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

Eur J Pharmacol. 2020 Aug 15;881:173236. doi: 10.1016/j.ejphar.2020.173236. Epub 2020 Jun 1.

Abstract

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.

Keywords: Apoptosis; Estrogen receptor α; GLP-1; Palmitate; Silychristin A; Type 2 diabetes mellitus.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line
  • Enteroendocrine Cells / drug effects*
  • Enteroendocrine Cells / enzymology
  • Estrogen Receptor alpha / metabolism*
  • Glucagon-Like Peptide 1 / metabolism*
  • Heme Oxygenase-1 / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects
  • Palmitic Acid / toxicity
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Silymarin / pharmacology*
  • Superoxide Dismutase / metabolism*

Substances

  • Antioxidants
  • Esr1 protein, mouse
  • Estrogen Receptor alpha
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Reactive Oxygen Species
  • Silymarin
  • Palmitic Acid
  • Glucagon-Like Peptide 1
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Superoxide Dismutase
  • superoxide dismutase 2
  • silychristin