PDF(Pubmed)
Abstract：
Geranylgeranoic acid (GGA) was developed as a preventative agent against second primary hepatoma, and was reported to induce cell death in human hepatoma cells via Toll-like receptor 4 (TLR4)-mediated pyroptosis. We recently reported that GGA is enzymatically biosynthesized from mevalonic acid in human hepatoma-derived HuH-7 cells and that endogenous GGA is found in most rat organs including the liver. An unbiased metabolomics analysis of ice-cold 50% acetonitrile extracts from control and GGA-treated cells was performed in this study to characterize the intracellular metabolic changes in GGA-induced pyroptosis and to analyze their relationship with the mechanism of GGA-induced cell death. The total positive ion chromatograms of the cellular extracts in ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry were apparently unchanged after GGA treatment, but an orthogonal partial least squares-discriminant analysis score plot clearly discriminated the intracellular metabolite profiles of GGA-treated cells from that of control cells. S-plot analysis revealed 15 potential biomarkers up-regulated by 24-h GGA treatment according to their variable importance in the projection value of more than 1, and the subsequent metabolomics analysis identified nine of these metabolites as a group of lysophospholipids containing lysophosphatidylcholine with C16:0, C20:4, or C20:3 fatty acids. The possible roles of these lysophospholipids in GGA-induced pyroptosis are discussed.
摘要：
香叶酸（GGA）被开发为第二原发性肝癌的预防剂，据报道，通过Toll样受体4（TLR4）介导的细胞凋亡诱导人肝癌细胞死亡。我们最近报道，GGA是在人肝癌衍生的HuH-7细胞中由甲羟戊酸酶生物合成的，并且在包括肝脏在内的大多数大鼠器官中都发现了内源性GGA。在这项研究中，对来自对照和GGA处理的细胞的冰冷的50％乙腈提取物进行了无偏代谢组学分析，以表征GGA诱导的焦亡的细胞内代谢变化，并分析它们与GGA诱导的细胞死亡机制的关系。GGA处理后，超高效液相色谱与四极杆飞行时间质谱联用中细胞提取物的总正离子色谱图明显不变，但是正交偏最小二乘判别分析得分图清楚地区分了GGA处理的细胞与对照细胞的细胞内代谢物谱。S图分析揭示了通过24小时GGA处理上调的15种潜在生物标志物,根据它们在大于1的预测值中的可变重要性,并且随后的代谢组学分析将这些代谢物中的9种鉴定为含有具有C16:0、C20:4或C20:3脂肪酸的溶血磷脂酰胆碱的一组溶血磷脂。讨论了这些溶血磷脂在GGA诱导的焦亡中的可能作用。
