内因性リガンドによるToll様受容体制御と慢性炎症疾患への関与の解明─ガングリオシドによるTLR4シグナルの恒常性維持と破綻のメカニズム─

DOI Web Site Web Site PubMed 参考文献48件
  • 狩野 裕考
    東北医科薬科大学薬学部分子生体膜研究所機能病態分子学教室

書誌事項

タイトル別名
  • Homeostatic and Pathophysiological Regulation of Toll-like Receptor 4 Signaling by GM3 Ganglioside Molecular Species
  • 内因性リガンドによるToll様受容体制御と慢性炎症疾患への関与の解明 : ガングリオシドによるTLR4シグナルの恒常性維持と破綻のメカニズム
  • ナイインセイ リガンド ニ ヨル Toll ヨウ ジュヨウタイ セイギョ ト マンセイ エンショウ シッカン エ ノ カンヨ ノ カイメイ : ガングリオシド ニ ヨル TLR4 シグナル ノ コウジョウセイ イジ ト ハタン ノ メカニズム

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<p>Chronic inflammation plays an important role in the pathogenesis of obesity and metabolic disorders. In obesity, pattern-recognition receptors in innate immune system, such as Toll-like receptor 4 (TLR4), cause chronic inflammation through prolonged activation by various endogenous ligands, including fatty acids and its metabolites. Gangliosides and other glycosphingolipids are important metabolites of fatty acids and saccharides. GM3, the simplest ganglioside comprising α2,3-sialyllactose, is expressed in insulin-sensitive peripheral tissues such as liver and adipose tissue, and furthermore secreted abundantly into serum. It has been shown that GM3 regulates the signal transduction of insulin receptor in adipose tissue as a component of membrane microdomains, and elevation in GM3 level causes insulin resistance. However, the homeostatic and pathophysiological functions of extracellularly secreted GM3 are poorly understood. We recently reported that GM3 species with differing fatty acid structures act as pro- and anti-inflammatory endogenous TLR4 ligands. GM3 with very long-chain fatty acid (VLCFA) and α-hydroxyl VLCFA strongly enhanced TLR4 activation. Conversely, GM3 with long-chain fatty acid (LCFA) and ω-9 unsaturated VLCFA inhibited TLR4 activation, counteracting the VLCFA species. GM3 interacted with the extracellular complex of TLR4 and promoted dimerization/oligomerization. In obesity and metabolic disorders, VLCFA species were increased in serum and adipose tissue, whereas LCFA species was relatively decreased; their imbalances were correlated to disease progression. Our findings suggest that GM3 species are disease-related endogenous TLR4 ligands, and “glycosphingolipid sensing” by TLR4 controls the homeostatic and pathological roles of innate immune signaling.</p>

収録刊行物

  • 薬学雑誌

    薬学雑誌 142 (3), 195-203, 2022-03-01

    公益社団法人 日本薬学会

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