College of Urban and Environmental Sciences, Northwest University, No. 1 Xuefu Ave., Guodu Education and Hi-Tech Industries Zone, Xi'an, 710075, China.
Department of Occupational and Environmental Health & Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Air Force Medical University, No.169, Changle West Road, Xi'an, 710032, China.
Environ Sci Pollut Res Int. 2023 Dec;30(60):125991-126008. doi: 10.1007/s11356-023-31086-3. Epub 2023 Nov 27.
Environmental lead (Pb) pollution is a worldwide public health problem and causes various diseases, especially neurodegenerative diseases. It is increasingly recognized that microglia-mediated neuroinflammation plays a crucial role in lead neurotoxicity, but the underlying mechanisms remain to be further explored. Recent studies indicated that cell metabolism, especially lipid metabolism, regulates many microglial functions, including cytokine secretion and phagocytosis. Whether lipid metabolism is involved in Pb-induced neuroinflammation is still unknown. In the current studies, we investigated the effects of Pb on microglial lipid metabolism by utilizing lipidomics. Histochemistry staining and oxygen consumption rate (OCR) were used to validate lipidomics results. Fenofibrate (FEN), a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, was applied to investigate whether lipid metabolism regulation mitigated Pb's neuroinflammatory response. Microglial autophagic proteins were detected to investigate the role of lipophagy in Pb's effect on lipid metabolism. Our results showed that Pb exposure increased concentrations of various lipid metabolites and induced lipid metabolism disorders, especially in fatty acid metabolism. Pb caused lipid droplet (LD) accumulation and slightly enhanced fatty acid oxidation (FAO) in microglia. FEN pretreatment markedly inhibited Pb's effects on LDs and further mitigated Pb-induced inflammatory response by reducing pro-cytokines' expression and enhancing phagocytosis function. FEN intervention also inhibited Pb's neurotoxicity by improving cognition-related behaviors. Pb exposure induced an abnormal increase of autophagic proteins, but the FEN addition partially neutralized Pb's effects on autophagy. Our data indicate that the Pb-induced neuroinflammation is regulated by fatty acid metabolism via the lipophagy process. Therapies focusing on lipid metabolism regulation are powerful tactics in Pb toxicity prevention and treatment.
环境铅 (Pb) 污染是一个全球性的公共卫生问题，可导致多种疾病，尤其是神经退行性疾病。人们越来越认识到，小胶质细胞介导的神经炎症在铅神经毒性中起着至关重要的作用，但潜在机制仍有待进一步探索。最近的研究表明，细胞代谢，特别是脂质代谢，调节小胶质细胞的许多功能，包括细胞因子的分泌和吞噬作用。脂质代谢是否参与 Pb 诱导的神经炎症仍不清楚。在目前的研究中，我们通过代谢组学研究了 Pb 对小胶质细胞脂质代谢的影响。组织化学染色和耗氧量 (OCR) 用于验证代谢组学结果。非诺贝特 (FEN)，一种过氧化物酶体增殖物激活受体-α (PPAR-α) 激动剂，用于研究脂质代谢调节是否减轻了 Pb 的神经炎症反应。检测小胶质细胞自噬蛋白，以研究脂噬在 Pb 对脂质代谢影响中的作用。研究结果表明，Pb 暴露增加了各种脂质代谢物的浓度并诱导脂质代谢紊乱，尤其是在脂肪酸代谢中。Pb 导致小胶质细胞脂滴 (LD) 积累，并略微增强脂肪酸氧化 (FAO)。FEN 预处理显著抑制了 Pb 对 LD 的影响，并通过降低前细胞因子的表达和增强吞噬作用功能进一步减轻了 Pb 诱导的炎症反应。FEN 干预还通过改善与认知相关的行为来抑制 Pb 的神经毒性。Pb 暴露诱导自噬蛋白异常增加，但 FEN 的添加部分中和了 Pb 对自噬的影响。研究数据表明，Pb 诱导的神经炎症通过脂噬过程受脂肪酸代谢调节。针对脂质代谢调节的治疗方法是预防和治疗 Pb 毒性的有效策略。
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