Cystic fibrosis: Lipid link

Lipidomics Gateway (24 February 2010) [doi:10.1038/lipidmaps.2010.5]

Reduced production of a lipid ligand of PPAR-γ contributes to pathological gene expression in cystic fibrosis.

Ciliated airway epithelial cells partially covered in mucus (courtesy of Professor Peter Jeffery, Imperial College). From Griesenbach et al. Gene Therapy 11, S43–S50 (2004) doi:10.1038/sj.gt.3302368

The lungs and digestive organs of patients with cystic fibrosis (CF) become clogged with dehydrated mucus. Causative mutations in the CF transmembrane conductance regulator, encoded by Cftr, are incurable at present, so treatments for CF focus on ameliorating disease severity. A study in mice now identifies a mechanism of CF pathology that might present new treatment options. Gregory Harmon et al. report in Nature Medicine that reduced production of a prostaglandin ligand of peroxisome proliferator-activated receptor-γ (PPAR-γ) in Cftr-deficient mice contributes to an aberrant program of gene expression, and can be pharmacologically corrected.

Cftr knockout mice (Cftr^-/- ) die early from digestive obstructions, but their survival is improved by a special diet. The authors analyzed gene expression in colonic epithelial cells isolated from Cftr^-/- and wild-type mice, and found that several genes involved in lipid metabolism were downregulated in the knockout cells. Pathway analysis suggested a defect in PPAR-dependent gene expression, but levels of PPAR-γ messenger RNAs were similar in cells from both genotypes. If Cftr knockout caused a problem upstream of PPAR-γ, then an exogenous ligand might restore normal gene expression. Accordingly, treatment with the synthetic PPAR-γ agonist rosiglitazone reversed some of the alterations in gene expression observed in the knockout cells, and in cells derived from a human CF patient. Furthermore, treatment with rosiglitazone reduced the rate of bowel obstruction and increased survival in the knockout mice.

To further characterize the PPAR-γ signaling defect, the authors used chromatin precipitation analysis to measure binding of PPAR-γ to regulatory regions of the affected target genes. For several of the genes, PPAR-γ binding was equivalent between wild-type and knockout cells. However, binding of a coactivator that interacts with PPAR-γ in a ligand-dependent manner was reduced in the Cftr^-/- cells. This suggested that the signaling defect arises from reduced PPAR-γ activation, due to reduced availability of ligands in the context of Cftr deficiency.

Many fatty acid and eicosanoid metabolites activate PPAR-γ, so the authors turned to lipidomic analysis to find out which might be deficient. One of the two most abundant eicosanoids in wild-type colonic epithelial cells was 15-keto-prostaglandin E2 (15-keto-PGE2), and this was reduced by about 65% in the knockout cells. Likewise, expression of the enzyme responsible for its synthesis was reduced by 70%. Treatment with the lipid induced expression of a PPAR-dependent gene.

This study suggests that reduced production of endogenous PPAR-γ activators, including 15-keto-PGE2, contributes to a pathogenic program of gene expression in CF. Genes involved in compensatory ion transport were among those affected, which links the signaling defect to mucus accumulation. Inflammation, another pathogenic feature of CF, might also be driven by an increase in PGE2 caused by reduced conversion to 15-keto-PGE2.

Further work will characterize functional differences in the ability of PPAR-γ ligands to compensate for Cftr deficiency, and show whether levels of 15-keto-PGE2 can serve as a biomarker for those patients most likely to benefit from this approach.

Emma Leah