BACKGROUNDMetabolic dysfunction-associated steatotic liver disease (MASLD) is becoming the most common form of chronic liver disease worldwide. We explored the potential mechanisms responsible for the protective role of sleeve gastrectomy (SG) on MASLD in a high-fat diet (HFD) rat model.METHODSRats were fed with HFD for 12 weeks to generate MASLD model that were subjected to SG or sham surgery. The endoplasmic reticulum stress (ERS) inhibitor 4-phenylbutyric acid (4-PBA) was injected intraperitoneally every day for 4 weeks after surgery to identify the impact of ERS.RESULTSThe MASLD rat model was generated successfully, as indicated by significant upregulation of metabolic parameters. Fibroblast growth factor 21 (FGF21) and ERS-related proteins were increased in HFD rats, while expression of fibroblast growth factor receptor 1 was decreased as expected. An HFD also induced swelling and blurring of the endoplasmic reticulum and mitochondria in hepatocytes, and the above transformation could be relieved by SG and 4-PBA. SG and an ERS inhibitor both inhibited MASLD, but their combined treatment had no additional benefit.CONCLUSIONSDysfunction of the FGF21 signaling pathway and hepatic steatosis and inflammation could be induced by an HFD, potentially causing MASLD. Bariatric surgery and ERS inhibition could alleviate MASLD by relieving ERS-mediated impairment of FGF21 signal transduction. These findings provide a new insight into the use of ERS inhibitors to treat MASLD, especially in patients who prefer to avoid surgery.

01 Aug 2023·Metabolic brain disease

Therapeutic potential of endoplasmic reticulum stress inhibitors in the treatment of diabetic peripheral neuropathy.

Review

Author: Patel, Shivangi ; Mahajan, Sakshi ; Majumdar, Anuradha ; Pangarkar, Arnika

Endoplasmic stress response, the unfolded protein response (UPR), is a homeostatic signaling pathway comprising transmembrane sensors that get activated upon alterations in ER luminal environment. Studies suggest a relation between activated UPR pathways and several disease states such as Parkinson, Alzheimer, inflammatory bowel disease, tumor growth, and metabolic syndrome. Diabetic peripheral neuropathy (DPN), a common microvascular complication of diabetes-related chronic hyperglycemia, causes chronic pain, loss of sensation, foot ulcers, amputations, allodynia, hyperalgesia, paresthesia, and spontaneous pain. Factors like disrupted calcium signaling, dyslipidemia, hyperglycemia, inflammation, insulin signaling, and oxidative stress disturb the UPR sensor levels manifesting as DPN. We discuss new effective therapeutic alternatives for DPN that can be developed by targeting UPR pathways like synthetic ER stress inhibitors like 4-PhenylButyric acid (4-PBA), Sephin 1, Salubrinal and natural ER stress inhibitors like Tauroursodeoxycholic acid (TUDCA), Cordycepin, Proanthocyanidins, Crocin, Purple Rice extract and cyanidin and Caffeic Acid Phenethyl Ester (CAPE).

01 Jan 2023·Frontiers in medicine

Bisphenol A exposure triggers endoplasmic reticulum stress pathway leading to ocular axial elongation in mice.

Article

Author: Chen, Junhan ; Kurihara, Toshihide ; Tsubota, Kazuo ; Kang, Longdan ; Ikeda, Shin-Ichi ; Negishi, Kazuno

BackgroundOcular axial elongation is one of the features of myopia progression. Endoplasmic reticulum (ER) stress-associated scleral remodeling plays an important role in ocular axial elongation. Bisphenol A (BPA) is one of the most common environmental pollutants and is known to affect various human organs through ER stress. However, whether BPA exerts an effect on scleral remodeling remains unknown. The purpose of this study was to determine the effect of BPA on the development of myopia and scleral ER stress.MethodsBPA was administered by intraperitoneal injection. 4-PBA was administered as an endoplasmic reticulum stress inhibitor by eye drops. Refraction and axial length were measured by refractometer and SD-OCT system. Western blot was performed to detect the expression level of ER stress-related proteins.ResultsBPA-administered mice exhibit axial elongation and myopic refractive shift with endoplasmic reticulum stress in the sclera. BPA administration activated scleral PERK and ATF6 pathways, and 4-PBA eye drops attenuated ER stress response and suppressed myopia progression.ConclusionBPA controlled axial elongation during myopia development in a mouse model by inducing scleral ER stress and activation of the PERK/ATF6 pathway. 4-PBA eye drops as ER stress inhibitor suppressed BPA-induced myopia development.

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