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: Miao-Hsi Hsieh謝妙禧                                  Time: 14:10~15:00, May. 26, 2010

Commentator: Yau-Sheng Tsai                                      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 accumulates excess amount of mucous 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, they analyze gene expression in the colon epithelial cells in Cftr ^-/- mice and found that the expression of genes involved in lipid metabolism and PPAR-dependent signaling pathway were decreased. There was no significant difference between wile-type mice and Cftr ^-/- mice in PPAR-γ mRNA expression level in colon. Therefore, the authors hypothesize that Cftr ^-/- mice treat with rosiglitazone, synthetic PPAR-γ agonist, might have effect(s). Cftr ^-/- mice with rosiglitazone treatment have higher survival rates compared to control mice. Cftr ^-/- mice treated with rosiglitazone also increases the expression of PPAR-γdownregulation genes (Acaa1b, Angptl4, Mgll, Hmgcs2) and other genes (Car2 and Car4) involved in bicarbonate production and secretion in the intestine. There are no difference in PPAR expression between wild- type and Cftr ^-/- mice in colonic epithelial, so they investigate PPAR-γ DNA binding affinity by chromatin immunoprecipitation (ChIP). They found TRAP220, PPAR-g co-activator, decrease recruitment in cftr^-/- mice. Finally, they investigate the role of lipid metabolism in cftr deficiency. They quantify 15-HETE and 15-keto-PGE₂ in wild-type and Cftr^−/− mice colonic epithelial cells, and found 15-keto PGE₂ expression in Cftr^−/− mice was lower than wile-type mice. The PPAR-γ target gene Angptl4 increase expression when HT-29 colonic epithelial cells treat with 15-keto PGE₂. 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).