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首页> 外文会议>American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics >Therapeutic Metabolomics Identifies Fatty Acid Metabolism as a Target for Treating Multiple Sclerosis
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Therapeutic Metabolomics Identifies Fatty Acid Metabolism as a Target for Treating Multiple Sclerosis

机译：治疗性代谢组学认为脂肪酸代谢作为治疗多发性硬化的靶标

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Multiple Sclerosis is an inflammatory demyelinating disease of the central nervous system that affects over 2 million people worldwide. Current therapies are not effective for all patients and do not prevent the accumulation of neurological disability over time. Untargeted metabolomics measures the end products of both gene and protein expression to determine the physiological state of the tissue or cell during normal function and disease states. We used liquid chromatography-mass spectrometry to examine the metabolite profiles in the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE) and mouse hepatitis virus infection (MHV), two animal models of multiple sclerosis, as well as in tissue sections from multiple sclerosis patients with active inflammatory lesions or chronic, inactive lesions. Significant upregulation of a number of acylcarnitine species was seen in the spinal cords of EAE and MHV mice as well as in multiple sclerosis patients with active inflammatory lesions. These species are formed during the beta-oxidation of fatty acids through the conjugation of fatty acids to carnitine facilitating their importation into the mitochondria. Using mass-based imaging, dysregulated acylcarnitines were found to be upregulated in inflammatory lesions in EAE spinal cord and treatment of mice with an inhibitor of carnitine palmitoyltransferase-1 (CPT-1), the enzyme that regulates the import of acylcamitines into the mitochondria, reduced disease severity. Mice treated with this drug showed decreased levels of inflammatory cells in the CNS and a reduction in acylcarnitine species. Inhibition of CPT-1 in encephalitogenic T cell cultures during antigen stimulation under low-glucose conditions lead to increased apoptosis. These results suggest that upregulation of fatty acid oxidation plays a role in inflammatory lesion formation during autoimmune demyelination and that inhibition of this pathway may be a novel therapeutic strategy for autoimmune disease of the central nervous system
机译：多发性硬化是中枢神经系统的炎症脱髓鞘疾病，影响全世界超过200万人。目前的疗法对于所有患者无效，并且不会阻止随着时间的推移积累神经障碍。未确定的代谢组学测量基因和蛋白质表达的最终产物，以确定正常功能和疾病状态期间组织或细胞的生理状态。我们使用液相色谱 - 质谱法以检查小鼠脊髓中的代谢物谱，用实验性自身免疫脑脊髓炎（EAE）和小鼠肝炎病毒感染（MHV），多种硬化症的两种动物模型，以及来自多发性硬化的组织切片患者有活性炎症病变或慢性，无活性病变。在EAE和MHV小鼠的脊髓以及多发性炎症病变中的多发性硬化患者中观察到许多酰基氨基碱物种的显着上调。在脂肪酸的β-氧化过程中形成这些物种通过将脂肪酸与肉毒碱的缀合，促进其进口到线粒体中。使用基于质量的成像，发现了失去的酰基甘油氨酸在EAE脊髓中的炎性病变中上调，并用肉氨基丙酰丙酰转移酶-1（CPT-1）的抑制剂治疗小鼠，该酶调节酰基氨基氨基进入线粒体，减少疾病严重程度。用该药物处理的小鼠显示CNS中炎性细胞水平降低以及酰基肉碱物种的还原。低葡萄糖条件下抗原刺激期间CPT-1对脑发生T细胞培养的抑制导致凋亡增加。这些结果表明，脂肪酸氧化的上调在自身免疫脱髓鞘期间对炎性病变形成起作用作用，并且该途径的抑制可能是中枢神经系统的自身免疫性疾病的新疗效策略

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