Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity
Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity
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DOI：
10.15252/embj.2019101732
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发表时间：
2020-05-07
期刊：
影响因子：
11.4
通讯作者：
Inokuchi, Jin-ichi
中科院分区：
文献类型：
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作者：
Kanoh, Hirotaka;Nitta, Takahiro;Inokuchi, Jin-ichi
通过TLR 4介导的天然免疫信号在代谢紊乱的发病机制中起着关键作用，但不同脂质种类在代谢紊乱和炎症性疾病中的作用尚不清楚。对来自不同阶段的胰岛素抵抗和慢性炎症患者的人血清GM 3种类的循环水平的分析揭示，VLCFA-GM 3水平在代谢紊乱中显著增加，而LCFA-GM 3血清水平降低。特定的GM 3种类也与疾病症状相关。肥胖小鼠脂肪组织中VLCFA-GM 3水平增加，这在TLR 4突变小鼠中被阻断。在培养的单核细胞中，GM 3本身对TLR 4的活化没有影响，而VLCFA-GM 3协同并选择性地增强LPS/HMGB 1对TLR 4的活化，而LCFA-GM 3和不饱和的VLCFA-GM 3抑制TLR 4的活化。配体-分子对接分析支持VLCFA-GM 3和LCFA-GM 3分别作为TLR 4活性的激动剂和拮抗剂，通过差异结合MD 2的疏水口袋。我们的研究结果表明VLCFA-GM 3是TLR 4介导的疾病进展的危险因素。
Innate immune signaling viaTLR4 plays critical roles in pathogenesis of metabolic disorders, but the contribution of different lipid species to metabolic disorders and inflammatory diseases is less clear.GM3 ganglioside in human serum is composed of a variety of fatty acids, including long-chain (LCFA) and very-long-chain (VLCFA). Analysis of circulating levels of human serumGM3 species from patients at different stages of insulin resistance and chronic inflammation reveals that levels ofVLCFA-GM3 increase significantly in metabolic disorders, whileLCFA-GM3 serum levels decrease. SpecificGM3 species also correlates with disease symptoms.VLCFA-GM3 levels increase in the adipose tissue of obese mice, and this is blocked inTLR4-mutant mice. In cultured monocytes,GM3 by itself has no effect onTLR4 activation; however,VLCFA-GM3 synergistically and selectively enhancesTLR4 activation byLPS/HMGB1, whileLCFA-GM3 and unsaturatedVLCFA-GM3 suppressesTLR4 activation.GM3 interacts with the extracellular region ofTLR4/MD2 complex to modulate dimerization/oligomerization. Ligand-molecular docking analysis supports thatVLCFA-GM3 andLCFA-GM3 act as agonist and antagonist ofTLR4 activity, respectively, by differentially binding to the hydrophobic pocket ofMD2. Our findings suggest thatVLCFA-GM3 is a risk factor forTLR4-mediated disease progression.