title: 3,4-Dihydroxyphenylacetic acid, a microbiota-derived metabolite of quercetin, protects against pancreatic β-cells dysfunction induced by high cholesterol.
abstract: Cholesterol plays an important role in inducing pancreatic β-cell dysfunction, characterized by an impaired insulin secretory response to glucose, representing a hallmark of the transition from pre-diabetes to diabetes. 3,4 dihydroxyphenylacetic acid (ES) is a scarcely studied microbiota-derived metabolite of quercetin with antioxidant properties. The aim of this study was to determine the protective effect of ES against apoptosis, mitochondrial dysfunction and oxidative stress induced by cholesterol in Min6 pancreatic β-cells. Cholesterol decreased viability, induced apoptosis and mitochondrial dysfunction by reducing complex I activity, mitochondrial membrane potential, ATP levels and oxygen consumption. Cholesterol promoted oxidative stress by increasing cellular and mitochondrial reactive oxygen species and lipid peroxidation and decreasing antioxidant enzyme activities; in addition, it slightly increased Nrf2 translocation to the nucleus. These events resulted in the impairment of the glucose-induced insulin secretion. ES increased Nrf2 translocation to the nucleus and protected pancreatic β-cells against impaired insulin secretion induced by cholesterol by preventing oxidative stress, apoptosis and mitochondrial dysfunction. Nrf2 activation seems to be involved in the mechanisms underlying the antioxidant protection exerted by ES in addition to preventing the disruption of antioxidant enzymatic defenses. Although additional in vivo experiments are required, this metabolite is suggested as a promising drug target for the prevention of the pathological development from a pre-diabetic to a diabetic state.
authors.affiliation: Department of Nutrition, Faculty of Medicine, University of Chile, Chile, Av. Independencia 1027, P.O. Box 8380453 Santiago, Chile; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: catalinacarrasco@med.uchile.cl.
authors.forename: Catalina
authors.initials: C
authors.lastname: Carrasco-Pozo
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; Institute of Nutrition and Food Technology, University of Chile, Av. Macul 5540, P.O. Box 138-11, Santiago, Chile.
authors.forename: Martin
authors.initials: M
authors.lastname: Gotteland
authors.affiliation: Pathophysiology Program, Faculty of Medicine, University of Chile, Av. Independencia 1027, P.O. Box 8380453, Santiago, Chile.
authors.forename: Rodrigo L
authors.initials: RL
authors.lastname: Castillo
authors.affiliation: Department of Nutrition, Faculty of Medicine, University of Chile, Chile, Av. Independencia 1027, P.O. Box 8380453 Santiago, Chile. Electronic address: chen.chen@uq.edu.au.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011794:Quercetin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D015102:3,4-Dihydroxyphenylacetic Acid; D002784:Cholesterol; D011794:Quercetin
keywords: 3,4 dihydroxyphenylacetic acid; ATP; Cholesterol; Insulin secretion; Mitochondrial dysfunction; Pancreatic β-cell; Superoxide anion radicals