An Integrative Genomics Approach Identifies Activation of Thioredoxin/Thioredoxin Reductase-1-Mediated Oxidative Stress Defense Pathway and Inhibition of Angiogenesis in Obese Nondiabetic Human Subjects
An Integrative Genomics Approach Identifies Activation of Thioredoxin/Thioredoxin Reductase-1-Mediated Oxidative Stress Defense Pathway and Inhibition of Angiogenesis in Obese Nondiabetic Human Subjects
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DOI：
10.1210/jc.2011-0101
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发表时间：
2011-08-01
影响因子：
5.8
通讯作者：
Elbein, Steven C.
中科院分区：
文献类型：
--
作者：
Das, Swapan K.;Sharma, Neeraj K.;Elbein, Steven C.
内容：肥胖症是一种复杂的疾病，涉及遗传和环境对脂肪组织中基因网络的干扰，并被认为是代谢后遗症的触发因素。目的：我们假设适应性反应基因网络中脂肪组织转录本的表达与脂肪质量百分比（PFAT）相关。在健康的非糖尿病受试者中维持代谢平衡，并且与响应于升高的脂肪酸而调节的基因重叠。在136名非糖尿病患者的皮下脂肪组织和棕榈酸诱导的细胞中测定了全基因组转录谱。在非糖尿病受试者的基因型信息和基因表达数据进行整合，以表征41肥胖相关的polymorphisms.Results的功能：参与炎症免疫反应，内质网应激，细胞-细胞外基质相互作用的基因与PFAT显着相关。NRF 2（核因子红细胞2相关因子-2）介导的氧化应激反应途径是强烈富集的脂肪中的PFAT相关的基因，也成为最丰富的棕榈酸酯在体外差异表达的基因之间的途径。硫氧还蛋白还原酶-1（TXNRD 1）是最强相关的基因（rho = 0.65）。与TXNRD 1表达共调节的基因表明，参与硫氧还蛋白介导的氧化应激防御机制和血管生成的基因的重要相互作用网络。促血管生成因子和抗血管生成因子分别与肥胖呈负相关和正相关。8个肥胖全基因组关联研究的单核苷酸多态性（SNP）与10个局部转录本的表达相关。SNP rs6861681是CPEB 4最强的cis-eQTL（P = 3.02 × 10（-9））。结论：我们的研究表明，在肥胖非糖尿病受试者中，上调TXN-TXNRD 1系统介导的氧化应激防御机制和下调血管生成途径作为一种适应性反应存在一种新的相互作用。肥胖相关SNP的一个子集作为顺式eQTL调节转录本的表达。（临床内分泌代谢杂志96：E1308-E1313，2011）
Context: Obesity is a complex disease that involves both genetic and environmental perturbations to gene networks in adipose tissue and is proposed as a trigger for metabolic sequelae.Objective: We hypothesized that expression of adipose tissue transcripts in gene networks for adaptive response would correlate with the percent fat mass (PFAT) in healthy nondiabetic subjects to maintain metabolic equilibrium and would overlap with genes modulated in response to elevated fatty acid.Design, Settings, and Patients: Genome-wide transcript profiles were determined in sc adipose tissue of 136 nondiabetics and in palmitate-induced cells. Genotype information and gene expression data in nondiabetic subjects were integrated to characterize the function of 41 obesity-associated polymorphisms.Results: Genes involved in inflammation-immune response, endoplasmic reticulum stress, and cell-extracellular matrix interactions were significantly correlated with PFAT. The NRF2 (nuclear factor erythroid 2-related factor-2)-mediated oxidative stress response pathway was strongly enriched among genes correlated with PFAT in adipose and also emerged as the most enriched pathway among genes differentially expressed by palmitate in vitro. Thioredoxin reductase-1 (TXNRD1) was the most strongly correlated gene (rho = 0.65). Genes coregulated with TXNRD1 expression indicated a significant interaction network of genes involved in thioredoxin-mediated oxidative stress defense mechanisms and angiogenesis. Pro-and antiangiogenic factors were negatively and positively correlated, respectively, with obesity. Eight obesity genome-wide association study single-nucleotide polymorphisms (SNP) were associated with expression of 10 local transcripts. SNP rs6861681 was the strongest cis-eQTL (expression quantitative trait loci) for CPEB4 (P = 3.02 X 10(-9)).Conclusions: Our study suggests a novel interaction of up-regulated TXN-TXNRD1 system-mediated oxidative stress defense mechanisms and down-regulated angiogenesis pathways as an adaptive response in obese nondiabetic subjects. A subset of obesity-associated SNP regulated expression of transcripts as cis-eQTL. (J Clin Endocrinol Metab 96: E1308-E1313, 2011)