Scopoletin intervention in pancreatic endoplasmic reticulum stress induced by lipotoxicity
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Endoplasmic reticulum (ER), a dynamic organelle, plays an essential role in organizing the signaling pathways involved in cellular adaptation, resilience, and survival. Impairment in the functions of ER occurs in a variety of nutritive disorders including obesity and type 2 diabetes. Here, we hypothesize that (scopoletin) SPL, a coumarin, has the potential to alleviate ER stress induced in vitro and in vivo models by lipotoxicity. To test this hypothesis, the ability of SPL to restore the levels of proteins of ER stress was analyzed. Rat insulinoma 5f (RIN5f) cells and Sprague Dawley rats were the models used for this study. Groups of control and high-fat, high-fructose diet (HFFD)-fed rats were treated with either SPL or 4-phenylbutyric acid. Status of ER stress was enumerated by quantitative RT-PCR, Western blot, electron microscopic, and immunohistochemical studies. Proximal proteins of ER stress inositol requiring enzyme 1 (IRE1), protein kinase like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) were reduced in the β-cells by SPL. The subsequent signaling proteins X-box binding protein 1, eukaryotic initiation factor2α, activating transcription factor 4, and C/EBP homologous protein were also suppressed in their expression levels when treated with SPL. IRE1, PERK signaling leads to c-Jun-N-terminal kinases phosphorylation, a kinase that interrupts insulin signaling, which was also reverted upon scopoletin treatment. Finally, we confirm that SPL has the ability to suppress the stress proteins and limit pancreatic ER stress which might help in delaying the progression of insulin resistance.
KeywordsScopoletin ER stress 4-Phenylbutyric acid Lipotoxicity
The authors wish to thank DST-FIST and UGC-SAP for the infrastructure facilities developed in the Department of Biochemistry and Biotechnology, Annamalai University, for executing the present study. We also thank Dr. Pushpa Viswanathan, Professor and Head, Dept. of Electron Microscope, Adyar Cancer Research Institute, Chennai, for conducting the electron microscopic studies successfully.
This work was supported by Department of Science and Technology, Women Scientists Scheme-A, New Delhi, India under “Disha Programme for Women in Science” (SR/WOS-A/LS-1170/2014).
Compliance with ethical standards
Experimental procedures were approved by the Institutional Animal Ethics Committee (IAEC), Annamalai University, and conducted according to the guidelines by the Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA) (Proposal No. 1091).
Conflict of interest
The authors declare that they have no conflicts of interest.
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