State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
Key Laboratory of Quality & Safety Control for Milk and Dairy Products of Ministry of Agriculture and Rural Affairs, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
Int J Mol Sci. 2019 May 14;20(10):2388. doi: 10.3390/ijms20102388.
As one of the typical Maillard reaction products, furosine has been widely reported in a variety of heat-processed food. Though furosine was shown to be toxic on organs, its toxicity mechanism is still unclear. The present study aimed to investigate the toxicity mechanism of furosine in liver tissue. An intragastric gavage mice model (42-day administration, 0.1/0.25/0.5 g/kg of furosine per day) and a mice primary hepatocyte model were employed to investigate the toxicity mechanism of furosine on mice liver tissue. A metabonomics analysis of mice liver, serum, and red blood cells (RBC) was performed. The special metabolic mediator of furosine, lysophosphatidylcholine 18:0 (LPC (18:0)) was identified. Then, the effect of the upstream gene phospholipase A2 gamma () on LPC (18:0), as well as the effect of furosine (100 mg/L) on the receptor-interacting serine/threonine-protein kinase (RIPK)1/RIPK3/mixed lineage kinase domain-like protein (MLKL) pathway and inflammatory factors, was determined in liver tissue and primary hepatocytes. PLA2-3 was found to regulate the level of LPC (18:0) and activate the expression of RIPK1, RIPK3, P-MLKL, and of the inflammatory factors including tumor necrosis factor α (TNF-α) and interleukin (IL-1β), both in liver tissue and in primary hepatocytes. Upon treatment with furosine, the upstream sensor PLA2-3 activated the RIPK1/RIPK3/MLKL necroptosis pathway and caused inflammation by regulating the expression of LPC (18:0), which further caused liver damage.
作为美拉德反应的典型产物之一，呋塞米已在各种热加工食品中广泛报道。虽然呋塞米被证明对器官有毒性，但它的毒性机制尚不清楚。本研究旨在探讨呋塞米对肝组织的毒性机制。采用灌胃给药小鼠模型（42 天给药，每天 0.1/0.25/0.5 g/kg 呋塞米）和小鼠原代肝细胞模型，研究呋塞米对小鼠肝组织的毒性机制。对小鼠肝、血清和红细胞（RBC）进行代谢组学分析。鉴定了呋塞米的特殊代谢调节剂溶血磷脂酰胆碱 18:0（LPC（18:0））。然后，测定了上游基因磷脂酶 A2 伽马（）对 LPC（18:0）的影响，以及呋塞米（100mg/L）对受体相互作用丝氨酸/苏氨酸蛋白激酶（RIPK）1/RIPK3/混合谱系激酶结构域样蛋白（MLKL）通路和炎症因子的影响在肝组织和原代肝细胞中。发现 PLA2-3 调节 LPC（18:0）的水平，并激活 RIPK1、RIPK3、P-MLKL 和炎症因子如肿瘤坏死因子-α（TNF-α）和白细胞介素（IL-1β）的表达，无论是在肝组织还是在原代肝细胞中。在呋塞米处理下，上游传感器 PLA2-3 通过调节 LPC（18:0）的表达激活 RIPK1/RIPK3/MLKL 坏死通路并引起炎症，从而导致肝损伤。
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