Xu Xiaofen, Jin Wumeng, Song Jingyi, Hu Xuanming, Lu Lu, Zhang Jida, Hu Changfeng
College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People's Republic of China.
Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, People's Republic of China.
J Inflamm Res. 2024 Oct 29;17:7913-7927. doi: 10.2147/JIR.S485979. eCollection 2024.
Liver injury, such as nonalcoholic fatty liver disease, is a common symptom observed in patients with gout/hyperuricaemia. However, the exact mechanisms are still unclear. There is ongoing controversy about whether representative agents like colchicine and febuxostat, commonly used to manage gout, could also help prevent the liver injury. Liver plays a crucial role in uric acid (UA) production and lipid metabolism. Thus, the study aimed to investigate the aberrant lipid metabolism in the liver during injury and the effects of these drugs.
An advanced multi-dimensional mass spectrometry-based shotgun lipidomics technology was employed for class-targeted lipid analysis of cellular lipidomes in hepatic tissue of a gouty model induced by a combination of monosodium urate crystals and high-fat diet with or without treatment with colchicine and febuxostat. Serum UA, blood urea nitrogen, creatinine, proinflammatory cytokines, expression of AMP-activated protein kinase protein, footpad histopathology, and footpad swelling and pain threshold of these mice were assessed to evaluate the progression of gout.
Lipidomics analysis clearly demonstrated that the ectopic fat accumulation as well as changes in fatty acyls composition in TAG pool, impaired mitochondrial function resulted by decreased tetra 18:2 cardiolipin, and reduced 4-hydroxyalkenal bioavailability in liver tissue could contribute to liver damage to the gouty model. Treatment with colchicine or febuxostat not only ameliorated gouty symptoms but also corrected these abnormal hepatic lipid metabolism patterns.
This study shed light on underlying mechanism(s) for liver injury in gout/hyperuricaemia and suggested that administration of drugs like colchicine and febuxostat could prevent liver injury.
肝损伤，如非酒精性脂肪性肝病，是痛风/高尿酸血症患者常见的症状。然而，确切机制仍不清楚。关于常用的痛风治疗药物，如秋水仙碱和非布司他，是否也有助于预防肝损伤，目前仍存在争议。肝脏在尿酸（UA）生成和脂质代谢中起关键作用。因此，本研究旨在探讨肝损伤期间肝脏中异常的脂质代谢以及这些药物的作用。
采用基于先进多维质谱的鸟枪法脂质组学技术，对尿酸钠晶体和高脂饮食联合诱导的痛风模型肝组织中的细胞脂质组进行类靶向脂质分析，该模型小鼠接受或未接受秋水仙碱和非布司他治疗。评估这些小鼠的血清UA、血尿素氮、肌酐、促炎细胞因子、AMP激活蛋白激酶蛋白的表达、足垫组织病理学以及足垫肿胀和疼痛阈值，以评估痛风的进展。
脂质组学分析清楚地表明，异位脂肪堆积以及TAG池中脂肪酰基组成的变化、由四18:2心磷脂减少导致的线粒体功能受损，以及肝组织中4-羟基烯醛生物利用度降低可能导致痛风模型肝损伤。秋水仙碱或非布司他治疗不仅改善了痛风症状还纠正了这些异常的肝脏脂质代谢模式。
本研究揭示了痛风/高尿酸血症肝损伤的潜在机制，并表明秋水仙碱和非布司他等药物的给药可以预防肝损伤。
