{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T12:18:37Z","timestamp":1783167517580,"version":"3.54.6"},"reference-count":35,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T00:00:00Z","timestamp":1749081600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Gastro and Hepatol"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background and Objectives<\/jats:title><jats:p>Lipid metabolism reprogramming regulates cellular inflammatory and immune functions in macrophages. The effects of macrophage\u2010specific PPAR\u03b3 on lipid metabolism and oxidative stress remain unclear. This study aimed to elucidate the impact of the modulation of macrophage PPAR\u03b3 expression on lipid metabolism, oxidative stress, inflammation, and the progression of nonalcoholic fatty liver disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>RAW264.7 cells, Kupffer cells, and bone marrow\u2013derived macrophages were exposed to saturated fatty acids to establish a NAFLD macrophage model. Techniques, including use of PPAR\u03b3 agonists\/antagonists, gene knockout, and gene overexpression, were applied to modulate PPAR\u03b3 expression in macrophages. NAFLD mouse models were established by feeding PPAR\u03b3<jats:sup>fl\/fl<\/jats:sup> and PPAR\u03b3<jats:sup>Lyz2cre<\/jats:sup> mice a high\u2010fat diet for 16\u2009weeks. 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Saturated fatty acid stimulation increased fatty acid oxidation while reducing de novo lipogenesis in RAW264.7 cells, concurrently increasing PPAR\u03b3 expression. Upregulation of PPAR\u03b3 in macrophages under high\u2010fat conditions further increased fatty acid oxidation, decreased ROS production, and inhibited inflammation. Downregulation of PPAR\u03b3 had the opposite effect. Moreover, PPAR\u03b3 increased the transcription of the Nrf2 gene and activated the Keap1\u2013Nrf2 pathway. PPAR\u03b3 overexpression inhibited cytokine secretion in PA\u2010incubated macrophages, subsequently affecting hepatocyte inflammation. In\u00a0vivo, macrophage\u2010specific PPAR\u03b3 knockout exacerbated liver inflammation and injury in NAFLD mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Modulating PPAR\u03b3 expression affected lipid metabolism, reduced oxidative stress, and suppressed inflammation in macrophages. The modulation of macrophage\u2010specific PPAR\u03b3 activity may represent a potential therapeutic target for NAFLD treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jgh.17033","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T02:35:15Z","timestamp":1749177315000},"page":"2119-2133","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Modulation of Lipid Metabolism and Keap1\u2013Nrf2 Pathway Activation in Macrophages by Targeting PPAR\u03b3 Affects NAFLD Progression"],"prefix":"10.1111","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0359-5674","authenticated-orcid":false,"given":"Yu\u2010Xin","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology  Shanghai China"},{"name":"Shanghai Institute of Digestive Disease  Shanghai China"},{"name":"NHC Key Laboratory of Digestive Diseases  Shanghai China"},{"name":"Renji 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