Mechanisms of Polyunsaturated Fatty Acid Alterations in Cystic Fibrosis
Njoroge, Sarah Wanjiku
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2013-07-29
Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Alterations in polyunsaturated fatty acid (PUFA) levels have been consistently described in patients and models of CF. These alterations include decreased linoleic acid (LA) and docosahexaenoic acid (DHA) and variably increased arachidonic acid (AA), and are independent of nutritional status and malabsorption. The use of DHA therapy to normalize PUFA levels in CF mouse models has resulted in reversal of certain pathologic manifestations of the disease, suggesting that PUFA changes may play a key role in the pathogenesis of CF. However, the precise mechanism(s) of the fatty acid changes and how they contribute to a CF phenotype is unknown. Additionally, the connection between these fatty acid changes and CFTR mutations, as well as the mechanism by which DHA therapy works to correct the PUFA abnormalities remains unknown. In this dissertation, we show that CF PUFA alterations are caused by increased expression and activity of the enzymes involved in PUFA metabolism, including Δ5 and Δ6-desaturase. DHA therapy corrects the PUFA abnormalities by suppressing the expression and activity of these enzymes, and by decreasing the levels of AA available to be converted to pro-inflammatory eicosanoids. In addition, we present a potential pathway that connects CFTR mutations to the fatty acid abnormalities via the excessive production of reactive oxygen species in CF.