Gu Xueqin, Song Yunlong, Chai Yifeng, Lu Feng, Gonzalez Frank J, Fan Guorong, Qi Yunpeng
Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Mol Biosyst. 2015 May;11(5):1329-37. doi: 10.1039/c5mb00048c.
Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, was found to exacerbate inflammation and tissue injury in experimental acute colitis mice. Through lipidomics analysis, bioactive sphingolipids were significantly up-regulated in the colitis group. In this study, to provide further insight into the PPARα-dependent exacerbation of colitis, gas chromatography-mass spectrometry (GC/MS) based metabolomics was employed to investigate the serum and colon of dextran sulfate sodium (DSS)-induced colitis mice treated with fenofibrate, with particular emphasis on changes in low-molecular-weight metabolites. With the aid of multivariate analysis and metabolic pathway analysis, potential metabolite markers in the amino acid metabolism, urea cycle, purine metabolism, and citrate cycle were highlighted, such as glycine, serine, threonine, malic acid, isocitric acid, uric acid, and urea. The level changes of these metabolites in either serum or colons of colitis mice were further potentiated following fenofibrate treatment. Accordingly, the expression of threonine aldolase and phosphoserine aminotransferase 1 was significantly up-regulated in colitis mice and further potentiated in fenofibrate/DSS-treated mice. It was revealed that beyond the control of lipid metabolism, PPARα also shows effects on the above pathways, resulting in enhanced protein catabolism and energy expenditure, increased bioactive sphingolipid metabolism and proinflammatory state, which were possibly related to the exacerbated colitis.
非诺贝特是一种过氧化物酶体增殖物激活受体α（PPARα）激动剂，研究发现它会加剧实验性急性结肠炎小鼠的炎症和组织损伤。通过脂质组学分析发现，生物活性鞘脂在结肠炎组中显著上调。在本研究中，为了进一步深入了解PPARα依赖性的结肠炎恶化机制，采用基于气相色谱-质谱联用（GC/MS）的代谢组学方法，对用非诺贝特治疗的葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠的血清和结肠进行研究，特别关注低分子量代谢物的变化。借助多变量分析和代谢途径分析，突出了氨基酸代谢、尿素循环、嘌呤代谢和柠檬酸循环中的潜在代谢物标志物，如甘氨酸、丝氨酸、苏氨酸、苹果酸、异柠檬酸、尿酸和尿素。非诺贝特治疗后，这些代谢物在结肠炎小鼠血清或结肠中的水平变化进一步增强。相应地，苏氨酸醛缩酶和磷酸丝氨酸氨基转移酶1的表达在结肠炎小鼠中显著上调，在非诺贝特/DSS治疗的小鼠中进一步增强。研究表明，除了控制脂质代谢外，PPARα还对上述途径产生影响，导致蛋白质分解代谢和能量消耗增强，生物活性鞘脂代谢增加和促炎状态，这可能与结肠炎恶化有关。
