Linked metabolic and cardiovascular comorbidities are prevalent in hyperuricemia and gout. For mechanistic insight into impact on inflammatory processes and cardiometabolic risk factors of xanthine oxidase inhibitor urate-lowering therapy (ULT) titration to target, we performed a prospective study of gout serum metabolomes from a ULT trial. Sera of gout patients meeting the 2015 ACR/EULAR gout classification criteria (n = 20) and with hyperuricemia were studied at time zero and weeks 12 and 24 of febuxostat or allopurinol dose titration ULT. Ultrahigh performance liquid chromatography-tandem mass spectroscopy acquired the serum spectra. Data were assessed using the Metabolon and Metaboloanalyst software. Lipolysis validation assays were done in febuxostat and/or colchicine-treated 3T3-L1 differentiated adipocytes. Serum urate decreased from time zero (8.21 ±1.139 SD) at weeks 12 (5.965 ± 1.734 SD) and 24 (5.655 ±1.763 SD). Top metabolites generated by changes in nucleotide and certain amino acid metabolism and polyamine pathways were enriched at 12 and 24 weeks ULT, respectively. Decreases in multiple fatty acid metabolites were observed at 24 weeks, linked with obesity. In cultured adipocytes, febuxostat significantly decreased while colchicine increased the lipolytic response to β-adrenergic-agonism or TNF. Metabolomic profiles linked xanthine oxidase inhibitor-based ULT titration to target with reduced serum free fatty acids. In vitro validation studies revealed that febuxostat, but not colchicine, reduced lipolysis in cultured adipocytes. Since soluble urate, xanthine oxidase inhibitor treatment, and free fatty acids modulate inflammation, our findings suggest that by suppressing lipolysis, ULT could regulate inflammation in gout and comorbid metabolic and cardiovascular disease.

中文翻译：

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黄嘌呤氧化酶抑制剂降尿酸治疗滴定可降低痛风中的血清游离脂肪酸并抑制脂肪细胞的脂肪分解

相关的代谢和心血管合并症在高尿酸血症和痛风中很普遍。为了从机制上深入了解黄嘌呤氧化酶抑制剂降尿酸治疗 (ULT) 滴定至目标对炎症过程和心脏代谢危险因素的影响，我们对 ULT 试验中的痛风血清代谢组进行了前瞻性研究。符合 2015 ACR/EULAR 痛风分类标准（n = 20）和高尿酸血症的痛风患者的血清在非布索坦或别嘌醇剂量滴定 ULT 的第 0 周和第 12 周和第 24 周进行了研究。超高效液相色谱-串联质谱法获得了血清谱图。使用 Metabolon 和 Metaboloanalyst 软件评估数据。在非布索坦和/或秋水仙碱处理的 3T3-L1 分化脂肪细胞中进行脂解验证测定。在第 12 周 (5.965 ± 1.734 SD) 和第 24 周 (5.655 ±1.763 SD)，血清尿酸盐从时间零 (8.21 ±1.139 SD) 开始下降。核苷酸和某些氨基酸代谢以及多胺途径变化产生的主要代谢物分别在 ULT 12 周和 24 周时富集。在 24 周时观察到多种脂肪酸代谢物减少，这与肥胖有关。在培养的脂肪细胞中，非布司他显着降低，而秋水仙碱增加了对 β-肾上腺素能激动剂或 TNF 的脂解反应。代谢组学特征将基于黄嘌呤氧化酶抑制剂的 ULT 滴定与血清游离脂肪酸减少的靶标联系起来。体外验证研究表明，非布索坦而非秋水仙碱可减少培养的脂肪细胞中的脂肪分解。由于可溶性尿酸盐、黄嘌呤氧化酶抑制剂治疗和游离脂肪酸可调节炎症，