NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of β-cells via JNK, p38 MAPK and p53 pathways

• Published in: PloS one Vol. 5; no. 12; p. e15726
• Main Authors: Yuan, Huiping, Zhang, Xiaoyong, Huang, Xiuqing, Lu, Yonggang, Tang, Weiqing, Man, Yong, Wang, Shu, Xi, Jianzhong, Li, Jian
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.12.2010; Public Library of Science (PLoS)
• Subjects: AKT protein; Animals; Apoptosis; Biology; Biomedical engineering; Cell growth; Cell Nucleus - metabolism; Clinical medicine; CYBB protein; Cytoplasm - metabolism; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Drug dosages; Endoplasmic reticulum; Engineering schools; Fatty acids; Fatty Acids, Nonesterified - metabolism; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; FOXO1 protein; Glucose; Hospitals; Hyperglycemia; Insulin; Insulin - metabolism; Insulin resistance; Insulin-Secreting Cells - cytology; JNK protein; Localization; MAP kinase; MAP Kinase Kinase 4 - metabolism; MAP Kinase Signaling System; Medicine; Membrane Glycoproteins - metabolism; Mice; Mitochondria - metabolism; Mitogen-Activated Protein Kinase 8 - metabolism; Molecular modelling; NAD(P)H oxidase; NADPH Oxidase 2; NADPH Oxidases - metabolism; NF-κB protein; Nitric oxide; Obesity; Oleic Acid - metabolism; Oxidative stress; Oxygen; p38 Mitogen-Activated Protein Kinases - metabolism; p53 Protein; Palmitic acid; Palmitic Acid - metabolism; Pancreas; Pathogenesis; Phosphatase; Phosphorylation; Preservation; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Transcription factors; Translocation; Tumor Suppressor Protein p53 - metabolism; Beijing China; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015726

Dysfunction of β-cell is one of major characteristics in the pathogenesis of type 2 diabetes. The combination of obesity and type 2 diabetes, characterized as 'diabesity', is associated with elevated plasma free fatty acids (FFAs). Oxidative stress has been implicated in the pathogenesis of FFA-induced β-cell dysfunction. However, molecular mechanisms linking between reactive oxygen species (ROS) and FFA-induced β-cell dysfunction and apoptosis are less clear. In the present study, we test the hypothesis that NOX2-derived ROS may play a critical role in dysfunction and apoptosis of β-cells induced by FFA. Our results show that palmitate and oleate (0.5 mmol/L, 48 h) induced JNK activation and AKT inhibition which resulted in decreased phosphorylation of FOXO1 following nuclear localization and the nucleocytoplasmic translocation of PDX-1, leading to the reducing of insulin and ultimately dysfunction of pancreatic NIT-1 cells. We also found that palmitate and oleate stimulated apoptosis of NIT-1 cells through p38MAPK, p53 and NF-κB pathway. More interestingly, our data suggest that suppression of NOX2 may restore FFA-induced dysfunction and apoptosis of NIT-1 cells. Our findings provide a new insight of the NOX2 as a potential new therapeutic target for preservation of β-cell mass and function.