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However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non\u2010alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non\u2010alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4\u2010II\u2010E\u2010C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (<jats:italic>Ptgs1<\/jats:italic>, <jats:italic>Ptgs2<\/jats:italic>, and <jats:italic>Ptgds<\/jats:italic>), PPAR gamma (<jats:italic>Pparg<\/jats:italic>), and PPAR gamma downstream targets involved in fatty acid uptake (<jats:italic>Cd36<\/jats:italic>, <jats:italic>Fatp2<\/jats:italic>, and <jats:italic>Fatp5<\/jats:italic>) as well as production of 15\u2010deoxy\u2010\u0394<jats:sup>12,14<\/jats:sup>PGJ<jats:sub>2<\/jats:sub> a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC\u2010560), whereas inhibition of PTGS2 had no effect. Moreover, SC\u2010560 attenuated 15\u2010deoxy\u2010\u0394<jats:sup>12,14<\/jats:sup>PGJ<jats:sub>2<\/jats:sub> production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine\u2010induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d\u2010PGJ<jats:sub>2<\/jats:sub> and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.<\/jats:p>","DOI":"10.1002\/jat.4272","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T00:55:16Z","timestamp":1639356916000},"page":"1004-1015","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Fluoxetine\u2010induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15\u2010deoxy\u2010\u0394<sup>12,14<\/sup>PGJ<sub>2<\/sub>"],"prefix":"10.1002","volume":"42","author":[{"given":"Ahmed","family":"Ayyash","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology McMaster University  Hamilton Ontario 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