Pharmacological correction of a defect in PPAR-γ signaling ameliorates disease severity in Cftr-deficient mice

Gregory S Harmon1, et al. Nature Medicine 16: 313-318, 2010

Speaker: 謝妙禧                                                   Time: 14:10~15:00, May. 26, 2010

Commentator: 蔡曜聲老師                                Place: Room 601

Abstract:

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (Cftr) on chromosome 7. The Cftr mutation causes an apical ion channel dysfunction and makes abound mucous accumulation in the airway and obstructs luminal organs. The Cftr knockout mice (Cftr ^-/- mice) die within the first 6 weeks of life because intestinal or colonic obstruction. But these mice can maintain their life by proving standard chow and electrolyte lavage solution (GoLYTELY). First, gene analysis Cftr ^-/- mice gene expression in the colon epithelial cells, which was found the lower expression involved lipid metabolism and defect PPAR-dependent gene expression. Analysis the wile-type mice PPAR-γ mRNA expression, these mice have high level expression in the colon. But compare to Cftr ^-/- mice which maintain byGoLYTELY the mRNA expression is not significant changes. Therefore the authors hypothesis synthetic PPAR-γ agonist rosiglitazone treat with Cftr ^-/- mice possibly have functional consequences. Compared to control group, Cftr ^-/- mice treated with rosiglitazone have higher survival rates. TheCftr ^-/- mice treat with rosiglitazone increase the gene expression including PPAR-γ downregulation gene (Acaa1b, Angptl4, Mgll, Hmgcs2 ) and the gene involve bicarbonate production and secretion in the intestine (Car2 and Car4 ) . Then the authors focus rosiglitazone how to impair PPAR-γ in the colonic epithelial cell. They generated mice lacking PPAR-γ in the intestinal epithelium and cftr knockout as cftr^-/-; Pparg^IEC−/− mice. Because PPAR-γ does not express in the cftr^-/-; Pparg^IEC−/− mice intestinal epithelium cells , resulting survival rates and PPAR-γ target gene expression in colonic epithelial cells do not increase by rosiglitazone. Finally, the authors used chromatin immunoprecipitation (ChIP) investigate whether PPAR-γ is dysfunction on the gene regulate. The result found recruitment of TRAP220 to PPREs dependent on PPAR-γ in wile-type mice. Because observe reduced recruitment of TRAP220 in cftr^-/- mice, the author thinks that possibility abundance endogenous fatty acid metabolites involved the disease. To proved lipid metabolism involved cftr deficiency, the authors quantify the15-HETE and 15-keto PGE in wild-type and Cftr^−/− colonic epithelial cells. 15-keto PGE in Cftr^−/− mice was lower expression than wile-type mice, and the HT-29 colonic epithelial cells treated with 15-keto PGE can increase PPAR-γ target gene Angptl4 expression. Altogether, these findings imply that PPAR-γ may be a new target for the treatment of cystic fibrosis.

References:

1. O’Sullivan, B.P. & Freedman, S.D. Cystic fibrosis. Lancet 373, 1891–1904 (2009).