Saturated fatty acid (SFA) induces pro-inflammatory response through a toll-like receptor (TLR)-mediated mechanism, which is associated with cardiometabolic diseases such as obesity, insulin resistance, and endothelial dysfunction. Consistent with this notion, TLR2 or TLR4 knock-out mice are protected from obesity-induced pro-inflammatory response and endothelial dysfunction. Although SFA causes endothelial dysfunction through TLR-mediated signaling pathways, the mechanisms underlying SFA-stimulated inflammatory response are not completely understood. To understand the pro-inflammatory response in vascular endothelial cells in high lipid conditions, we compared the pro-inflammatory responses stimulated by palmitic acid (PA) and other canonical TLR agonists (LPS, Pam₃CSK_4, orMALP2) in human aortic endothelial cells. The expression profiles of E-selectin and the signal transduction pathways stimulated by PA were distinct from those stimulated by canonical TLR agonists. Inhibition of long-chain acyl-CoA synthetases (ACSL) by a pharmacological inhibitor or knock-down of ACSL1 blunted the PA-stimulated, but not the LPS- or Pam₃CSK₄-stimulated pro-inflammatory responses. Furthermore, triacsin C restored the insulin-stimulated vasodilation, which was impaired by PA. From the results, we concluded that PA stimulates the pro-inflammatory response in the vascular endothelium through an ACSL1-mediated mechanism, which is distinct from LPS- or Pam3CSK4-stimulated responses. The results suggest that endothelial dysfunction caused by PA may require to undergo intracellular metabolism. This expands the understanding of the mechanisms by which TLRs mediate inflammatory responses in endothelial dysfunction and cardiovascular disease.

中文翻译：

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长链酰基辅酶 A 合成酶 1 介导棕榈酸诱导的人主动脉内皮细胞炎症反应。

饱和脂肪酸 (SFA) 通过 Toll 样受体 (TLR) 介导的机制诱导促炎反应，这与肥胖、胰岛素抵抗和内皮功能障碍等心脏代谢疾病有关。与这一观点一致，TLR2 或 TLR4 基因敲除小鼠免受肥胖诱导的促炎反应和内皮功能障碍的影响。尽管 SFA 通过 TLR 介导的信号通路引起内皮功能障碍，但 SFA 刺激炎症反应的潜在机制尚不完全清楚。为了解高脂条件下血管内皮细胞的促炎反应，我们比较了棕榈酸 (PA) 和其他典型 TLR 激动剂（LPS、Pam ₃ CSK ₄或MALP2) 在人主动脉内皮细胞中。E-选择素的表达谱和 PA 刺激的信号转导通路与经典 TLR 激动剂刺激的不同。通过药理抑制剂抑制长链酰基辅酶 A 合成酶 (ACSL) 或敲低 ACSL1 会减弱 PA 刺激，但不会减弱 LPS- 或 Pam ₃ CSK ₄-刺激的促炎反应。此外，triacsin C 恢复了胰岛素刺激的血管舒张，而这被 PA 削弱了。根据结果​​，我们得出结论，PA 通过 ACSL1 介导的机制刺激血管内皮细胞的促炎反应，这与 LPS 或 Pam3CSK4 刺激的反应不同。结果表明，PA引起的内皮功能障碍可能需要进行细胞内代谢。这扩展了对 TLR 介导内皮功能障碍和心血管疾病炎症反应机制的理解。