1 Department of Nutrition, Faculty of Medicine, University of Chile, Santiago, Chile. 2 School of Biomedical Sciences, The University of Queensland, Brisbane, Australia. 3 The University of Queensland Centre for Clinical Research, Brisbane, Australia
Scope: This study aimed to determine the mechanisms by which quercetin protects against pancreatic β-cell dysfunction induced by cholesterol-induced apoptosis, mitochondrial bioenergetic impairment and oxidative stress. Methods and results: Quercetin increased sirtuin 1 and forkhead box O (FOXO) 3A expression, decreased FOXO1 expression, and prevented the cholesterol-induced decrease in cell viability and apoptosis by inhibiting caspase activation, cytochrome c leakage and DNA fragmentation in Min6 cells. Quercetin increased peroxisome proliferator-activated receptor gamma coactivator- 1-alpha and peroxisome proliferator-activated receptor alpha expression, and prevented cholesterol-induced mitochondrial dysfunction and bioenergetic impairment by preserving mitochondrial membrane potential, ATP turnover, and mitochondrial respiration. Quercetin induced the nuclear factor (erythroid-derived 2)-like 2 pathway and inhibited cholesterol-induced oxidative stress by preventing formation of cellular/mitochondrial reactive oxygen species and lipid peroxidation enhancement, and decreases in antioxidant enzyme activity. Quercetin prevented cholesterol-induced nuclear factor-kappa B (NF-kB) activation and pro-inflammatory cytokine production.Conclusion: Our findings highlight the cellular and molecular mechanisms underlying cholesterol-induced cytotoxicity in pancreatic β-cells and the protective effects of quercetin, including its anti-apoptotic, antioxidant and anti-inflammatory properties, and in its ability to prevent mitochondrial dysfunction and bioenergetic impairment. Our results provide a foundation upon which quercetin can be developed as a nutraceutical for β-cell dysfunction prevention. Financiado por proyecto FONDECYT de iniciación.