Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
Int J Mol Sci. 2022 May 20;23(10):5700. doi: 10.3390/ijms23105700.
Leptin is a crucial regulator of metabolism and energy homeostasis in mammals. Many studies have investigated the impacts of leptin on human cancers, such as proliferation and metastasis. However, the mechanisms underlying leptin-mediated regulation of lipid metabolism in nasopharyngeal carcinoma (NPC) remain incompletely understood. In the current study, leptin downregulation ameliorated lipid accumulation, triglyceride, and cholesterol levels. Mechanistically, diminished leptin by siRNA not only inhibited sterol regulatory element-binding protein 1 (SREBP1), a master regulator of lipid metabolism, at the mRNA and protein levels, but also reduced SREBP1 downstream target expressions, such as fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD1), in NPC cells. In addition, leptin expression could modulate the promoter activity of SREBP1. We also found that pharmacological inhibition of poly-ADP ribose polymerase-γ (PPAR-γ) resulted in increased SREBP1 expression in leptin-depleted NPC cells. Functionally, SREBP1 overexpression overcame the effects of leptin-silencing attenuated triglyceride level, cholesterol level and cell survival in NPC cells. Taken together, our results demonstrate that leptin is an important regulator of lipid metabolism in NPC cells and might could be a potential therapeutic target for treatment of NPC patients.
瘦素是哺乳动物代谢和能量平衡的重要调节剂。许多研究已经调查了瘦素对人类癌症的影响，如增殖和转移。然而，瘦素介导的鼻咽癌（NPC）脂质代谢调节的机制仍不完全清楚。在本研究中，瘦素下调改善了脂质积累、甘油三酯和胆固醇水平。在机制上，siRNA 介导的瘦素减少不仅在 mRNA 和蛋白水平上抑制了脂质代谢的主要调节因子固醇调节元件结合蛋白 1（SREBP1），还降低了 SREBP1 下游靶基因的表达，如脂肪酸合酶（FASN）和硬脂酰辅酶 A 去饱和酶 1（SCD1），在 NPC 细胞中。此外，瘦素表达可以调节 SREBP1 的启动子活性。我们还发现，聚 ADP 核糖聚合酶-γ（PPAR-γ）的药理学抑制导致瘦素耗尽的 NPC 细胞中 SREBP1 表达增加。功能上，SREBP1 的过表达克服了瘦素沉默减弱 NPC 细胞中甘油三酯水平、胆固醇水平和细胞存活的作用。总之，我们的结果表明，瘦素是 NPC 细胞脂质代谢的重要调节剂，可能是治疗 NPC 患者的潜在治疗靶点。
