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CtBP2 ameliorates palmitate-induced insulin resistance in HepG2 cells through ROS mediated JNK pathway
Pingli Liu1, Li Shi2, Xiaomin Cang1
1Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province, People's Republic of China.
Abstract:
Oxidative stress plays a significant role in the development of hepatic insulin resistance, but the underlying molecular mechanisms remain poorly understood. In this study, we discovered that C-terminal-binding protein 2 (CtBP2) level was decreased in insulin resistance. Taking into account the relationship between CtBP family protein (ANGUSTIFOLIA) and reactive oxygen species (ROS) accumulation, we conjectured CtBP2 was involved in insulin resistance through ROS induced stress. In order to verify this hypothesis, we over-expressed CtBP2 in palmitate (PA) treated HepG2 cells. Here, we found that over-expression of CtBP2 ameliorated insulin sensitivity by increasing phosphorylation of glycogen synthase kinase 3β (GSK3β) and protein kinase B (AKT). These data suggest that CtBP2 plays a critical role in the development of insulin resistance. Moreover, CtBP2 reversed the effects of PA on ROS level, lipid accumulation, hepatic glucose uptake and gluconeogenesis. We also found that over-expression of CtBP2 could suppress PA induced c-jun NH2 terminal kinase (JNK) activation. Furthermore, JNK inhibitor SP600125 was shown to promote the effect of CtBP2 on insulin signaling. Thus, we demonstrated that CtBP2 ameliorated PA-induced insulin resistance via ROS-dependent JNK pathway.
Insights
C-terminal-binding protein 2 (CtBP2) deficiency worsens hepatic insulin resistance by increasing oxidative stress. Restoring CtBP2 levels improves insulin sensitivity and reduces liver damage, suggesting CtBP2 is a key factor in metabolic health.
Area of Science:
- Metabolic diseases
- Molecular biology
- Cellular stress response
Background:
- Oxidative stress is implicated in hepatic insulin resistance, but molecular drivers are unclear.
- C-terminal-binding protein 2 (CtBP2) levels are reduced in insulin resistance.
- CtBP2's role in reactive oxygen species (ROS) regulation suggests involvement in insulin resistance.
Purpose of the Study:
- To investigate the role of CtBP2 in hepatic insulin resistance.
- To determine if CtBP2 mitigates oxidative stress and improves insulin sensitivity.
- To elucidate the molecular pathway involving CtBP2, ROS, and JNK signaling.
Main Methods:
- Overexpression of CtBP2 in palmitate-treated HepG2 cells.
- Assessed insulin sensitivity markers: GSK3β and AKT phosphorylation.
- Measured ROS levels, lipid accumulation, glucose uptake, and gluconeogenesis.
- Investigated the involvement of c-jun NH2-terminal kinase (JNK) pathway.
Main Results:
- CtBP2 overexpression enhanced insulin sensitivity by increasing GSK3β and AKT phosphorylation.
- CtBP2 reversed palmitate-induced increases in ROS, lipid accumulation, and altered glucose metabolism.
- CtBP2 suppressed palmitate-induced JNK activation.
- JNK inhibition potentiated CtBP2's beneficial effects on insulin signaling.
Conclusions:
- CtBP2 plays a critical role in ameliorating hepatic insulin resistance.
- CtBP2 protects against oxidative stress and improves insulin signaling.
- The protective effect of CtBP2 involves the ROS-dependent JNK pathway.
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