Recent observations implicate CFTR, in addition to known effects on
fatty acid and
cholesterol metabolism, in the regulation of
sphingolipid metabolism and suggest that this pathway is relevant to
inflammation and
infection. A common mechanism on how CFTR affects such a wide spectrum of
lipid classes is currently not known. One mechanism for low
linoleic acid, amenable to inhibition by
docosahexaenoic acid, is increased metabolism in the
n-6 fatty acid pathway. Accumulation of free
cholesterol in distinct perinuclear compartments, reversible by overexpression of rab9, suggests that
cystic fibrosis and the
lysosomal storage disease Niemann-Pick-C could share similar cell signaling defects, in addition to increased cAMP signaling and
sterol-regulatory element binding protein (SREBP) expression that affect
cholesterol metabolism. Novel is the recognition that CFTR modulates
ceramide mass and uptake of sphingosine-1-
phosphate. Experiments in different
cystic fibrosis-mouse models, although not able to establish whether
ceramide mass is increased or decreased, suggest that normalization of
ceramide decreases
infection and selected parameters of
inflammation, of relevance to the complex phenotype that characterizes
cystic fibrosis.
SUMMARY: