Polyunsaturated fatty acid supplementation reverses cystic fibrosis-related fatty acid abnormalities in CFTR-/- mice by suppressing fatty acid desaturases.
Cystic fibrosis patients and model systems exhibit consistent abnormalities in metabolism of polyunsaturated fatty acids that appear to play a role in disease pathophysiology. Recent in vitro studies have suggested that these changes are due to overexpression of fatty acid desaturases that can be reversed by supplementation with the long-chain polyunsaturated fatty acids docosahexaenoate and eicosapentaenoate. However, these findings have not been tested in vivo. The current study aimed to test these results in an in vivo model system, the CFTR(-/-) knockout mouse. When compared with wild-type mice, the knockout mice exhibited fatty acid abnormalities similar to those seen in cystic fibrosis patients and other model systems. The abnormalities were confined to lung, ileum and pancreas, tissues that are affected by the disease. Similar to in vitro models, these fatty acid changes correlated with increased expression of Δ5- and Δ6-desaturases and elongase 5. Dietary supplementation with high-dose free docosahexaenoate or a combination of lower-dose docosahexaenoate and eicosapentaenoate in triglyceride form corrected the fatty acid abnormalities and reduced expression of the desaturase and elongase genes in the ileum and liver of knockout mice. Only the high-dose docosahexaenoate reduced histologic evidence of disease, reducing mucus accumulation in ileal sections. These results provide in vivo support for the hypothesis that fatty acid abnormalities in cystic fibrosis result from abnormal expression and activity of metabolic enzymes in affected cell types. They further demonstrate that these changes can be reversed by dietary n-3 fatty acid supplementation, highlighting the potential therapeutic benefit for cystic fibrosis patients.
['Njoroge|Sarah W|SW|', 'Laposata|Michael|M|', 'Boyd|Kelli L|KL|', 'Seegmiller|Adam C|AC|']
D000818:Animals D003550:Cystic Fibrosis D019587:Dietary Supplements D004281:Docosahexaenoic Acids D004305:Dose-Response Relationship, Drug D015118:Eicosapentaenoic Acid D044943:Fatty Acid Desaturases D007082:Ileum D008168:Lung D051379:Mice D018181:Mice, Inbred CFTR D018345:Mice, Knockout D010179:Pancreas
Fatty acid Desaturase Cystic fibrosis Docosahexaenoate Eicosapentaenoate Arachidonate