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

• Published in: PloS one 2018-09, Vol.13 (9), p.e0203466-e0203466
• Main Authors: Karnati, Srikanth, Oruqaj, Gani, Janga, Harshavardhan, Tumpara, Srinu, Colasante, Claudia, Van Veldhoven, Paul P, Braverman, Nancy, Pilatz, Adrian, Mariani, Thomas J, Baumgart-Vogt, Eveline
• Format: Article
• Language: English
• Subjects: Anilides - pharmacology; Animals; Biology; Biology and Life Sciences; Biosynthesis; Bronchi - metabolism; Bronchi - pathology; Catalase; Cell proliferation; Cytoplasm; Emphysema; Epithelium; Fatty acids; Gene expression; Gene Expression Regulation; Homeostasis; Immunofluorescence; Labeling; Labelling; Ligands; Lipids; Lungs; Medicine and Health Sciences; Metabolism; Mice; Mice, Knockout; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Pediatrics; Peroxisome proliferator-activated receptors; Peroxisomes; Peroxisomes - genetics; Peroxisomes - metabolism; PPAR alpha - antagonists & inhibitors; PPAR alpha - biosynthesis; PPAR alpha - genetics; PPAR gamma - deficiency; Proteins; Pulmonary Emphysema - genetics; Pulmonary Emphysema - metabolism; Pulmonary Emphysema - pathology; Respiratory tract; siRNA; Transfection; Urology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0203466

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.