The role of essential fatty acids in cystic fibrosis and normalizing effect of fenretinide
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Cellular and Molecular Life Sciences
REVIEW
The role of essential fatty acids in cystic fibrosis and normalizing effect of fenretinide Dušan Garić1,5 · Daciana Catalina Dumut2,5 · Juhi Shah3,5 · Juan Bautista De Sanctis4 · Danuta Radzioch1,2,4,5 Received: 15 June 2019 / Revised: 28 February 2020 / Accepted: 15 April 2020 © Springer Nature Switzerland AG 2020
Abstract Cystic fibrosis (CF) is the most common autosomal-recessive disease in Caucasians caused by mutations in the CF transmembrane regulator (CFTR) gene. Patients are usually diagnosed in infancy and are burdened with extensive medical treatments throughout their lives. One of the first documented biochemical defects in CF, which predates the cloning of CFTR gene for almost three decades, is an imbalance in the levels of polyunsaturated fatty acids (PUFAs). The principal hallmarks of this imbalance are increased levels of arachidonic acid and decreased levels of docosahexaenoic acids (DHA) in CF. This proinflammatory profile of PUFAs is an important component of sterile inflammation in CF, which is known to be detrimental, rather than protective for the patients. Despite decades of intensive research, the mechanistic basis of this phenomenon remains unclear. In this review we summarized the current knowledge on the biochemistry of PUFAs, with a focus on the metabolism of AA and DHA in CF. Finally, a synthetic retinoid called fenretinide (N-(4-hydroxy-phenyl) retinamide) was shown to be able to correct the pro-inflammatory imbalance of PUFAs in CF. Therefore, its pharmacological actions and clinical potential are briefly discussed as well. Keywords Cystic fibrosis · Lipids · PUFAs · CFTR · Fenretinide
Polyunsaturated fatty acids and their metabolism in CF Metabolism of PUFAs Unsaturated fatty acids are carboxylic acids that contain one or more double bonds and more than four carbons in the acyl * Danuta Radzioch [email protected] 1
Department of Human Genetics, McGill University, Montreal, QC, Canada
2
Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada
3
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
4
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
5
Program in Infectious Diseases and Immunity in Global Health, McGill University Health Center, 1001 Decarie Boulevard, Room EM3‑3211, Montreal, QC H4A 3J1, Canada
chain. Monounsaturated fatty acids contain one double bond, whereas polyunsaturated fatty acids (PUFAs) contain two or more double bonds. The most common naturally occurring PUFAs are ω-3 and ω-6 PUFAs. The designation ω refers to the position of the most distal double bond counted from the last carbon of the acyl chain (e.g., ω-3 PUFAs have its first double-bond three carbons away from the most distal methyl group). Alternatively, the n letter instead of the ω can be used with the same meaning and fatty acids can be designated as n-3 and n-6. For exa
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