Decreased expression of peroxisome proliferator activated receptor γ in CFTR-/- mice

Abstract

Some of the pathological manifestations of cystic fibrosis are in accordance with an impaired expression and/or activity of PPARγ. We hypothesized that PPARγ expression is altered in tissues lacking the normal cystic fibrosis transmembrane regulator protein (CFTR). PPARγ mRNA levels were measured in colonic mucosa, ileal mucosa, adipose tissue, lung, and liver from wild-type and cftr-/- mice by quantitative RT-PCR. PPARγ expression was decreased twofold in CFTR-regulated tissues (colon, ileum, and lung) from cftr-/- mice compared to wild-type littermates. In contrast, no differences were found in fat and liver. Immunohistochemical analysis of PPARγ in ileum and colon revealed a predominantly nuclear localization in wild-type mucosal epithelial cells while tissues from cftr -/- mice showed a more diffuse, lower intensity labeling. A significant decrease in PPARγ expression was confirmed in nuclear extracts of colon mucosa by Western blot analysis. In addition, binding of the PPARγ/RXR heterodimer to an oligonucletotide containing a peroxisome proliferator responsive element (PPRE) was also decreased in colonic mucosa extracts from cftr-/- mice. Treatment of cftr-/- mice with the PPARγ ligand rosiglitazone restored both the nuclear localization and binding to DNA, but did not increase RNA levels. We conclude that PPARγ expression in cftr-/- mice is downregulated at the RNA and protein levels and its function diminished. These changes may be related to the loss of function of CFTR and may be relevant to the pathogenesis of metabolic abnormalities associated with cystic fibrosis in humans. © 2004 Wiley-Liss, Inc.