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Involvement of Estrogen Receptor-? in the Activation of Nrf2-Antioxidative Signaling Pathways by Silibinin in Pancreatic ?-Cells.

ABSTRACT: Silibinin exhibits antidiabetic potential by preserving the mass and function of pancreatic ?-cells through up-regulation of estrogen receptor-? (ER?) expression. However, the underlying protective mechanism of silibinin in pancreatic ?-cells is still unclear. In the current study, we sought to determine whether ER? acts as the target of silibinin for the modulation of antioxidative response in pancreatic ?-cells under high glucose and high fat conditions. Our in vivo study revealed that a 4-week oral administration of silibinin (100 mg/kg/day) decreased fasting blood glucose with a concurrent increase in levels of serum insulin in high-fat diet/streptozotocin- induced type 2 diabetic rats. Moreover, expression of ER?, NF-E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in pancreatic ?-cells in pancreatic islets was increased by silibinin treatment. Accordingly, silibinin (10 µM) elevated viability, insulin biosynthesis, and insulin secretion of high glucose/palmitate-treated INS-1 cells accompanied by increased expression of ER?, Nrf2, and HO-1 as well as decreased reactive oxygen species production in vitro. Treatment using an ER? antagonist (MPP) in INS-1 cells or silencing ER? expression in INS-1 and NIT-1 cells with siRNA abolished the protective effects of silibinin. Our study suggests that silibinin activates the Nrf2-antioxidative pathways in pancreatic ?-cells through regulation of ER? expression.

SUBMITTER: Chu C

PROVIDER: S-EPMC7059807 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Involvement of Estrogen Receptor-α in the Activation of Nrf2-Antioxidative Signaling Pathways by Silibinin in Pancreatic β-Cells.

Chu Chun C Gao Xiang X Li Xiang X Zhang Xiaoying X Ma Ruixin R Jia Ying Y Li Dahong D Wang Dongkai D Xu Fanxing F

Biomolecules & therapeutics 20200301 2

Silibinin exhibits antidiabetic potential by preserving the mass and function of pancreatic β-cells through up-regulation of estrogen receptor-α (ERα) expression. However, the underlying protective mechanism of silibinin in pancreatic β-cells is still unclear. In the current study, we sought to determine whether ERα acts as the target of silibinin for the modulation of antioxidative response in pancreatic β-cells under high glucose and high fat conditions. Our <i>in vivo</i> study revealed that ...[more]

PMID: 31649209

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Project description:The effects of 17-β-estradiol in osteoblasts are primarily mediated by the nuclear transcription factors, estrogen receptor (ER)α and ERβ. ERs function through three general modes of action: DNA-binding dependent through estrogen response elements (EREs; designated nuclear ERE signaling); nuclear signaling via protein-protein interactions to other transcription factors (nuclear non-ERE signaling); and extra-nuclear signaling (membrane-bound functions of ERs). Identification of the specific transcriptional signatures regulated by each of these modes of action should contribute to an enhanced understanding of estrogen signaling in osteoblasts. To achieve this goal, we utilized specific mutations of ERα that eliminate the ability of the receptor to signal through a specific mode of action. The non-classical ERα knock-in (NERKI) mutation is incapable of signaling through direct DNA binding to EREs and the nuclear only ERα (NOER) mutation eliminates all membrane-localized signaling. Comparison of the gene expression patterns elicited by these mutations with the wild-type ERα (WT) pattern provides mode-specific data concerning transcriptional regulation by ERα. We expressed these constructs in the ER-negative osteoblastic cell line hFOB (-/+ estrogen) and performed global RNA-sequencing. Using a series of pair-wise comparisons, we generated three lists of genes that were regulated either by the nuclear ERE-dependent, nuclear ERE-independent, or extra-nuclear actions of ERα. Pathway and gene ontology analyses revealed that genes regulated through the nuclear ERE and nuclear non-ERE pathways were largely involved in transcriptional regulation, whereas genes regulated through extra-nuclear mechanisms are involved in cytoplasmic signaling transduction pathways. We also intersected our data with genes linked to bone density and fractures from a recent genome-wide association study and found 25 of 72 genes (35%) regulated by estrogen. These data provide a comprehensive list of genes and pathways targeted by these specific modes of ERα action and suggest that "mode-specific" ligands could be developed to modulate specific ERα functionality in bone.

Dataset Information

Involvement of Estrogen Receptor-? in the Activation of Nrf2-Antioxidative Signaling Pathways by Silibinin in Pancreatic ?-Cells.

Publications

Involvement of Estrogen Receptor-α in the Activation of Nrf2-Antioxidative Signaling Pathways by Silibinin in Pancreatic β-Cells.

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