Attenuation of endoplasmic reticulum stress with chemical chaperones reverses endocrinemetabolic disturbances in prediabetic rats

FARROMEQUE VÁSQUEZ SHERLEY CATHERINE; ROMÁN, CAROLINA LISI; FLORES, LUIS EMILIO; MAIZTEGUI, BARBARA

Conferencia; Buenos Aires Research Conference2023 Autophagy and Vesicular Trafficking, Mechanisms and Disease; 2023

Rats consuming a fructose-rich diet (FRD) show endocrine-metabolic changes like those described in human prediabetes (PD). Insulin resistance (IR) present in PD induces a β-cell overload that activates endoplasmic reticulum stress (ERS) and autophagy as a compensatory mechanism. Aim: to evaluate the effect of 4-phenylbutyric acid (4-PBA), a chemical chaperone that attenuates ERS, on the endocrine-metabolic alterations described in PD rats. Methods: Normal rats were maintained for 21 days with a standard diet (C), 10% fructose in the drinking water (FRD), or FRD plus 4-PBA at last 5 days of treatment (FRD+4-PBA). Serum levels of glucose, triglycerides (TG), total cholesterol, HDL-cholesterol (HDL-C), and TG/HDL-C ratio (IR index) were measured. Glucose tolerance test was performed and the area under the curve (AUC) was calculated. In pancreatic islets, gene expression (qPCR) of ERS, autophagy, and apoptosis markers were analyzed. Results: FRD rats displayed impaired glucose tolerance (IGT), which was significantly restored by 4-PBA treatment (AUC: C: 19,403.0±473.5; FRD: 25,155.0±939.1; FRD+4-PBA: 21,517.0±1,084.0 mg/dl/120min). 4-PBA reversed the decrease of HDL-C, and the increase of TG, non-HDL-C, and IR index induced by FRD. FRD animals showed increased mRNA levels of ERS markers (CHOP: 24.0±0.5; ATF4: 36.0±1.2; Xbp1s: 48.0±1.3% increase), autophagy (Hsc70: 70.0±1.7; p62: 48.0±2% increase), and stress-specific caspase (Casp-12: 97.0±2.6% increase), which were reversed by 4-PBA. Conclusion: Our results indicate that all the alterations induced by FRD like ERS, IGT, and autophagy were reversed/attenuated by 4-PBA, indicating that the use of chemical chaperones could be a promising therapeutic alternative to prevent type 2 diabetes development.