Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA.
Department of Gastroenterology, Tongji Medical College and The Central Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan 430000, PR. China.
Exp Biol Med (Maywood). 2020 Aug;245(14):1268-1279. doi: 10.1177/1535370220928276. Epub 2020 May 21.
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.
饱和脂肪酸（SFA）引起的脂毒性在多种肥胖相关代谢紊乱的发病机制中起关键作用；然而，脂毒性发展的确切机制仍不清楚。肝脏在调节肝内和循环脂质稳态方面起着核心作用。在本研究中，我们发现雷帕霉素复合物 1（mTORC1）的激活在调节棕榈酸酯在肝细胞中的有害作用方面起着重要作用，特别是在细胞死亡和 TG 过度产生方面。此外，我们的数据证实，棕榈酸酯诱导的 mTORC1 激活归因于其对内质网应激期间激活的三个经典途径之一 IRE1α的刺激作用。重要的是，IRE1α 的抑制可防止棕榈酸酯触发的细胞死亡和 TG 过度产生，表明 mTORC1-IRE1α 途径在棕榈酸酯脂毒性中具有机制相关性。本研究获得的数据支持进一步研究探索靶向 mTORC1-IRE1α 途径的治疗潜力，作为一种治疗涉及脂毒性的代谢紊乱的新的临床策略。
