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Given the important role of inflammation and metabolism in atherosclerotic cardiovascular disease, here we examined the role of PRMT5 in atherosclerosis using the specific PRMT5 inhibitor GSK3326595. Cultured thioglycollate\u2010elicited peritoneal macrophages were exposed to GSK3326595 or DMSO control and stimulated with either 1\u00a0ng\/mL LPS or 100\u2009ng\/mL interferon\u2010gamma for 24\u2009h. Furthermore, male low\u2010density lipoprotein (LDL) receptor knockout mice were fed an atherogenic Western\u2010type diet and injected intraperitoneally 3\u00d7\/week with a low dose of 5\u00a0mg\/kg GSK3326595 or solvent control for 9\u2009weeks. In vitro, GSK3326595 primed peritoneal macrophages to interferon\u2010gamma\u2010induced M1 polarization, as evidenced by an increased M1\/M2 gene marker ratio. In contrast, no difference was found in the protein expression of iNOS (M1 marker) and ARG1 (M2 marker) in peritoneal macrophages of GSK3326595\u2010treated mice. Also no change in the T cell activation state or the susceptibility to atherosclerosis was detected. However, chronic GSK3326595 treatment did activate genes involved in hepatic fatty acid acquisition, i.e. SREBF1, FASN, and CD36 (+59%, +124%, and +67%, respectively; <jats:italic>p<\/jats:italic>\u00a0&lt;\u20090.05) and significantly increased hepatic triglyceride levels (+50%; <jats:italic>p<\/jats:italic>\u00a0&lt;\u20090.05). PRMT5 inhibition by low\u2010dose GSK3326595 treatment does not affect the inflammatory state or atherosclerosis susceptibility of Western\u2010type diet\u2010fed LDL receptor knockout mice, while it induces hepatic triglyceride accumulation. Severe side effects in liver, i.e. development of non\u2010alcoholic fatty liver disease, should thus be taken into account upon chronic treatment with this PRMT5 inhibitor.<\/jats:p>","DOI":"10.1111\/jcmm.17676","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T07:42:37Z","timestamp":1679470957000},"page":"1056-1068","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["PRMT5 inhibition induces pro\u2010inflammatory macrophage polarization and increased hepatic triglyceride levels without affecting atherosclerosis in mice"],"prefix":"10.1111","volume":"27","author":[{"given":"Yiheng","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR) Leiden University  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin A. 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