Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei, China.
Department of Electromyogram, 3rd Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
J Cell Biochem. 2019 Apr;120(4):5777-5789. doi: 10.1002/jcb.27864. Epub 2018 Oct 26.
Abnormal lipid metabolism and SREBP-1 downregulation are reported to be involved in the pathogenesis of diabetic peripheral neuropathy (DPN). In the current study, the relationship between PI3K/Akt signaling pathway and SREBP-1 expression was explored in Schwann cells of DPN. The phospho-Akt (Ser 473), phospho-Akt (Thr 308), and SREBP-1 expression were inhibited in the sciatic nerves of diabetic mice versus those of normal mice, accompanied with the atrophy of nerve fiber and the irregular myelin sheath. High concentration glucose suppressed phospho-Akt (Ser 473), phospho-Akt (Thr 308), and SREBP-1 expression in cultured Schwann cell (RSC96 cell) in vitro, and 25 mmol/L glucose was enough to lead to the maximum inhibitory effect. The time-course effect of high glucose showed that Akt phosphorylation gradually decreased with the extension of stimulation time. Somewhat differently, short-term high-glucose exposure enhanced SREBP-1 expression and prolonged high-glucose stimulation reduced the SREBP-1 expression in RSC96 cells. Similarly, prolonged high-glucose stimulation also downregulated FASN messenger RNA (mRNA), ACC mRNA, intracellular triglyceride, and cholesterol. LY294002 suppressed Akt activation followed by the decreased SREBP-1, FASN, ACC, triglyceride, and cholesterol. Contrarily, the PI3K/Akt signaling pathway agonist insulin pretreatment avoided prolonged high-glucose stimulation-blocked Akt activation and increased SREBP-1, FASN, and ACC expression in the levels of protein and mRNA in RSC96 cells. The knockdown of SREBP-1 by shRNA prevented insulin-induced enhanced FASN, ACC mRNA expression, triglyceride, and cholesterol in high-glucose-treated RSC96 cells. In conclusion, prolonged high-glucose exposure inhibits the SREBP-1/FASN/ACC expression in the Schwann cells of DPN via the blockage of the PI3K/Akt signaling pathway.
异常的脂质代谢和 SREBP-1 下调被报道与糖尿病周围神经病变（DPN）的发病机制有关。在本研究中，探讨了 DPNSchwann 细胞中 PI3K/Akt 信号通路与 SREBP-1 表达之间的关系。与正常小鼠相比，糖尿病小鼠坐骨神经中的磷酸化 Akt（Ser473）、磷酸化 Akt（Thr308）和 SREBP-1 表达受到抑制，伴随着神经纤维萎缩和髓鞘不规则。体外培养的 Schwann 细胞（RSC96 细胞）中高浓度葡萄糖抑制磷酸化 Akt（Ser473）、磷酸化 Akt（Thr308）和 SREBP-1 的表达，25mmol/L 葡萄糖足以达到最大抑制作用。高葡萄糖的时程效应表明，Akt 磷酸化随着刺激时间的延长逐渐降低。略有不同的是，短期高葡萄糖暴露增强了 SREBP-1 的表达，而延长高葡萄糖刺激则降低了 RSC96 细胞中的 SREBP-1 表达。同样，延长高葡萄糖刺激也下调了 FASN 信使 RNA（mRNA）、ACC mRNA、细胞内三酰甘油和胆固醇。LY294002 抑制 Akt 激活，随后 SREBP-1、FASN、ACC、三酰甘油和胆固醇减少。相反，PI3K/Akt 信号通路激动剂胰岛素预处理可避免延长高葡萄糖刺激阻断 Akt 激活，并增加 RSC96 细胞中 SREBP-1、FASN 和 ACC 的蛋白和 mRNA 表达。shRNA 敲低 SREBP-1 可防止胰岛素诱导的高葡萄糖处理的 RSC96 细胞中 FASN、ACC mRNA 表达、三酰甘油和胆固醇增加。总之，延长的高葡萄糖暴露通过阻断 PI3K/Akt 信号通路抑制 DPNSchwann 细胞中 SREBP-1/FASN/ACC 的表达。
