Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Kanti, M.
Fueling lung regeneration: The significance of lipid metabolism in the repair of lung injury
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp.
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Höfler Gerald
- Kwapiszewska-Marsh Grazyna
- Olschewski Andrea
- Altmetrics:
- Abstract:
- Our lungs face constant exposure to harmful environmental factors like toxins, particulate matter, and pathogens, leading to potential long-term damage. However, the airway and alveolar epithelial cells in our lungs can quickly regenerate and repair the injured areas. Failure to regenerate the epithelia efficiently lies at the core of many prevalent lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, lung fibrosis, and lung cancer. Transcriptional regulation of lung epithelial repair mechanisms is relatively well understood. However, it is still unknown how cellular energy metabolism contributes to this process in the context of lipid metabolism. To understand the importance of lipid metabolism in lung regeneration, we studied mice lacking Adipose triglyceride lipase (ATGL)- the first and rate-limiting enzyme for lipid-droplet triglyceride hydrolysis (lipolysis). ATGL-mediated intracellular lipolysis provides energy-rich fatty acids (FA). These FAs are essential for rapid cellular regeneration because they serve as substrates for mitochondrial energy metabolism, as building blocks for cell membrane biogenesis, and as signaling molecules. Therefore, we hypothesized that ATGL-mediated lipid catabolism is essential for optimal lung regeneration. Deletion of the gene encoding ATGL, Pnpla2 (also known as Atgl) in mice induced substantial triglyceride accumulation, decreased mitochondrial numbers, and decreased mitochondrial respiration in club cells. After naphthalene-induced epithelial denudation, a regenerative defect was apparent. The observed phenotype can be attributed to dysfunctional PPARα lipid-signaling mechanisms because (a) ATGL mediated PPARα lipid-signaling was needed in regenerating bronchioles, and (b) restoration of normal bronchiolar club cell ultrastructure and regenerative potential through administration of the specific PPARα agonist WY14643. In mice globally lacking Atgl, AT2 cells display huge neutral lipid accumulation and reduced surfactant phospholipids. Similarly, in the tamoxifen-inducible AT2-specific Atgl-knockout mouse model with Rosa26-Yfp linage tracer, we noted gross neutral lipid accumulation in linage-positive/Atgl-/-AT2 cells. In the organoid assay, lineage-positive AT2 cells from the control group recapitulated the critical aspect of in vivo regeneration and structural maturation, and organoids formed by linage-positive/Atgl-/- AT2 cells were significantly fewer in numbers and showed poor structural patterning. Additionally, in vivo, 21 days post-PNX surgery, the knockout group had fewer lineage-positive AT2 cells than the control group. These findings pointed to defective alveoli formation without intact lipolysis in AT2 cells. Altogether, our data emphasize the importance of cellular energy metabolism for lung epithelial regeneration and highlight the significance of ATGL-mediated lipid catabolism for lung health.