Sigma‑1 receptor overexpression promotes proliferation and ameliorates cell apoptosis in β‑cells

Ke,Mengting; Lin,Fengping; Wang,Huawei; He,Guangzhen; Feng,Jieyuan; Song,Linyang; Xu,Yancheng; Liu,Jie

doi:10.3892/mmr.2022.12686

Sigma‑1 receptor overexpression promotes proliferation and ameliorates cell apoptosis in β‑cells

Authors:
- Mengting Ke
- Fengping Lin
- Huawei Wang
- Guangzhen He
- Jieyuan Feng
- Linyang Song
- Yancheng Xu
- Jie Liu
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Affiliations: Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Endocrinology, Xianning Central Hospital, Xianning, Hubei 437100, P.R. China, Department of Pediatrics, Affiliated Taihe Hospital of Hubei University of Medicine, Shiyan, Hubei 442002, P.R. China
Published online on: March 17, 2022 https://doi.org/10.3892/mmr.2022.12686
Article Number: 170
Copyright: © Ke et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sigma‑1 receptor (Sig‑1R) is a class of orphan receptors, the potential role of which in pancreatic islet cells remains poorly understood. The present study aimed to investigate the role of Sig‑1R in islet β‑cell proliferation and examine the effects of Sig‑1R on islet β‑cell injury under lipotoxic conditions. Sig‑1R‑overexpressing MIN6 cells were generated by lentiviral vector transfection. The effect of Sig‑1R overexpression on cell proliferation detected by EdU staining, cell cycle progression by propidium iodide (PI), apoptosis by Annexin V‑APC/PI, mitochondrial membrane potential by Mitolite Red and cytoplasmic Ca²⁺ levelsby Fura‑2/AM in islet β‑cells were measured by flow cytometry. Western blot analysis was used to measure protein expression levels of endoplasmic reticulum (ER) stress markers glucose‑regulated protein 78 and C/EBP homologous protein, mitochondrial apoptotic proteins Bcl‑2‑associated X and Bcl‑2 and cytochrome c. In addition, ATP levels and insulin secretion were separately measured using ATP Assay and mouse insulin ELISA. Mitochondria‑associated ER membrane (MAM) structures in MIN6 cells were then detected using transmission electron microscopy. Protein disulfide isomerase expression and possible colocalization between inositol 1,4,5‑trisphosphate receptor and voltage‑dependent anion channel 1 were examined using immunofluorescence. Sig‑1R overexpression was found to promote β‑cell proliferation by accelerating cell cycle progression. Furthermore, Sig‑1R overexpression ameliorated the apoptosis rate whilst impairing insulin secretion induced by palmitic acid by relieving ER stress and mitochondrial dysfunction in MIN6 cells. Sig‑1R overexpression also promoted Ca²⁺ transport between mitochondria and ER by increasing the quantity of ER adjacent to mitochondria in the 50‑nm range. It was concluded that Sig‑1R overexpression conferred protective effects on β‑cells against lipotoxicity as a result of the promotion of cell proliferation and inhibition of ER stress and oxidative stress, by regulating the structure of MAM.

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