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Exercise and\/or docosahexaenoic acid (DHA) supplementation have shown beneficial effects on MASLD. The current study aims to assess the relationships between <jats:italic>Sirt1<\/jats:italic>, <jats:italic>Foxo1<\/jats:italic> mRNA levels and several MASLD biomarkers, as well as the effects of DHA-rich n-3 PUFA supplementation and\/or exercise in the steatotic liver of aged obese female mice, and in peripheral blood mononuclear cells (PBMCs) of postmenopausal women with overweight\/obesity. In the liver of 18-month-old mice, <jats:italic>Sirt1<\/jats:italic> levels positively correlated with the expression of genes related to fatty acid oxidation, and negatively correlated with lipogenic and proinflammatory genes. Exercise (long-term treadmill training), especially when combined with DHA, upregulated hepatic <jats:italic>Sirt1<\/jats:italic> mRNA levels. Liver <jats:italic>Foxo1<\/jats:italic> mRNA levels positively associated with hepatic triglycerides (TG) content and the expression of lipogenic and pro-inflammatory genes, while negatively correlated with the lipolytic gene <jats:italic>Hsl<\/jats:italic>. In PBMCs of postmenopausal women with overweight\/obesity, <jats:italic>FOXO1<\/jats:italic> mRNA expression negatively correlated with the hepatic steatosis index (HSI) and the Zhejiang University index (ZJU). After 16-weeks of DHA-rich PUFA supplementation and\/or progressive resistance training (RT), most groups exhibited reduced MASLD biomarkers and risk indexes accompanying with body fat mass reduction, but no significant changes were found between the intervention groups. However, in PBMCs n-3 supplementation upregulated <jats:italic>FOXO1<\/jats:italic> expression, and the RT groups exhibited higher <jats:italic>SIRT1<\/jats:italic> expression. In summary, SIRT1 and FOXO1 could be involved in the beneficial mechanisms of exercise and n-3 PUFA supplementation related to MASLD manifestation.<\/jats:p>","DOI":"10.1007\/s13105-024-01044-9","type":"journal-article","created":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T14:04:51Z","timestamp":1726149891000},"page":"697-712","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["SIRT1 and FOXO1 role on MASLD risk: effects of DHA-rich n-3 PUFA supplementation and exercise in aged obese female mice and in post-menopausal overweight\/obese women"],"prefix":"10.1007","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8519-2878","authenticated-orcid":false,"given":"Jinchunzi","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4633-1289","authenticated-orcid":false,"given":"Elisa","family":"F\u00e9lix-Soriano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Mart\u00ednez-Gayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Iba\u00f1ez-Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0298-3031","authenticated-orcid":false,"given":"Neira","family":"S\u00e1inz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5218-6941","authenticated-orcid":false,"given":"J Alfredo","family":"Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2018-6434","authenticated-orcid":false,"given":"Mar\u00eda J.","family":"Moreno-Aliaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,12]]},"reference":[{"key":"1044_CR1","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.jbbm.2006.11.008","volume":"70","author":"R Akamine","year":"2007","unstructured":"Akamine R, Yamamoto T, Watanabe M, Yamazaki N, Kataoka M, Ishikawa M et al (2007) Usefulness of the 5\u2019 region of the cDNA encoding acidic ribosomal phosphoprotein P0 conserved among rats, mice, and humans as a standard probe for gene expression analysis in different tissues and animal species. 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