Fenretinide inhibits obesity and fatty liver disease but induces Smpd3 to increase serum ceramides and worsen atherosclerosis in LDLR −/− mice

Thompson, D., Mahmood, S., Morrice, N., Kamli-Salino, S., Dekeryte, R., Hoffmann, P. A., Doherty, M. K., Whitfield, P. D. , Delibegović, M. and Mody, N. (2023) Fenretinide inhibits obesity and fatty liver disease but induces Smpd3 to increase serum ceramides and worsen atherosclerosis in LDLR −/− mice. Scientific Reports, 13, 3937. (doi: 10.1038/s41598-023-30759-w) (PMID:36894641) (PMCID:PMC9998859)

Abstract

Fenretinide is a synthetic retinoid that can prevent obesity and improve insulin sensitivity in mice by directly altering retinol/retinoic acid homeostasis and inhibiting excess ceramide biosynthesis. We determined the effects of Fenretinide on LDLR−/− mice fed high-fat/high-cholesterol diet ± Fenretinide, a model of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Fenretinide prevented obesity, improved insulin sensitivity and completely inhibited hepatic triglyceride accumulation, ballooning and steatosis. Moreover, Fenretinide decreased the expression of hepatic genes driving NAFLD, inflammation and fibrosis e.g. Hsd17b13, Cd68 and Col1a1. The mechanisms of Fenretinide’s beneficial effects in association with decreased adiposity were mediated by inhibition of ceramide synthesis, via hepatic DES1 protein, leading to increased dihydroceramide precursors. However, Fenretinide treatment in LDLR−/− mice enhanced circulating triglycerides and worsened aortic plaque formation. Interestingly, Fenretinide led to a fourfold increase in hepatic sphingomyelinase Smpd3 expression, via a retinoic acid-mediated mechanism and a further increase in circulating ceramide levels, linking induction of ceramide generation via sphingomyelin hydrolysis to a novel mechanism of increased atherosclerosis. Thus, despite beneficial metabolic effects, Fenretinide treatment may under certain circumstances enhance the development of atherosclerosis. However, targeting both DES1 and Smpd3 may be a novel, more potent therapeutic approach for the treatment of metabolic syndrome.

• Item Type: Articles
• Additional Information: This study was supported by funds from the British Heart Foundation (PG16/90/32518) project grant to N. Mody and a PhD studentship to S.M. by the James Mearns Trust and School of Medicine, Medical Sciences and Nutrition, University of Aberdeen (UoA).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Whitfield, Mr Phil
• Authors: Thompson, D., Mahmood, S., Morrice, N., Kamli-Salino, S., Dekeryte, R., Hoffmann, P. A., Doherty, M. K., Whitfield, P. D., Delibegović, M., and Mody, N.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Scientific Reports 13: 3937
• Publisher Policy: Reproduced under a Creative Commons License