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Published on: January 26, 2010
Association of PM2.5 with Insulin Resistance Signaling Pathways on a Microfluidic Liver-Kidney Microphysiological
Xiaoxiao Duan1, Xinlian Zhang1, Jianmin Chen1
1Shanghai Key Laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 2005 Songhu Road, Shanghai 200438, P. R. China.
Abstract:
Insulin resistance (IR) is a typical sign of metabolic dysregulation caused by fine particulate matter (PM2.5), but the underlying signaling has not been clearly determined. Herein, a microfluidic liver-kidney microphysiological system (LK-MPS) is presented to assess the signaling pathways of IR generated by PM2.5 at 200 μg/mL for 24 h. The LK-MPS device consisted of a biomimetic liver-kidney architecture and reconstructed two circulation paths: the liver metabolism-kidney excretion (LM-KE) and kidney excretion-liver metabolism (KE-LM), by which PM2.5 is feasibly distributed in the two organs. Transmission electron microscopy (TEM) analysis revealed that PM2.5 can embed in the cytoplasm and nuclei, undergo transport by vesicles, and lead to the destruction of mitochondria. Further comprehensive immunofluorescence, enzyme-linked immunosorbent assays (ELISAs) and untargeted metabolomic analyses confirmed that PM2.5 disturbed the classic IRS-1/AKT signaling pathway (INSR, IRS-1, PI3K, AKT, GLUT2, GLUT4, and FOXO1 downregulated) and IR-related metabolic pathways: UDP-hexosamine (UDP-GlcNAc), gluconeogenesis (β-d-glucose 6-phosphate), and lipid biosynthesis (ceramide (Cer) and triacylglycerol (TG)) pathways, leading to the disorder of glucose levels. Collectively, these disorders aggravate hepatic and renal IR. Pearson's correlation coefficient test showed that elemental carbon (EC), polycyclic aromatic hydrocarbons (PAHs), and metals (Ca, Co, and V) were negatively correlated to the dysregulated proteins (INSR, IRS-1, AKT, FOXO1, GLUT2, and GLUT4). These findings may partially explain IR-related signaling pathways triggered by PM2.5.
Insights
Fine particulate matter (PM2.5) exposure causes insulin resistance by disrupting liver and kidney metabolic pathways and the IRS-1/AKT signaling cascade. This study utilized a novel microfluidic system to investigate these effects.
Area of Science:
- Environmental Health
- Toxicology
- Metabolic Physiology
Background:
- Insulin resistance (IR) is a key indicator of metabolic dysfunction linked to fine particulate matter (PM2.5) exposure.
- The precise molecular signaling pathways mediating PM2.5-induced IR remain incompletely understood.
- Investigating these pathways is crucial for understanding the health impacts of air pollution.
Purpose of the Study:
- To elucidate the signaling mechanisms underlying insulin resistance induced by PM2.5.
- To assess the impact of PM2.5 on liver and kidney function using a microfluidic system.
- To identify specific PM2.5 components correlated with IR-related protein dysregulation.
Main Methods:
- Development and application of a microfluidic liver-kidney microphysiological system (LK-MPS) with biomimetic architecture.
- Exposure of the LK-MPS to PM2.5 (200 μg/mL for 24 h) to simulate environmental exposure.
- Utilized Transmission Electron Microscopy (TEM), immunofluorescence, ELISAs, untargeted metabolomics, and correlation analysis.
Main Results:
- PM2.5 exposure disrupted mitochondrial integrity and was observed within cellular compartments.
- The IRS-1/AKT signaling pathway (INSR, IRS-1, PI3K, AKT, GLUT2, GLUT4, FOXO1) and key metabolic pathways (UDP-hexosamine, gluconeogenesis, lipid biosynthesis) were significantly disturbed.
- Elemental carbon, PAHs, and specific metals (Ca, Co, V) showed negative correlations with key IR-related proteins.
Conclusions:
- PM2.5 exposure triggers hepatic and renal insulin resistance through disruption of critical signaling and metabolic pathways.
- The LK-MPS is an effective model for studying the complex interactions between air pollutants and organ systems.
- Specific PM2.5 components may be key drivers of pollution-induced metabolic dysregulation.
