title: Lipid metabolism in cystic fibrosis.
abstract: OBJECTIVE
  Expression of defective cystic fibrosis transmembrane conductance regulator (CFTR), the cause for cystic fibrosis, affects fatty acid, cholesterol and sphingolipid metabolism. This review summarizes recent observations and evaluates current understanding of mechanisms.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Expression of defective CFTR has profound effects on fatty acid, cholesterol and sphingolipid metabolism, for which mechanisms are currently poorly understood. Recent studies in different cystic fibrosis models suggest a causal relationship between altered ceramide mass and increased inflammation and susceptibility to infection. Studies in cystic fibrosis knockout mouse models suggest that normalization of ceramide decreases infection and inflammation. Studies that evaluate the diagnostic and clinical relevance of sphingolipids in patients with cystic fibrosis are needed.
authors.affiliation: Department of Pathology, Pediatrics and Institute of Human Nutrition, Columbia University, BB 457, New York 10032, USA. tpw7@columbia.edu
authors.forename: Tilla S
authors.initials: TS
authors.lastname: Worgall
mesh_terms: D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D019587:Dietary Supplements; D005227:Fatty Acids / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D002518:Ceramides; D005227:Fatty Acids; D013107:Sphingolipids; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002784:Cholesterol