Metabolite profiling identifies pathways associated with metabolic risk in humans.
Metabolite profiling identifies pathways associated with metabolic risk in humans.
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DOI：
10.1161/circulationaha.111.067827
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发表时间：
2012-05-08
期刊：
影响因子：
37.8
通讯作者：
Wang TJ
中科院分区：
文献类型：
--
作者：
Cheng S;Rhee EP;Larson MG;Lewis GD;McCabe EL;Shen D;Palma MJ;Roberts LD;Dejam A;Souza AL;Deik AA;Magnusson M;Fox CS;O'Donnell CJ;Vasan RS;Melander O;Clish CB;Gerszten RE;Wang TJ
虽然已知代谢风险因素聚集在容易发展为糖尿病和心血管疾病的个体中，但对潜在的生物学机制仍然知之甚少。为了确定与心脏代谢风险相关的途径，我们使用液相色谱/质谱法测定了45种不同代谢物的血浆浓度，并在Frachial Heart研究（FHS; N=1015）和Malmö饮食与癌症研究（MDC; N=746）中检查了它们与心脏代谢风险的关系。然后，我们询问了心血管和代谢疾病的实验模型中的重要发现。我们观察到代谢危险因素（肥胖、胰岛素抵抗、高血压、血脂异常）与多种代谢物相关，包括支链氨基酸、其他疏水性氨基酸、色氨酸分解产物和核苷酸代谢物。我们观察到胰岛素抵抗性状与谷氨酰胺（标准化回归系数为-0.04至-0.22，谷氨酰胺对数每1 SD变化，P<0.001），谷氨酸（0.05 ~ 0.14，P<0.001），谷氨酰胺-谷氨酸比值在发现样本（FHS）中（-0.05至-0.20，P<0.001）;在复制样本（MDC）中观察到类似的关联。在FHS中，高谷氨酰胺-谷氨酸比值与糖尿病发病风险降低相关（OR 0.79;校正后P=0.03），但在MDC中不相关。在实验模型中，谷氨酰胺给药导致小鼠葡萄糖耐量增加（P=0.01）和血压降低（P<0.05）。生化分析确定了以前与代谢特征无关的循环代谢物。通过对这些途径之一的实验研究表明，外源性给药导致的谷氨酰胺相对于谷氨酸过量与小鼠代谢风险降低相关。
Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes and cardiovascular disease, the underlying biological mechanisms remain poorly understood. To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; N=1015) and the Malmö Diet and Cancer Study (MDC; N=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, dyslipidemia) were associated with multiple metabolites including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients −0.04 to −0.22, per 1-SD change in log-glutamine, P<0.001), glutamate (0.05 to 0.14, P<0.001), and glutamine-glutamate ratio (−0.05 to −0.20, P<0.001) in the discovery sample (FHS); similar associations were observed in the replication sample (MDC). High glutamine-glutamate ratio was associated with lower risk of incident diabetes in FHS (OR 0.79; adjusted P=0.03), but not in MDC. In experimental models, administration of glutamine in mice led to both increased glucose tolerance (P=0.01) and to lower blood pressure (P<0.05). Biochemical profiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice.