Fatty acid abnormalities in cystic fibrosis-the missing link for a cure?

Abstract

The care for cystic fibrosis (CF) has dramatically changed with the development of modulators, correctors, and potentiators of the CFTR molecule, which lead to improved clinical status of most people with CF (pwCF). The modulators influence phospholipids and ceramides, but not linoleic acid (LA) deficiency, associated with more severe phenotypes of CF. The LA deficiency is associated with upregulation of its transfer to arachidonic acid (AA). The AA release from membranes is increased and associated with increase of pro-inflammatory prostanoids and the characteristic inflammation is present before birth and bacterial infections. Docosahexaenoic acid is often decreased, especially in associated liver disease Some endogenously synthesized fatty acids are increased. Cholesterol and ceramide metabolisms are disturbed. The lipid abnormalities are present at birth, and before feeding in transgenic pigs and ferrets. This review focus on the lipid abnormalities and their associations to clinical symptoms in CF, based on clinical studies and experimental research.

Keywords: Clinical genetics; Health sciences; Human genetics; Internal medicine; Medical specialty; Medicine; Molecular biology; Respiratory medicine.

Graphical abstract

Figure 1

A basic simplified overview of the hypothetical relation between fatty acid abnormalities in relation to CFTR and clinical implications CFTR must fit in the membrane for normal function. CFTR variants are processed in the cell and abnormal CFTR are sorted in the endoplasmic reticulum, where most aberrant CFTR is withdrawn, and not all reach the membranes where the localization or function may be impaired in the context of membrane lipids. In normal cells glucocorticoids interfere with the annexin synthesis, which possibly by phosphorylation regulate PLA₂ activity by inhibition both of its release of arachidonic acid and activity of COX 2 for PGE₂ release. In CF down-regulation of annexin synthesis increases arachidonic acid release with subsequent increasing synthesis from linoleic acid. Thereby linoleic decreases in the membranes interfering with the membrane stereochemistry hampering CFTR activity, and thus impairing the action between CFTR and membranes. Fatty acid composition differs in membranes and organelles, whereby the defective CFTR transfer/function might occur in different compartment localizations in cells and organs. Defective metabolism of ceramides and cholesterol interferes with the raft building (not shown), where the CFTR have its action. Low DHA have been described in cystic fibrosis liver disease (CFRLD) and may be connected with cystic fibrosis related diabetes (CFRD) and may be related to low LXA₄. The boxes to the left summarize lipid related processes described in the section “associations between clinical symptoms and fatty acid balance”. GR, Glucocorticoid Receptor; AA, arachidonic acid; ER, endoplasmic reticulum; LA, linoleic acid; PLA₂, phospholipase A_2,; PGE₂, prostaglandin E₂; LXA_4, lipoxin A4. Differences in arrow size reflect relative transfer activity.