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.