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Oliveira, F. ; Papa, C. ; Hagemann, T. ; Schipper, R.* ; Geier, F. ; Röxe, T.* ; Zulfqar, F. ; Prönnecke, C.* ; Schmidt, L.* ; Stryhanyuk, H.* ; Hoffmann, A. ; Kyselova, A.* ; Karantanou, C.* ; Buckley. Y. ; Farhan, M.A.* ; Rodriguez Aguilera, J.R. ; Ambreen, S.* ; Rodríguez-Aguilera, J.R. ; Arif, A.* ; Martin, H.N.G. ; Ebert, T.* ; Klöting-Blüher, N. ; Blüher, M. ; Shahzad, K.* ; Boeckel, J.N.* ; Hagberg, C.E.* ; Chakaroun, R.* ; Bibli, S.I.* ; Sheikh, B.N.

Fluoxetine disrupts cholesterol metabolism in endothelial cells via SREBP2 activation.

Transl. Psychiatry 16:318 (2026)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) commonly prescribed for the treatment of depressive disorders. Recent clinical reports and studies in animal models have suggested that fluoxetine increases the risk of cardiovascular diseases, but the underlying mechanisms remain unknown. Here, we uncover that fluoxetine disrupts lipid and cholesterol metabolism in primary human endothelial cells (ECs). Fluoxetine triggered an upregulation of cholesterol metabolism genes, leading to the accumulation of lipid droplets in ECs. We find higher levels of cholesterol esters, ceramides, sphingolipids and fatty acids in ECs treated with fluoxetine. The disruption of lipid homeostasis was driven by increased cholesterol biosynthesis, as well as low-density lipoprotein (LDL) uptake and transcytosis via the LDL receptor. Fluoxetine accumulated in ECs in the endoplasmic reticulum (ER), caused ER expansion and reduced protein translation, without inducing ER stress markers. Mechanistically, fluoxetine activated the SREBP2 transcription factor in an INSIG-dependent manner. SREBP2 inhibition attenuated the fluoxetine-mediated upregulation of the LDL receptor and lipid accumulation. Our findings reveal that fluoxetine reprograms lipid metabolism and leads to endothelial dysfunction.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Serotonin Reuptake Inhibitors; Hepatic Lipid-accumulation; Ldl Transcytosis; Atherosclerosis; Obesity; Pharmacokinetics; Antidepressants; Abnormalities; Dysfunction; Pathway
ISSN (print) / ISBN 2158-3188
e-ISSN 2158-3188
Journal Translational Psychiatry
Quellenangaben Volume: 16, Issue: 1, Pages: , Article Number: 318 Supplement: ,
Publisher Springer
Publishing Place The Campus, 4 Crinan St, London, N1 9xw, England
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Grants Allen Foundation (Allen Foundation Inc.)
Alexander von Humboldt-Stiftung (Alexander von Humboldt Foundation)
Deutsche Forschungsgemeinschaft (German Research Foundation)