己糖激酶2在脓毒症诱导的小胶质细胞中促进酰基辅酶a合成酶长链家族成员4的isgyylation。

IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Journal of Lipid Research Pub Date : 2025-04-01 Epub Date: 2025-03-12 DOI:10.1016/j.jlr.2025.100776
Guangyang Bai, Shun Ke, Jun Lu, Shanshan Yu, Shusheng Li, Minghao Fang, Jianmin Ling
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引用次数: 0

摘要

代谢重编程常在败血症相关的小胶质细胞中观察到。然而,对于参与脓毒症相关脑病(SAE)的神经炎症和小胶质细胞脂质积累的异常代谢基因知之甚少。在这里,我们发现己糖激酶2 (HK2)在脂多糖诱导的BV2细胞中上调,并与炎症反应和脂质代谢密切相关。下调HK2可降低BV2细胞及盲肠结扎和穿刺诱导雄性脓毒症小鼠海马中含有3的nod样受体信号传导家族pyrin结构域的激活。此外,抑制HK2可促进脂滴减少。在机制上,小胶质细胞中HK2的敲低降低了干扰素刺激基因15 (ISG15)对酰基辅酶a合成酶长链家族成员4 (ACSL4)的is基化。值得注意的是,siISG15在脂多糖诱导的BV2细胞中有效下调ACSL4的表达。我们的研究结果通过调节ACSL4 isg酰化为HK2在小胶质细胞中的作用机制提供了新的见解,提示了以HK2为靶点治疗SAE的有希望的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Hexokinase 2 promotes ISGylation of Acyl-CoA synthetase long-chain family member 4 in sepsis-induced microglia cells.

Metabolic reprogramming is often observed in sepsis-associated microglial cells. However, little is known about the aberrant metabolic genes involved in neuroinflammation and lipid accumulation in microglial cells of sepsis-associated encephalopathy (SAE). Here, we show that hexokinase 2 (HK2) is upregulated and strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Downregulation of HK2 lowered the activation of NOD-like receptor signaling family pyrin domain containing 3, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) by interferon-stimulated gene 15 (ISG15). Notably, siISG15 effectively down-regulated the expression of ACSL4 in lipopolysaccharide-induced BV2 cells. Our findings provide new mechanistic insights into HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2. Our findings suggest that HK2 modulates ISGylation of ACSL4 in sepsis-induced microglial cells, indicating that therapeutic targeting of HK2 may constitute a promising strategy for SAE.

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来源期刊
Journal of Lipid Research
Journal of Lipid Research 生物-生化与分子生物学
CiteScore
11.10
自引率
4.60%
发文量
146
审稿时长
41 days
期刊介绍: The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.
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