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Published on: June 23, 2013
Modulation of Lipid Metabolism and Keap1-Nrf2 Pathway Activation in Macrophages by Targeting PPARγ Affects NAFLD
Yu-Xin Chen1,2,3,4, Yan-Ping Wu1,2,3,4, Yi Zhang1,2,3,4
1Division of Gastroenterology and Hepatology, Shanghai, China.
Background And Objectives:
Lipid metabolism reprogramming regulates cellular inflammatory and immune functions in macrophages. The effects of macrophage-specific PPARγ on lipid metabolism and oxidative stress remain unclear. This study aimed to elucidate the impact of the modulation of macrophage PPARγ expression on lipid metabolism, oxidative stress, inflammation, and the progression of nonalcoholic fatty liver disease.
Methods:
RAW264.7 cells, Kupffer cells, and bone marrow-derived macrophages were exposed to saturated fatty acids to establish a NAFLD macrophage model. Techniques, including use of PPARγ agonists/antagonists, gene knockout, and gene overexpression, were applied to modulate PPARγ expression in macrophages. NAFLD mouse models were established by feeding PPARγfl/fl and PPARγLyz2cre mice a high-fat diet for 16 weeks. Changes in lipid metabolism, oxidative stress, and inflammation were assessed. Primary hepatocytes were incubated with conditioned medium from RAW264.7 cells to establish conditional coculture systems.
Results:
Saturated fatty acid stimulation increased fatty acid oxidation while reducing de novo lipogenesis in RAW264.7 cells, concurrently increasing PPARγ expression. Upregulation of PPARγ in macrophages under high-fat conditions further increased fatty acid oxidation, decreased ROS production, and inhibited inflammation. Downregulation of PPARγ had the opposite effect. Moreover, PPARγ increased the transcription of the Nrf2 gene and activated the Keap1-Nrf2 pathway. PPARγ overexpression inhibited cytokine secretion in PA-incubated macrophages, subsequently affecting hepatocyte inflammation. In vivo, macrophage-specific PPARγ knockout exacerbated liver inflammation and injury in NAFLD mice.
Conclusion:
Modulating PPARγ expression affected lipid metabolism, reduced oxidative stress, and suppressed inflammation in macrophages. The modulation of macrophage-specific PPARγ activity may represent a potential therapeutic target for NAFLD treatment.
Insights
Modulating peroxisome proliferator-activated receptor gamma (PPARγ) in macrophages impacts lipid metabolism, reduces oxidative stress, and suppresses inflammation, offering a potential therapeutic strategy for nonalcoholic fatty liver disease (NAFLD).
Area of Science:
- Cellular Biology
- Metabolic Diseases
- Immunology
Background:
- Lipid metabolism reprogramming influences macrophage inflammatory and immune functions.
- The specific role of macrophage PPARγ in lipid metabolism and oxidative stress in NAFLD is not fully understood.
Purpose of the Study:
- To investigate the impact of modulating macrophage PPARγ expression on lipid metabolism, oxidative stress, and inflammation.
- To assess the role of macrophage PPARγ in the progression of nonalcoholic fatty liver disease (NAFLD).
Main Methods:
- Established NAFLD macrophage models using RAW264.7 cells, Kupffer cells, and bone marrow-derived macrophages exposed to saturated fatty acids.
- Utilized PPARγ agonists/antagonists, gene knockout, and overexpression to modulate PPARγ in macrophages.
- Created NAFLD mouse models and assessed lipid metabolism, oxidative stress, and inflammation in vivo and in vitro.
Main Results:
- PPARγ upregulation in macrophages enhanced fatty acid oxidation, reduced ROS production, and inhibited inflammation.
- PPARγ activation of the Keap1-Nrf2 pathway was observed.
- Macrophage-specific PPARγ knockout worsened liver inflammation and injury in NAFLD mice.
Conclusions:
- Modulating PPARγ expression in macrophages influences lipid metabolism, oxidative stress, and inflammation.
- Targeting macrophage-specific PPARγ activity presents a potential therapeutic avenue for NAFLD.
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