Dimethyl fumarate treatment induces lipid metabolism alterations that are linked to immunological changes
Dimethyl fumarate treatment induces lipid metabolism alterations that are linked to immunological changes
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DOI：
10.1002/acn3.676
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发表时间：
2019-01-01
影响因子：
5.3
通讯作者：
Calabresi, Peter A.
中科院分区：
文献类型：
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作者：
Bhargava, Pavan;Fitzgerald, Kathryn C.;Calabresi, Peter A.
目的确定富马酸二甲酯（DMF）处理引起的代谢变化，并将其与免疫效应联系起来。方法18例MS患者在DMF治疗前和治疗后6个月采血。我们还招募了18名健康对照进行比较。我们对血浆进行了整体代谢组学研究，并使用加权相关网络分析（WGCNA）来识别相关代谢物的模块。我们确定了随治疗而变化的模块，随后进行了靶向代谢组学研究，以证实全球分析中确定的变化。我们将代谢物模块和单个代谢物的变化与免疫学参数的变化相关联。结果我们确定了DMF处理后脂质代谢的改变-两个模块（磷脂、溶血磷脂和缩醛磷脂）的增加和一个模块（饱和和多不饱和脂肪酸）特征代谢物值的减少（所有P < 0.05）。脂肪酸模块的变化在淋巴细胞减少的参与者中更大，并且与绝对淋巴细胞计数的减少（r = 0.65; P = 0.005）和CD 8 + T细胞亚群的变化密切相关。我们还注意到淋巴细胞计数的变化与多种脂肪酸水平（通过靶向或非靶向方法测量）的显著相关性。解释本研究表明，DMF处理改变了脂质代谢，脂肪酸水平的变化与DMF诱导的免疫学变化相关。
Objective Identify metabolic changes produced by dimethyl fumarate (DMF) treatment and link them to immunological effects. Methods We enrolled 18 MS patients and obtained blood prior to DMF and 6 months postinitiation. We also enrolled 18 healthy controls for comparison. We performed global metabolomics on plasma and used weighted correlation network analysis (WGCNA) to identify modules of correlated metabolites. We identified modules that changed with treatment, followed by targeted metabolomics to corroborate changes identified in global analyses. We correlated changes in metabolite modules and individual metabolites with changes in immunological parameters. Results We identified alterations in lipid metabolism after DMF treatment - increases in two modules (phospholipids, lysophospholipids and plasmalogens) and reduction in one module (saturated and poly-unsaturated fatty acids) eigen-metabolite values (all P < 0.05). Change in the fatty acid module was greater in participants who developed lymphopenia and was strongly associated with both reduction in absolute lymphocyte counts (r = 0.65; P = 0.005) and change in CD8+ T cell subsets. We also noted significant correlation of change in lymphocyte counts with multiple fatty acid levels (measured by targeted or untargeted methods). Interpretation This study demonstrates that DMF treatment alters lipid metabolism and that changes in fatty acid levels are related to DMF-induced immunological changes.