Carrasco-Pozo Catalina, Gotteland Martin, Castillo Rodrigo L, Chen Chen
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.
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.
Exp Cell Res. 2015 Jun 10;334(2):270-82. doi: 10.1016/j.yexcr.2015.03.021. Epub 2015 Apr 4.
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.
胆固醇在诱导胰腺β细胞功能障碍中起重要作用，其特征是对葡萄糖的胰岛素分泌反应受损，这是从糖尿病前期向糖尿病转变的一个标志。3,4-二羟基苯乙酸（ES）是一种研究较少的具有抗氧化特性的槲皮素微生物衍生代谢产物。本研究的目的是确定ES对胆固醇诱导的Min6胰腺β细胞凋亡、线粒体功能障碍和氧化应激的保护作用。胆固醇通过降低复合体I活性、线粒体膜电位、ATP水平和氧消耗来降低细胞活力、诱导凋亡和线粒体功能障碍。胆固醇通过增加细胞和线粒体活性氧及脂质过氧化并降低抗氧化酶活性来促进氧化应激；此外，它还略微增加了Nrf2向细胞核的转位。这些事件导致葡萄糖诱导的胰岛素分泌受损。ES增加了Nrf2向细胞核的转位，并通过防止氧化应激、凋亡和线粒体功能障碍，保护胰腺β细胞免受胆固醇诱导的胰岛素分泌受损。Nrf2激活似乎除了防止抗氧化酶防御的破坏外，还参与了ES发挥抗氧化保护作用的潜在机制。尽管还需要额外的体内实验，但这种代谢产物被认为是预防从糖尿病前期到糖尿病状态病理发展的一个有前景的药物靶点。
