Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
Biomed Pharmacother. 2016 Oct;83:785-791. doi: 10.1016/j.biopha.2016.07.028. Epub 2016 Aug 1.
Swertiamarin, a bitter secoiridoid glycoside, is an antidiabetic drug with lipid lowering activity meliorates insulin resistance in Type 2 Diabetes condition. Therefore, the study was designed to explore the antioxidant and hypolipidemic activity of swertiamarin in ameliorating NAFLD caused due to hepatic lipid accumulation, inflammation and insulin resistance. Steatosis was induced in HepG2 cells by supplementing 1mM oleic acid (OA) for 24h which was marked by significant accumulation of lipid droplets. This was determined by Oil Red O (ORO) staining and triglyceride accumulation. Swertiamarin (25μg/ml) decreased triglyceride content by 2 folds and effectively reduced LDH release (50%) activity by protecting membrane integrity thus, preventing apoptosis evidenced by reduced cleavage of Caspase 3 and PARP1. We observed that swertiamarin significantly increased the expressions of major insulin signaling proteins like Insulin receptor (IR), PI(3)K, pAkt with concomitant reduction in p307 IRS-1. AMPK was activated by swertiamarin action, thus restoring insulin sensitivity in hepatocytes. In addition, qPCR results confirmed OA up-regulated Sterol Regulatory Element Binding Protein (SREBP)-1c and fatty acid synthase (FAS), resulting in increased fatty acid synthesis. Swertiamarin effectively modulated PPAR-α, a major potential regulator of carbohydrate metabolism which, in turn, decreased the levels of the gluconeogenic enzyme PEPCK, further restricting hepatic glucose production and fatty acid synthesis. Cumulatively, swertiamarin targets potential metabolic regulators AMPK and PPAR-α, through which it regulates hepatic glycemic burden, fat accumulation, insulin resistance and ROS in hepatic steatosis which emphasizes clinical significance of swertiamarin in regulating metabolism and as a suitable candidate for treating NAFLD.
獐牙菜苦苷是一种具有降血脂活性的裂环环烯醚萜苷类化合物，是一种改善 2 型糖尿病胰岛素抵抗的抗糖尿病药物。因此，本研究旨在探讨獐牙菜苦苷在改善由肝脂质堆积、炎症和胰岛素抵抗引起的非酒精性脂肪性肝病（NAFLD）中的抗氧化和降血脂活性。通过补充 1mM 油酸（OA）24 小时诱导 HepG2 细胞发生脂肪变性，这表现为脂滴明显堆积。通过油红 O（ORO）染色和甘油三酯积累来确定。獐牙菜苦苷（25μg/ml）可使甘油三酯含量减少 2 倍，并通过保护膜完整性有效降低 LDH 释放（50%）活性，从而防止凋亡，证据是 Caspase 3 和 PARP1 的裂解减少。我们观察到，獐牙菜苦苷显著增加了主要胰岛素信号蛋白的表达，如胰岛素受体（IR）、PI（3）K、pAkt，同时减少了 p307 IRS-1 的表达。AMPK 被獐牙菜苦苷的作用激活，从而恢复肝细胞的胰岛素敏感性。此外，qPCR 结果证实，OA 上调了固醇调节元件结合蛋白-1c（SREBP-1c）和脂肪酸合酶（FAS），导致脂肪酸合成增加。獐牙菜苦苷有效地调节了过氧化物酶体增殖物激活受体-α（PPAR-α），这是碳水化合物代谢的主要潜在调节因子，它反过来降低了糖异生酶磷酸烯醇丙酮酸羧激酶（PEPCK）的水平，进一步限制了肝葡萄糖生成和脂肪酸合成。综上所述，獐牙菜苦苷通过调节 AMPK 和 PPAR-α 等潜在代谢调节剂，调节肝糖负荷、脂肪堆积、胰岛素抵抗和肝脂肪变性中的 ROS，强调了獐牙菜苦苷在调节代谢中的临床意义，并作为治疗非酒精性脂肪性肝病的合适候选药物。
