Modulation of Lipid Metabolism and Keap1–Nrf2 Pathway Activation in Macrophages by Targeting PPARγ Affects NAFLD Progression

ABSTRACT 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 PPARγ fl/fl and PPARγ Lyz2cre 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.