Despite the widespread use of silica nanoparticles (SiNPs), their metabolic impact and mechanisms of action have not been well studied. Exposure to SiNPs induces insulin resistance (IR) in hepatocytes by endoplasmic reticulum (ER) stress via inositol-requiring protein 1α (IRE1α) activation of c-Jun N-terminal kinases (JNK). It has been well established that stearoyl CoA desaturase (SCD1) and its major product oleic acid elicited beneficial effects in restoring ER homeostasis. However, the potential coordination of SCD1 and IRE1α in determining SiNP regulation of insulin signaling is unclear. Herein, we investigated the effects of SCD1 and oleic acid on IR induced by SiNPs or thapsigargin in hepatocytes. SCD1 overexpression or oleic acid efficiently reversed SiNP-induced ER stress and IR, whereas the effects of thapsigargin treatment could not be restored. Thapsigargin diminished SCD1 protein levels, leading to the accumulation of IRE1α and sustained activation of the IRE1α/JNK pathway. Moreover, knockdown of activating transcription factor 4 (ATF4) upstream of SCD1 suppressed SiNP-induced SCD1 expression, rescued the activated IRE1α, and inhibited insulin signaling but was not able to restore the effects of thapsigargin. Collectively, downregulation of SCD1 and excess accumulation of IRE1α protein prevented the beneficial effects of exogenous oleic acid on IR induced by ER stress. Our results provide valuable mechanistic insights into the synergic regulation of IR by SiNPs and ER stress and suggest a combinational strategy to restore ER homeostasis by targeting SCD1 and IRE1α proteins, as well as supplementation of unsaturated fatty acids.

中文翻译：

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硬脂酰 CoA 去饱和酶 1 和需要肌醇的蛋白 1α 确定油酸在减轻二氧化硅纳米颗粒诱导的胰岛素抵抗中的效率。

尽管二氧化硅纳米粒子 (SiNPs) 被广泛使用，但它们的代谢影响和作用机制尚未得到很好的研究。暴露于 SiNPs 通过内质网 (ER) 应激通过c-Jun N 末端激酶 (JNK) 的肌醇需要蛋白 1 α (IRE1 α ) 激活诱导肝细胞中的胰岛素抵抗 (IR )。众所周知，硬脂酰辅酶 A 去饱和酶 (SCD1) 及其主要产物油酸在恢复内质网稳态方面发挥了有益作用。然而，SCD1 和 IRE1 α的潜在协调在确定胰岛素信号传导的 SiNP 调节方面尚不清楚。在此，我们研究了 SCD1 和油酸对 SiNPs 或毒胡萝卜素在肝细胞中诱导的 IR 的影响。SCD1 过表达或油酸有效地逆转了 SiNP 诱导的内质网应激和 IR，而毒胡萝卜素治疗的效果无法恢复。毒胡萝卜素降低 SCD1 蛋白水平，导致 IRE1 α的积累和 IRE1 α /JNK 通路的持续激活。此外，SCD1 上游激活转录因子 4（ATF4）的敲低抑制了 SiNP 诱导的 SCD1 表达，挽救了激活的 IRE1 α，并抑制胰岛素信号，但不能恢复毒胡萝卜素的作用。总的来说，SCD1 的下调和 IRE1 α蛋白的过度积累阻止了外源性油酸对 ER 应激诱导的 IR 的有益影响。我们的研究结果为 SiNPs 和 ER 应激对 IR 的协同调节提供了有价值的机制见解，并提出了通过靶向 SCD1 和 IRE1 α蛋白以及补充不饱和脂肪酸来恢复 ER 稳态的组合策略。