子结合蛋白的结合和降低转录活性的aP 2启动子。在7,899名参与者的群体遗传学研究中，与WT等位基因纯合子受试者相比，携带这种T-87 C多态性的个体血清甘油三酯水平较低，冠心病和2型糖尿病的风险显著降低。综上所述，我们的结果表明，在人类中aP 2活性的减少产生代谢有利的表型，这是类似于aP 2缺乏症的实验模型。
Obesity and the associated pathologies including dyslipidemia, insulin resistance, type 2 diabetes, and cardiovascular disease constitute a major threat to global human health. Yet, the genetic factors that differentially predispose individuals to this cluster of pathologies are unclear. The fatty acid-binding protein aP2 is a cytoplasmic lipid chaperon expressed in adipocytes and macrophages. Mice with aP2 deficiency are partially resistant to obesity-induced insulin resistance and type 2 diabetes, have lower circulating triglycerides, and exhibit marked protection against atherosclerosis. Here, we demonstrate a functionally significant genetic variation at the aP2 locus in humans that results in decreased adipose tissue aP2 expression due to alteration of the CAAT box/enhancer-binding protein binding and reduced transcriptional activity of the aP2 promoter. In population genetic studies with 7,899 participants, individuals that carry this T-87C polymorphism had lower serum triglyceride levels and significantly reduced risk for coronary heart disease and type 2 diabetes compared with subjects homozygous for the WT allele. Taken together, our results indicate that reduction in aP2 activity in humans generate a metabolically favorable phenotype that is similar to aP2 deficiency in experimental models.