Cystic fibrosis (CF) is an autosomal recessive disease caused by absence of functional cystic fibrosis Tran's membrane conductance regulator (CFTR) protein in epithelial cells. The major cause of morbidity and mortality in patients with CF is chronic pulmonary disease characterized by persistent inflammation and recurrent infections. CF patients have characteristic alterations in polyunsaturated fatty acid (PUFA) composition in CFTR-expressing tissues, including increased arachidonic acid, and reduced linoleic acid and docosahexaenoic acid (DHA). These alterations are a consequence of altered PUFA metabolism in CF, including increased expression and activity of ?6-desaturase (D6D). In a CF mouse model, DHA supplementation diminishes the CF phenotype, suggesting that these alterations play an important role in CF pathogenesis. However, the mechanism by which CFTR mutations lead to alterations in PUFA metabolism is unclear. Preliminary data suggests that increased AMP-activated protein kinase (AMPK) activity in CF plays a role. The proposed study seeks to test the hypothesis that PUFA metabolic alterations in CF are a consequence of increased AMPK activity through completion of the following aims: (1) elucidate the mechanism by which AMPK activity is increased in CF, and (2) determine the impact of AMPK activity on PUFA metabolism in CF. Completion of the proposed study will provide insight into the mechanism linking CF and PUFA metabolism. Better understanding of this mechanism will contribute to the development of potential lipid-based therapies for CF patients.
Cystic fibrosis is a heritable disease affecting approximately 30,000 people in the United States, and patients have a life expectancy of less than 40 years of age. Alterations in polyunsaturated fatty acid metabolism play a role in the development of the disease and are a potential target for therapy. To aid in the development of life- lengthening therapies for CF, the proposed study seeks to define the mechanism by which these fatty acid alterations arise in CF.
|Umunakwe, Obi C; Seegmiller, Adam C (2014) Abnormal n-6 fatty acid metabolism in cystic fibrosis is caused by activation of AMP-activated protein kinase. J Lipid Res 55:1489-97|