Insulin resistance (IR), caused by impaired insulin signal and decreased insulin sensitivity, is generally responsible for the pathophysiology of type 2 diabetes mellitus (T2DM). Sesquiterpene glycosides (SGs), the exclusive natural products from loquat leaf, have been regarded as potential lead compounds owing to their high efficacy in hypoglycemia and hypolipidemia. Here, we evaluated the beneficial effects of four single SGs isolated from loquat leaf, including SG1, SG2, SG3 and one novel compound SG4 against palmitic acid-induced insulin resistance in HepG2 cells. SG1, SG3 and SG4 could significantly enhance glucose uptake of insulin-resistant HepG2 cells at non-cytotoxic concentration. Meanwhile, Oil Red O staining showed the decrease of both total cholesterol and triglyceride content, suggesting the amelioration of lipid accumulation by SGs in insulin-resistant HepG2 cells. Further investigations found that the expression levels of phosphorylated AMPK, ACC, IRS-1, and Akt were significantly up-regulated after SGs treatment, on the contrary, the expression levels of SREBP-1 and FAS were significantly down-regulated. Notably, AMPK inhibitor Compound C (CC) blocked the regulative effects, while AMPK activator AICAR mimicked the effects of SGs in PA-treated insulin-resistant HepG2 cells. In conclusion, SGs (SG4>SG1≈SG3>SG2) improved lipid accumulation in insulin-resistant HepG2 cells through the AMPK signaling pathway.

中文翻译：

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枇杷（Eriobotrya japonica）叶中的四种倍半萜苷通过AMPK信号通路改善HepG2细胞中棕榈酸诱导的胰岛素抵抗和脂质积累

由胰岛素信号受损和胰岛素敏感性降低引起的胰岛素抵抗 (IR) 通常是 2 型糖尿病 (T2DM) 的病理生理学原因。倍半萜糖苷（SGs）是枇杷叶的独特天然产物，因其对低血糖和低血脂的高效治疗而被认为是潜在的先导化合物。在这里，我们评估了从枇杷叶中分离的四种单一 SGs，包括 SG1、SG2、SG3 和一种新型化合物 SG4，对 HepG2 细胞中棕榈酸诱导的胰岛素抵抗的有益作用。SG1、SG3 和 SG4 可以在非细胞毒性浓度下显着增强胰岛素抵抗 HepG2 细胞的葡萄糖摄取。同时，油红O染色显示总胆固醇和甘油三酯含量均降低，表明 SGs 在胰岛素抵抗的 HepG2 细胞中改善了脂质积累。进一步研究发现，SGs处理后磷酸化AMPK、ACC、IRS-1和Akt的表达水平显着上调，相反，SREBP-1和FAS的表达水平显着下调。值得注意的是，AMPK 抑制剂化合物 C (CC) 阻断了调节作用，而 AMPK 激活剂 AICAR 在 PA 处理的胰岛素抵抗 HepG2 细胞中模拟了 SGs 的作用。总之，SGs (SG4>SG1≈SG3>SG2) 通过 AMPK 信号通路改善了胰岛素抵抗 HepG2 细胞中的脂质积累。SREBP-1和FAS的表达水平显着下调。值得注意的是，AMPK 抑制剂化合物 C (CC) 阻断了调节作用，而 AMPK 激活剂 AICAR 在 PA 处理的胰岛素抵抗 HepG2 细胞中模拟了 SGs 的作用。总之，SGs (SG4>SG1≈SG3>SG2) 通过 AMPK 信号通路改善了胰岛素抵抗 HepG2 细胞中的脂质积累。SREBP-1和FAS的表达水平显着下调。值得注意的是，AMPK 抑制剂化合物 C (CC) 阻断了调节作用，而 AMPK 激活剂 AICAR 在 PA 处理的胰岛素抵抗 HepG2 细胞中模拟了 SGs 的作用。总之，SGs (SG4>SG1≈SG3>SG2) 通过 AMPK 信号通路改善了胰岛素抵抗 HepG2 细胞中的脂质积累。