PPARα-mediated peroxisome induction compensates PPARγ-deficiency in bronchiolar club cells

Despite the important functions of PPAR gamma in various cell types of the lung, PPAR gamma-deficiency in club cells induces only mild emphysema. Peroxisomes are distributed in a similar way as PPAR gamma in the lung and are mainly enriched in club and AECII cells. To date, the effects of PPAR gamma-deficiency on the overall peroxisomal compartment and its metabolic alterations in pulmonary club cells are unknown. Therefore, we characterized wild-type and club cell-specific PPAR gamma knockout-mice lungs and used C22 cells to investigate the peroxisomal compartment and its metabolic roles in the distal airway epithelium by means of 1) double-immunofluorescence labelling for peroxisomal proteins, 2) laser-assisted microdissection of the bronchiolar epithelium and subsequent qRT-PCR, 3) siRNA-transfection of PPAR gamma and PPRE dual-luciferase reporter activity in C22 cells, 4) PPARg inhibition by GW9662, 5) GC-MS based lipid analysis. Our results reveal elevated levels of fatty acids, increased expression of PPAR alpha and PPRE activity, a strong overall upregulation of the peroxisomal compartment and its associated gene expression (biogenesis, alpha-oxidation, beta-oxidation, and plasmalogens) in PPAR gamma-deficient club cells. Interestingly, catalase was significantly increased and mistargeted into the cytoplasm, suggestive for oxidative stress by the PPAR gamma-deficiency in club cells. Taken together, PPAR alpha-mediated metabolic induction and proliferation of peroxisomes via a PPRE-dependent mechanism could compensate PPAR gamma-deficiency in club cells.