Silychristin A activates Nrf2-HO-1/SOD2 pathway to reduce apoptosis and improve GLP-1 production through upregulation of estrogen receptor α in GLUTag cells.

Jinyu Wang, Xiaoying Zhang, Luxin Zhang, Tingxu Yan, Bo Wu, Fanxing Xu, Ying Jia

European journal of pharmacology 2020 Aug 15

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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. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Jinyu Wang, Xiaoying Zhang, Luxin Zhang, Tingxu Yan, Bo Wu, Fanxing Xu, Ying Jia. Silychristin A activates Nrf2-HO-1/SOD2 pathway to reduce apoptosis and improve GLP-1 production through upregulation of estrogen receptor α in GLUTag cells. European journal of pharmacology. 2020 Aug 15;881:173236