Fluoxetine‐induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15‐deoxy‐Δ^12,14PGJ₂

Abstract

Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as nonalcoholic 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-alcoholic 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-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ 12,14 PGJ 2 a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ 12,14 PGJ 2 production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ 2 and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.15-deoxy-Δ 12,14 PGJ 2 (15d-PGJ 2 ), fatty acid uptake, fluoxetine, non-alcoholic fatty liver disease (NAFLD), peroxisome proliferator-activated receptor gamma (PPARG), prostaglandin, prostaglandin-endoperoxide synthase 1 (PTGS1), prostaglandin-endoperoxide synthase 2 (PTGS2), selective serotonin reuptake inhibitor (SSRI), steatosis 1 | INTRODUCTION Major depressive disorder (MDD) is a prevalent and often recurrent illness affecting nearly 350 million individuals worldwide and is predicted to be the leading cause of disability by 2030 (Longfei et al., 2015; World Health Organization, 2017). A global burden of disease study saw a 49.86% increase in incident cases of depression worldwide from 1990 to 2017 (Liu et al., 2020), with the financial burden of MDD in 2010 exceeding USD 210.5 billion in the

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