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Fenretinide differentially modulates the levels of long- and very long-chain ceramides by downregulating Cers5 enzyme: evidence from bench to bedside

Garić, Dušan
Author Garić, Dušan Department of Human Genetics, McGill University, Montreal, Quebec, Canada
De Sanctis, Juan B
Author De Sanctis, Juan B Department of Immunology, Central University of Venezuela, Caracas, Bolivarian Republic of Venezuela
Wojewodka, Gabriella
Author Wojewodka, Gabriella Department of Human Genetics, McGill University, Montreal, Quebec, Canada Academic Neuroscience Centre, King's College London, London, UK
Houle, Daniel
Author Houle, Daniel McGill University Health Center, 1001 Decarie Boulevard, Room EM 23242, Montreal, Quebec, H4A 3J1, Canada
Cupri, Shanon
Author Cupri, Shanon McGill University Health Center, 1001 Decarie Boulevard, Room EM 23242, Montreal, Quebec, H4A 3J1, Canada
Abu-Arish, Asmahan
Author Abu-Arish, Asmahan Department of Physiology, McGill University, Montreal, Quebec, Canada
Hanrahan, John W
Author Hanrahan, John W Department of Physiology, McGill University, Montreal, Quebec, Canada
Hajduch, Marian
Author Hajduch, Marian Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
Matouk, Elias
Author Matouk, Elias McGill University Health Center, 1001 Decarie Boulevard, Room EM 23242, Montreal, Quebec, H4A 3J1, Canada
Radzioch, Danuta
Author Radzioch, Danuta ORCID Department of Human Genetics, McGill University, Montreal, Quebec, Canada. danuta.radzioch@mcgill.ca McGill University Health Center, 1001 Decarie Boulevard, Room EM 23242, Montreal, Quebec, H4A 3J1, Canada. danuta.radzioch@mcgill.ca

Journal of molecular medicine (Berlin, Germany). 2017 Oct ; 95 (10) : 1053-1064. [epub] 20170710

J Mol Med (Berl)
ISSN 1432-1440 | 0946-2716
Source

Language English Country Germany Media print-electronic

Document type Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid28695226

PubMed 28695226
DOI 10.1007/s00109-017-1564-y
PII: 10.1007/s00109-017-1564-y
Knihovny.cz E-resources

Keywords
Ceramides, Cystic fibrosis, Fenretinide,
MeSH
Transcriptional Activation drug effects MeSH
Cell Line MeSH
Ceramides analysis blood metabolism MeSH
Cystic Fibrosis blood drug therapy metabolism MeSH
Adult MeSH
Down-Regulation drug effects MeSH
Fenretinide therapeutic use MeSH
Middle Aged MeSH
Humans MeSH
Adolescent MeSH
Young Adult MeSH
Disease Models, Animal MeSH
Mice, Inbred C57BL MeSH
Mice, Knockout MeSH
PPAR gamma agonists MeSH
Sphingosine N-Acyltransferase antagonists & inhibitors genetics metabolism MeSH
Animals MeSH
Check Tag
Adult MeSH
Middle Aged MeSH
Humans MeSH
Adolescent MeSH
Young Adult MeSH
Male MeSH
Female MeSH
Animals MeSH
Publication type
Journal Article MeSH
Clinical Trial MeSH
Research Support, Non-U.S. Gov't MeSH
Names of Substances
Ceramides MeSH
CERS5 protein, human MeSH Browser
Fenretinide MeSH
PPAR gamma MeSH
Sphingosine N-Acyltransferase MeSH

UNLABELLED: Cystic fibrosis is the most common genetic disease, in which symptoms may be alleviated but not fully eliminated. Ceramides have long been implicated in the inflammatory etiology of cystic fibrosis, with contradicting reports with regards to their role. Recently, significant biological and biophysical differences have been observed between long- and very long-chain ceramides. This work reveals that long-chain ceramides are upregulated whereas very long-chain ceramides are downregulated in cell lines, mouse animal model, and patients with cystic fibrosis, compared with their controls. Treatment with fenretinide decreases the levels of long-chain ceramides and increases the levels of very long-chain ceramides. Our results show that restoration of cystic fibrosis conductance regulator (CFTR) expression is associated with normalization of aberrant levels of specific ceramides. This demonstrates for the first time a correlation between CFTR protein expression and regulation of specific ceramide levels. Furthermore, using cystic fibrosis lung epithelial cell lines, we demonstrate that this effect can be attributed to the transcriptional downregulation of ceramide synthase 5 (Cers5) enzyme. We also discovered a partial synergism between fenretinide and zinc (Zn2+), which deficiency has been reported in patients with cystic fibrosis. Overall, in addition to having direct translational application, we believe that our findings contribute to the understanding of ceramide metabolism in cystic fibrosis, as well as other inflammatory diseases where imbalances of ceramides have also been observed. KEY MESSAGES: Long- and very long-chain ceramides (LCCs and VLCCs) are biochemically distinct. LCCs are upregulated whereas VLCCs are downregulated in cystic fibrosis. Fenretinide downregulates the levels of LCCs and upregulates the levels of VLCCs. Fenretinide changes the balance of LCCs and VLCCs by downregulating Cers5 enzyme. Fenretinide and zinc ions cooperate in the modulation of ceramide levels.

Academic Neuroscience Centre King's College London London UK

Department of Human Genetics McGill University Montreal Quebec Canada

Department of Immunology Central University of Venezuela Caracas Bolivarian Republic of Venezuela

Department of Physiology McGill University Montreal Quebec Canada

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

McGill University Health Center 1001 Decarie Boulevard Room EM 23242 Montreal Quebec H4A 3J1 Canada

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