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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
D. Garić, JB. De Sanctis, G. Wojewodka, D. Houle, S. Cupri, A. Abu-Arish, JW. Hanrahan, M. Hajduch, E. Matouk, D. Radzioch,
Jazyk angličtina Země Německo
Typ dokumentu klinické zkoušky, časopisecké články
Medline Complete (EBSCOhost) od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest) od 1997-01-01 do Před 1 rokem
Odkazy
PubMed
28695226
DOI
10.1007/s00109-017-1564-y
Knihovny.cz E-zdroje
- 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
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.
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
McGill University Health Center 1001 Decarie Boulevard Room EM 23242 Montreal Quebec H4A 3J1 Canada
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- $a 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.
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