Biology subjects

Gustafsson, J.-A.

Publications and source records attributed to Gustafsson, J.-A..

4 recordsLinked to original sources

bioRxiv2022

G protein-coupled oestrogen receptor activation by Bisphenol-A disrupts protection from apoptosis conferred by oestrogen receptors ERα and ERβ in pancreatic beta cells

17{beta}-estradiol protects pancreatic {beta}-cells from apoptosis via the estrogen receptors ER, ER{beta} and GPER. Conversely, the endocrine disruptor Bisphenol-A (BPA), which exerts multiple effects in this cell type via the same estrogen receptors, increased basal apoptosis. The molecular initiated events that trigger these opposite actions have yet to be identified. We demonstrated that combined genetic downregulation and pharmacological blockade of each estrogen receptor increased apoptosis to a different extent. The increase in apoptosis induced by BPA was diminished by the pharmacological blockade or the genetic silencing of GPER, and it was partially reproduced by the GPER agonist G1. BPA and G1-induced apoptosis were abolished upon pharmacological inhibition, silencing of ER and ER{beta}, or in dispersed islet cells from ER{beta} knockout (BERKO) mice. Yet, the ER and ER{beta} agonists, PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ER and ER{beta} form homodimers and heterodimers. Molecular dynamic simulations together with proximity ligand assay and coimmunoprecipitation experiments indicated that the interaction of BPA with ER and ER{beta} as well as the GPER activation by G1 decreased ER{beta} heterodimers. We propose that ER{beta} heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decrease in ER{beta} heterodimers leads to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors. HighlightsO_LIPharmacological blockade and gene silencing of estrogen receptors ER, ER{beta} and GPER indicate that they are antiapoptotic in basal conditions. C_LIO_LIGPER activation by G1 and BPA triggered apoptosis via a crosstalk with ER and ER{beta}. C_LIO_LIBPA interaction with ER and ER{beta} as well as GPER activation decreased ER{beta} heterodimers, which was associated to increased apoptosis. C_LIO_LIThis pathway represents a novel molecular initiating event underlying the pro-apoptotic effect of BPA C_LIO_LIThe EndoC-{beta}H1 cell line may be a valid model of human {beta}-cells for identifying diabetogenic pollutants. C_LI

physiology↗

bioRxiv2020

Bisphenol-S and Bisphenol-F alter mouse pancreatic β-cell ion channel expression and activity and insulin release through an estrogen receptor ERβ mediated pathway

Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic {beta}-cells from wild type (WT) and estrogen receptor {beta} (ER{beta}) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in {beta}-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive K+ (KATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in {beta}-cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ER{beta} pathways. Molecular dynamics simulations indicated differences in ER{beta} ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ER{beta} whose activation alters three key cellular events in {beta}-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols.

pharmacology and toxicology↗

bioRxiv2019

Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity

Estrogen receptor {beta} (ER{beta}) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ER{beta}, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ER{beta} is expressed in both basal and luminal cells in the prostate while AR is expressed in luminal but not in the basal cell layer which harbors the prostate stem cells. To investigate the mechanisms of action of ER{beta} and its potential cross-talk with AR, we used RNA-seq to study the effects of estradiol or the synthetic ligand, LY3201, in AR-positive LNCaP PCa cells which had been engineered to express ER{beta}. Transcriptomic analysis indicated relatively few changes in gene expression with ER{beta} overexpression, but robust responses following ligand treatments. There is significant overlap of responsive genes between the two ligands, as well as ligand-specific alterations. Gene set analysis of down-regulated genes identified an enrichment of androgen-responsive genes, such as FKBP5, CAMKK2, and TBC1D4. Consistently, AR transcript, protein levels, and transcriptional activity were down-regulated following ER{beta} activation. In agreement with this, we find that the phosphorylation of the CAMKK2 target, AMPK, was repressed by ligand-activated ER{beta}. Down-regulation of TBC1D4, a major regulator of glucose uptake in prostate, indicates that ER{beta} is changing glucose metabolism in the prostate. These findings suggest that ER{beta}-mediated signaling pathways are involved in the negative regulation of AR expression and activity, thus supporting a tumor suppressive role for ER{beta} in PCa.

cancer biology↗

bioRxiv2019

Liver X Receptor regulates Th17 and RORγt+ Treg cells by distinct mechanisms

The gastrointestinal microenvironment, dominated by dietary compounds and the commensal bacteria, is a major driver of intestinal CD4+ T helper (Th) cell differentiation. Dietary compounds can be sensed by nuclear receptors (NRs) that consequently exerts pleiotropic effects including immune modulation. However, how NRs regulate distinct intestinal Th subsets remain poorly understood. Here, we found that under homeostatic condition Liver X receptor (LXR), a sensor of cholesterol metabolites, controls ROR{gamma}t+ Treg and Th17 cells in the intestine draining mesenteric lymph node (MLN). Mechanistically, while lack of LXR signaling in CD11c+ myeloid cells led to an increase in ROR{gamma}t+ Treg, modulation of MLN Th17 was independent of LXR signaling in either immune or epithelial cells. Of note, LXR modulated only the Th17 cells, but not ROR{gamma}t+ Treg in the MLN and horizontal transfer of microbiota between LXR-/- and WT mice was sufficient to partially increase the MLN Th17 in WT mice. While LXR deficiency increased the abundance of Ruminococcaceae and Lachnospiraceae bacterial families compared to the WT littermates, microbiota ablation including ablation of SFB was not sufficient to dampen LXR-mediated expansion of MLN Th17. Altogether, our results suggest that LXR modulates ROR{gamma}t+ Treg and Th17 cells in the MLN through distinct mechanisms.

immunology↗