School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
Eur J Pharmacol. 2020 Aug 15;881:173236. doi: 10.1016/j.ejphar.2020.173236. Epub 2020 Jun 1.
Glucagon-like peptide-1 (GLP-1), a glucagon-like peptide secreted mainly from intestinal L cells, possesses the functions of promoting synthesis and secretion of insulin in pancreatic β-cells, and maintaining glucose homeostasis in an insulin-independent manner. Silychristin A, a major flavonolignan from silymarin, was reported to protect pancreatic β-cells from oxidative damage in streptozotocin (STZ)-induced diabetic rats. However, the role of silychristin A in the protection of intestinal L-cells is still unknown. Our current study demonstrated that palmitate (PA) inhibited protein expression of NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and superoxide dismutase 2 (SOD2), and subsequently increased reactive oxygen species level to induce apoptosis and decrease GLP-1 content in intestinal L-cell line GLUTag cells. Pre-incubation of silychristin A effectively reversed PA-inactivated Nrf2-HO-1/SOD2 antioxidative pathway accompanied with decreased apoptosis level and increased GLP-1 level in GLUTag cells. As a potential target of silychristin A, estrogen receptor α was shown to be downregulated by PA stimulation, and the expression of which was improved by silychristin A in a concentration-dependent manner. Further study revealed that the treatment of estrogen receptor α antagonist MPP induced apoptosis and blocked the stimulation of GLP-1 production by silychristin A through the activation of Nrf2-HO-1/SOD2 pathway in GLUTag cells. Taken together, our study found silychristin A activated estrogen receptor α-dependent Nrf2-HO-1/SOD2 pathway to decrease apoptosis and upregulate GLP-1 production in GLUTag cells.
胰高血糖素样肽-1（GLP-1）是一种主要由肠道 L 细胞分泌的胰高血糖素样肽，具有促进胰岛β细胞胰岛素合成和分泌的功能，并以胰岛素非依赖性方式维持血糖稳态。水飞蓟宾 A 是水飞蓟宾中的一种主要类黄酮木脂素，据报道可保护链脲佐菌素（STZ）诱导的糖尿病大鼠的胰岛β细胞免受氧化损伤。然而，水飞蓟宾 A 对肠道 L 细胞的保护作用尚不清楚。我们目前的研究表明，棕榈酸（PA）抑制 NF-E2 相关因子 2（Nrf2）、血红素加氧酶-1（HO-1）和超氧化物歧化酶 2（SOD2）的蛋白表达，随后增加活性氧水平，诱导凋亡，并降低肠 L 细胞系 GLUTag 细胞中的 GLP-1 含量。水飞蓟宾 A 的预孵育可有效逆转 PA 失活的 Nrf2-HO-1/SOD2 抗氧化途径，同时降低 GLUTag 细胞的凋亡水平并增加 GLP-1 水平。作为水飞蓟宾 A 的潜在靶标，雌激素受体α（ERα）被发现被 PA 刺激下调，并且其表达被水飞蓟宾 A 以浓度依赖的方式改善。进一步的研究表明，雌激素受体α拮抗剂 MPP 的处理诱导凋亡，并通过激活 GLUTag 细胞中的 Nrf2-HO-1/SOD2 途径阻断水飞蓟宾 A 对 GLP-1 产生的刺激。总之，我们的研究发现水飞蓟宾 A 通过激活雌激素受体α依赖性 Nrf2-HO-1/SOD2 途径减少 GLUTag 细胞的凋亡并上调 GLP-1 的产生。
