脂肪酸棕榈酸酯通过 C2C12 肌管中的 PERK 和 IRE1 未折叠蛋白反应抑制 FoxO1 表达,Toxicology in Vitro

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脂肪酸棕榈酸酯通过 C2C12 肌管中的 PERK 和 IRE1 未折叠蛋白反应抑制 FoxO1 表达
Toxicology in Vitro ( IF 2.6 ) Pub Date : 2022-08-24 , DOI: 10.1016/j.tiv.2022.105459
Boya Zhang ₁ , Ruijiao Zhu ₁ , Xiaotong Sun ₁ , Qian Guo ₂ , Yao Zhang ₁ , Nanxi Zhang ₁ , Yuri Oh ₃ , Lei Fan ₄ , Changlin Wang ₁ , Ning Gu ₁

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Forkhead Box O1 (FoxO1) 是一种转录因子，具有独特的叉头结构域，间接参与多种生理过程，在 2 型糖尿病中发挥重要作用。棕榈酸酯是最丰富的游离脂肪酸，占人血浆中总游离脂肪酸的 28-32%。棕榈酸酯与胰岛素抵抗诱导的 2 型糖尿病之间存在直接关系。此外，棕榈酸酯可以激活内质网（ER）应激诱导的未折叠蛋白反应信号通路。本研究旨在调查 FoxO1 对棕榈酸酯的反应以及与 C2C12 肌管中 ER 应激的关系。棕榈酸酯或衣霉素的处理促进了 ER 应激相关基因的表达，但抑制了 FoxO1 的表达，而 4-苯基丁酸在棕榈酸预处理的 C2C12 肌管中表现出相反的活性，表明 ER 应激可能与 FoxO1 表达密切相关。此外，当用 GSK2656157 或 4μ8C 处理抑制 PERK 和 IRE-1 信号通路时，棕榈酸抑制的 FoxO1 表达在 C2C12 细胞中被逆转。然而，当 ATF6 信号通路被 ATF6 基因敲除抑制时，没有观察到差异。这些发现表明棕榈酸酯通过 PERK 和 IRE1 信号通路抑制 FoxO1 的表达。当 ATF6 信号通路被 ATF6 基因敲除抑制时，没有观察到差异。这些发现表明棕榈酸酯通过 PERK 和 IRE1 信号通路抑制 FoxO1 的表达。当 ATF6 信号通路被 ATF6 基因敲除抑制时，没有观察到差异。这些发现表明棕榈酸酯通过 PERK 和 IRE1 信号通路抑制 FoxO1 的表达。

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Fatty acid palmitate suppresses FoxO1 expression via PERK and IRE1 unfolded protein response in C2C12 myotubes

Forkhead Box O1 (FoxO1) is a transcription factor with a unique fork head domain that indirectly participates in a variety of physiological processes and plays an important role in type 2 diabetes. Palmitate as the most abundant free fatty acid, accounting for 28–32% of total free fatty acids in human plasma. There is a direct relationship between palmitate and insulin resistance-induced type 2 diabetes. In addition, palmitate can activate the unfolded protein response signaling pathway induced by endoplasmic reticulum (ER) stress. This study aimed to investigate the response of FoxO1 to palmitate and the relationship with ER stress in C2C12 myotubes. Treatment of palmitate or tunicamycin promoted ER stress-related genes expression but suppressed FoxO1 expression, while 4-phenylbutyrate presented the opposite activity in palmitate-pretreated C2C12 myotubes, indicating that ER stress might be closely associated with FoxO1 expression. Moreover, palmitate-suppressed FoxO1 expression was reversed in C2C12 cells when the PERK and IRE-1 signaling pathway was inhibited by treatment with GSK2656157 or 4μ8C. However, no differences were observed when the ATF6 signaling pathway was suppressed by knockout of the ATF6 gene. These findings suggest that palmitate suppressed FoxO1 expression via the PERK and IRE1 signaling pathways.

更新日期：2022-08-24

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