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

Abstract

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.

• Authors: Huiping Yuan, Xiaoyong Zhang, Xiuqing Huang, Yonggang Lu, Weiqing Tang, Yong Man, Shu Wang, Jianzhong Xi, Jian Li
• Journal: PloS one (PLoS One) Vol. 5 Issue 12 Pg. e15726 (Dec 29 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 21209957 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids, Nonesterified
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• Insulin
• Membrane Glycoproteins
• Reactive Oxygen Species
• Tumor Suppressor Protein p53
• Oleic Acid
• Palmitic Acid
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidases
• Mitogen-Activated Protein Kinase 8
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4

Topics

• Animals
• Apoptosis
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• Fatty Acids, Nonesterified (metabolism)
• Forkhead Box Protein O1
• Forkhead Transcription Factors (metabolism)
• Insulin (metabolism)
• Insulin-Secreting Cells (cytology)
• MAP Kinase Kinase 4 (metabolism)
• MAP Kinase Signaling System
• Membrane Glycoproteins (metabolism)
• Mice
• Mitochondria (metabolism)
• Mitogen-Activated Protein Kinase 8 (metabolism)
• NADPH Oxidase 2
• NADPH Oxidases (metabolism)
• Oleic Acid (metabolism)
• Palmitic Acid (metabolism)
• Reactive Oxygen Species (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)