Liu Jing-Yi, Zhang Yi-Chen, Song Li-Ni, Zhang Lin, Yang Fang-Yuan, Zhu Xiao-Rong, Cheng Zhi-Qiang, Cao Xi, Yang Jin-Kui
Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University Beijing 100730 China
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine Baltimore MD 21205 USA.
RSC Adv. 2019 Nov 29;9(67):39394-39404. doi: 10.1039/c9ra06527j. eCollection 2019 Nov 27.
Inflammation constitutes an important component of non-alcoholic fatty liver disease. STAT3 is a direct target of inflammatory cytokines, but also mediates glycolipid metabolism in the liver. As a potent inhibitor of STAT3, the effect of Nifuroxazide (Nifu) on glycolipid metabolism in liver has not been reported. In this study, we used palmitic acid (PA)-induced HepG2 cells to examine the expression of inflammatory factors and apoptosis-related proteins and the content of triglyceride (TG), total cholesterol (TC), and glycogen. The expression of hepatic lipogenic proteins (ACCα, SREBP-1c, FAS), gluconeogenesis enzymes (PEPCK, G6Pase, and IRS2), the IL-6/STAT3/SOCS3 inflammatory axis, and the insulin signaling pathway was determined. Our study shows that Nifu significantly improves lipid metabolism disorders in the PA-induced HepG2 cells, whereas, it remarkably reduced intracellular free fatty acid (FFA), TG, and TC content, suppressed lipid synthesis, and increased lipid decomposition. Our results also showed that Nifu significantly improved dysregulated glucose metabolism in the PA-treated HepG2 cells, increased glycogen content, and inhibited gluconeogenesis. Further research indicated that Nifu markedly inhibited activation of the IL-6/STAT3/SOCS3 signaling pathway. Finally, due to anti-inflammatory stress, Nifu enhanced insulin signaling in the PA-induced HepG2 cells. Therefore, Nifu can improve glucose and lipid metabolism in the PA-induced HepG2 cells, which provides new evidence that Nifu has a positive effect on PA-induced cellular hepatic steatosis and improves glucose metabolism in HepG2 cells, providing a new perspective for studying drug treatment of glucose and lipid metabolism disorders.
炎症是非酒精性脂肪性肝病的一个重要组成部分。信号转导和转录激活因子3（STAT3）是炎性细胞因子的直接靶点，同时也介导肝脏中的糖脂代谢。作为一种有效的STAT3抑制剂，硝唑尼特（Nifu）对肝脏糖脂代谢的影响尚未见报道。在本研究中，我们使用棕榈酸（PA）诱导的HepG2细胞来检测炎性因子和凋亡相关蛋白的表达以及甘油三酯（TG）、总胆固醇（TC）和糖原的含量。测定了肝脏生脂蛋白（ACCα、SREBP-1c、FAS）、糖异生酶（PEPCK、G6Pase和IRS2）、IL-6/STAT3/SOCS3炎性轴以及胰岛素信号通路的表达。我们的研究表明，Nifu显著改善了PA诱导的HepG2细胞中的脂质代谢紊乱，同时，它显著降低了细胞内游离脂肪酸（FFA）、TG和TC含量，抑制了脂质合成，并增加了脂质分解。我们的结果还表明，Nifu显著改善了PA处理的HepG2细胞中失调的葡萄糖代谢，增加了糖原含量，并抑制了糖异生。进一步的研究表明，Nifu显著抑制了IL-6/STAT3/SOCS3信号通路的激活。最后，由于抗炎应激，Nifu增强了PA诱导的HepG2细胞中的胰岛素信号。因此，Nifu可以改善PA诱导的HepG2细胞中的葡萄糖和脂质代谢，这为Nifu对PA诱导的细胞性肝脂肪变性具有积极作用并改善HepG2细胞中的葡萄糖代谢提供了新的证据，为研究糖脂代谢紊乱的药物治疗提供了新的视角。
