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

Dawn Thompson* (Corresponding Author), Shehroz Mahmood, Nicola Morrice, Sarah Kamli-Salino, Ruta Dekeryte, Philip Hoffmann, Mary K Doherty, Philip D. Whitfield, Mirela Delibegović, Nimesh Mody* (Corresponding Author)

*Corresponding author for this work

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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 4-fold 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.
Original languageEnglish
Article number3937
JournalScientific Reports
Volume13
DOIs
Publication statusPublished - 9 Mar 2023

Bibliographical note

Acknowledgements
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). No potential conflicts of interest relevant to this article are reported. N. Mody and D.T. conceived the study, designed the experiments and wrote the manuscript. D.T., S.M, N. Morrice, R.D., S.K.S, P.H. performed experiments. P.W. and M.D. performed the ceramide analysis, M.D. contributed to the study conception, discussions and reviewed the manuscript.
N.Mody is the guarantor of this work and, as such, had full access to all the data in this study and takes responsibility for the integrity and accuracy of the data analysis.
The authors thank the UoA animal research facility, qPCR core facility (Institute of Medical Sciences, UoA) and Linda Davidson (NHS Grampian) for their technical contributions regarding animal studies, qPCR and histology respectively and Alison Rutter at UHI for lipidomics support. We thank UoA Masters students Emma Forbes and Nawaf Alsulami for assisting in experiments on ApoE-/- mice. The authors also wish to thank Patrick W F Hadoke (University of Edinburgh)
and Heather M Wilson (UoA) for invaluable discussions about mechanisms of atherosclerosis and review of the manuscript, Matteo Zanda, Sergio Dall’Angelo, Chiara Zanato and Ilaria Patruno (all UoA) for medicinal chemistry support.

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