Abstract
Despite the important functions of PPARγ in various cell types of the lung, PPARγ-deficiency in club cells induces only mild emphysema. Peroxisomes are distributed in a similar way as PPARγ in the lung and are mainly enriched in club and AECII cells. To date, the effects of PPARγ-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 PPARγ 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 PPARγand 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 PPARα and PPRE activity, a strong overall upregulation of the peroxisomal compartment and its associated gene expression (biogenesis, α-oxidation, β-oxidation, and plasmalogens) in PPARγ-deficient club cells. Interestingly, catalase was significantly increased and mistargeted into the cytoplasm, suggestive for oxidative stress by the PPARγ-deficiency in club cells. Taken together, PPARα-mediated metabolic induction and proliferation of peroxisomes via a PPRE-dependent mechanism could compensate PPARγ-deficiency in club cells.
Highlights
Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor family [1]
Peroxisomal biogenesis and reactive oxygen species (ROS) metabolizing enzyme are increased in peroxisome proliferator activated receptor γ (PPARγ)-deficient club cells
The PEX14p labelling intensity and the number of peroxisomes were significantly increased in the PPARγ-deficient club cells suggesting a proliferation of the peroxisomal compartment with active peroxisomal biogenesis (Fig 1B, 1D, 1F, 1H and 1I)
Summary
Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor family [1]. Peroxisomes in PPARγ-deficient club cells chronic obstructive pulmonary disease; RXR, retinoid X receptor. The highest expression of PPARγ was found in club and AECII cells where it was suggested to regulate epithelial cell differentiation and to control airway inflammatory processes [3]. All PPARs exhibit a similar molecular mode of action and a partially overlapping lipid ligand spectrum with different binding sensitivities. After binding their preferred ligand, they form heterodimers with the nuclear receptor RXR, are targeted to the nucleus, and subsequently bind to DNA-response elements in the target genes known as peroxisome proliferator response elements (PPREs). PPREs are present in many genes regulating the transcription of proteins involved in the biogenesis and metabolism of peroxisomes
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