Perfluorooctanoic Acid Promotes Pancreatic Β Cell Dysfunction and Apoptosis Through ER Stress and the ATF4/CHOP/TRIB3 Pathway
| Autor: | Xiaowei He, Dan Wu, Yanan Xu, Yaqin Zhang, Yue Sun, Xiaoai Chang, Yunxia Zhu, Wei Tang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Health
Toxicology and Mutagenesis Apoptosis Cell Cycle Proteins General Medicine Protein Serine-Threonine Kinases Endoplasmic Reticulum Stress Pollution Activating Transcription Factor 4 Repressor Proteins Mice Glucose Diabetes Mellitus Type 2 Insulin-Secreting Cells Environmental Chemistry Animals Humans |
| DOI: | 10.21203/rs.3.rs-1022358/v1 |
| Popis: | Perfluorooctanoic acid (PFOA), a widely used chemical substance, causes an increased risk of human type 2 diabetes (T2D) through a currently unknown mechanism. The aim of the present study was to investigate whether PFOA regulates the functions of pancreatic β cells, which are specialized for biosynthesis and secretion of insulin, and to reveal the underlying mechanism. Treatment of the MIN6 β-cell line with PFOA caused a time- and dose-dependent inhibition of cell viability in CCK-8 assays. Annexin V/PI and TUNEL staining results confirmed that exposure to a high PFOA dose (500 μM) promoted apoptosis of MIN6 cells, while a low dose (300 μM) had no effects on β-cell survival. PFOA treatment, even at a low dose, diminished glucose-stimulated insulin secretion (GSIS) in both primary islet perfusion and MIN6 cell experiments. Bulk RNA-sequencing data showed a significantly increased expression of endoplasmic reticulum (ER) stress-associated genes, with tribbles homolog 3 (Trib3) ranking first among the altered genes. Activation of ER stress pathways was verified by qRT-PCR assays, and the ATF4/CHOP/TRIB3 pathway contributed to PFOA-induced β-cell damage. Inhibition of TRIB3 expression significantly protected MIN6 cells from PFOA-induced GSIS defects and apoptosis by ameliorating ER stress. These findings reveal a link between ER stress and PFOA-induced β-cell defects, opening up an entirely new set of questions about the pathogenesis of T2D due to environmental chemicals. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|