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PubMed

Záznam pochází z PubMed

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

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

Jazyk angličtina Země Německo Médium print-electronic

Typ dokumentu klinické zkoušky, časopisecké články, práce podpořená grantem

Perzistentní odkaz 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-zdroje

Klíčová slova
Ceramides, Cystic fibrosis, Fenretinide,
MeSH
aktivace transkripce účinky léků MeSH
buněčné linie MeSH
ceramidy analýza krev metabolismus MeSH
cystická fibróza krev farmakoterapie metabolismus MeSH
dospělí MeSH
down regulace účinky léků MeSH
fenretinid terapeutické užití MeSH
lidé středního věku MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
modely nemocí na zvířatech MeSH
myši inbrední C57BL MeSH
myši knockoutované MeSH
PPAR gama agonisté MeSH
sfingosin-N-acyltransferasa antagonisté a inhibitory genetika metabolismus MeSH
zvířata MeSH
Check Tag
dospělí MeSH
lidé středního věku MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
mužské pohlaví MeSH
ženské pohlaví MeSH
zvířata MeSH
Publikační typ
časopisecké články MeSH
klinické zkoušky MeSH
práce podpořená grantem MeSH
Názvy látek
ceramidy MeSH
CERS5 protein, human MeSH Prohlížeč
fenretinid MeSH
PPAR gama MeSH
sfingosin-N-acyltransferasa 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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