Scopoletin intervention in pancreatic endoplasmic reticulum stress induced by lipotoxicity

Abstract

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.

Chimonanthus salicifolius attenuated vascular remodeling by alleviating endoplasmic reticulum stress in spontaneously hypertensive rats

“…Previous studies have confirmed that some of the above ingredients have abilities of the regulation of ER stress. For instance, the intervention of scopoletin, 41 caffeic acid, 42 and chlorogenic acid 43 could alleviate the endoplasmic reticulum stress induced by high-fat diet, glycated low-density lipoproteins and palmitic acid, respectively. Thus, it was plausible that the inhibition of ER stress is involved in the protection of CS against cell apoptosis and vascular remodeling.…”

Dietary Coumarins

“…This coumarin lowered postprandial hyperglycemia through inhibition of carbohydrate digestive enzymes, e.g., α-glucosidase and α-amylase (Jang et al 2018). Kalaivanan et al (2018a) exhibited that 9 intervention could suppress pancreatic endoplasmic reticulum stress (normally observed in type 2 diabetes sufferers) induced by lipotoxicity and revealed its potential in delaying the progression of insulin resistance. The same group also showed that supplementation of 9 could improve insulin sensitivity in rats by attenuating the imbalance of insulin signaling through 5 0 -adenosine-monophosphate-activated protein kinase (Kalaivanan et al 2018b).…”

The possible mechanisms of high-fructose diet-induced pancreatic disturbances

“…ER stress markers, such as glucose regulated protein 78 (GRP78), protein kinase like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), X box-binding protein1 (XBP1), and C/EBP homologous protein (CHOP) were found to be elevated in the pancreas of high-fat/highfructose-fed rats [17]. Similarly, the expression of ER stress-related proteins, including IRE1, PERK, and activating transcription factor 6 (ATF6) were increased in the pancreatic tissue of high-fat/high-fructose-fed rats [52]. Also, it was determined an increase in oxidative parameters, including CAT, glutathione (GSH), and MDA as well as ER stress-related proteins such as binding immunoglobulin protein (BIP) and CHOP in the pancreas of rats fed with a high-fat/high-fructose diet from birth to young adulthood [18].…”