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Cellular senescence has been associated with age\u2010dependent hepatosteatosis. Thus, we investigated the role of OPN in the age\u2010related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild\u2010type (WT) mice, serum and liver OPN were increased at 10\u00a0months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN\u2010deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN\u2010KO mice liver were associated with the decrease of 78\u00a0kDa glucose\u2010regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and CD36 levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in CD36 levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53\u2010OPN axis is required to inhibit the onset of age\u2010related hepatosteatosis.<\/jats:p>","DOI":"10.1111\/acel.13183","type":"journal-article","created":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T00:52:14Z","timestamp":1594169534000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Liver osteopontin is required to prevent the progression of age\u2010related nonalcoholic fatty liver disease"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6607-7973","authenticated-orcid":false,"given":"Beatriz","family":"G\u00f3mez\u2010Santos","sequence":"first","affiliation":[{"name":"Department of Physiology Faculty of Medicine and Nursing University of Basque Country UPV\/EHU Leioa Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Saenz de Urturi","sequence":"additional","affiliation":[{"name":"Department of Physiology Faculty of 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