Lipotoxicity induced by saturated fatty acids (SFA) plays a pivotal role in the pathogenesis of a variety of obesity-related metabolic disorders; however, the exact mechanism(s) underlying lipotoxicity development remains elusive. The liver plays a central role in regulating intrahepatic and circulatory lipid homeostasis. In the current study, we identified that mammalian target of rapamycin complex 1 (mTORC1) activation plays an important role in regulating the detrimental effects of SFA palmitate in hepatocytes, in specific cell death, and TG overproduction. Furthermore, our data confirmed that palmitate-induced mTORC1 activation is attributable to its stimulatory effect on IRE1α, one of three canonical pathways activated during ER stress. Importantly, IRE1α inhibition prevented palmitate-triggered cell death and TG overproduction, suggesting mTORC1-IRE1α pathway is mechanistically implicated in palmitate lipotoxicity. The data obtained in the current investigation support future study to explore the therapeutic potential of targeting the mTORC1-IRE1α pathway as a novel clinical strategy for the treatment of metabolic disorders involving lipotoxicity.

中文翻译：

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mTORC1-IRE1α 通路激活有助于肝细胞中棕榈酸引发的甘油三酯分泌和细胞死亡。

饱和脂肪酸 (SFA) 诱导的脂毒性在多种肥胖相关代谢紊乱的发病机制中起着关键作用；然而，脂肪毒性发展的确切机制仍然难以捉摸。肝脏在调节肝内和循环脂质稳态中起核心作用。在目前的研究中，我们发现哺乳动物雷帕霉素复合物 1 (mTORC1) 的靶标在调节 SFA 棕榈酸酯对肝细胞、特定细胞死亡和 TG 过量产生的不利影响方面起着重要作用。此外，我们的数据证实，棕榈酸酯诱导的 mTORC1 激活可归因于其对 IRE1α 的刺激作用，IRE1α 是在内质网应激期间激活的三种经典途径之一。重要的是，IRE1α 抑制阻止了棕榈酸引发的细胞死亡和 TG 过量产生，表明 mTORC1-IRE1α 通路在机械上与棕榈酸酯脂毒性有关。当前调查中获得的数据支持未来的研究，以探索靶向 mTORC1-IRE1α 通路作为治疗涉及脂毒性的代谢紊乱的新临床策略的治疗潜力。