{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T17:51:14Z","timestamp":1790445074589,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T00:00:00Z","timestamp":1665446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background &amp; Aims<\/jats:title><jats:p>Macrophages display remarkable plasticity and can interact with surrounding cells to affect hepatic immunity and tissue remodelling during the progression of liver diseases. Peroxisome proliferator\u2010activated receptor gamma (PPAR\u03b3) plays a critical role in macrophage maturation, polarization and metabolism. In this study, we investigated the role of PPAR\u03b3 in macrophage\u2013hepatic stellate cell (HSC) interaction during non\u2010alcoholic steatohepatitis (NASH) development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Wild\u2010type, Pparg<jats:sup>fl\/fl<\/jats:sup> and Pparg<jats:sup>\u0394Lyz2<\/jats:sup> mice were fed a methionine\u2010 and choline\u2010deficient (MCD) diet to induce NASH. Depletion of macrophages was performed using an injection of gadolinium chloride intraperitoneally. PPAR\u03b3\u2010overexpressing or PPAR\u03b3\u2010knockout macrophages were stimulated with saturated fatty acid (SFA) and cocultured with HSCs in a conditioned medium or the transwell coculture system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Depletion of macrophages inhibited HSC activation and ameliorated NASH progression in MCD diet\u2010fed mice. Coculturing HSCs with macrophages or culturing HSCs in a macrophage\u2010conditioned medium\u2010facilitated HSC activation, and this effect was magnified when macrophages were metabolically activated by SFA. Moreover, the absence of PPAR\u03b3 in macrophages enhanced metabolic activation, promoting the migration and activation of HSCs through IL\u20101\u03b2 and CCL2. In contrast, overexpression of PPAR\u03b3 in macrophages obtained the opposite effects. In vivo, macrophage\u2010specific PPAR\u03b3 knockout affected the phenotype of hepatic macrophages and HSCs, involving the MAPK and NLRP3\/caspase\u20101\/IL\u20101\u03b2 signalling pathways. Infiltrating hepatic monocyte\u2010derived macrophages became the predominant macrophages in NASH liver, especially in Pparg<jats:sup>\u0394Lyz2<\/jats:sup> mice, paralleling with aggravated inflammation and fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Regulating macrophage PPAR\u03b3 affected the metabolic activation of macrophages and their interaction with HSCs. Macrophage\u2010specific PPAR\u03b3 may be an attractive therapeutic target for protecting against NASH\u2010associated inflammation and fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15441","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T10:12:30Z","timestamp":1664273550000},"page":"2696-2712","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Regulation of the macrophage\u2010hepatic stellate cell interaction by targeting macrophage peroxisome proliferator\u2010activated receptor gamma to prevent non\u2010alcoholic steatohepatitis progression in mice"],"prefix":"10.1111","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3361-3703","authenticated-orcid":false,"given":"Xi Xi","family":"Ni","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; 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