Adipose triglyceride lipase–mediated lipid catabolism is essential for bronchiolar regeneration
Manu Manjunath Kanti, … , Gerald Hoefler, Paul Willibald Vesely
Manu Manjunath Kanti, … , Gerald Hoefler, Paul Willibald Vesely
Published March 29, 2022
Citation Information: JCI Insight. 2022;7(9):e149438. https://doi.org/10.1172/jci.insight.149438.
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Research Article Metabolism Pulmonology

Adipose triglyceride lipase–mediated lipid catabolism is essential for bronchiolar regeneration

Abstract

The lung airways are constantly exposed to inhaled toxic substances, resulting in cellular damage that is repaired by local expansion of resident bronchiolar epithelial club cells. Disturbed bronchiolar epithelial damage repair lies at the core of many prevalent lung diseases, including chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, and lung cancer. However, it is still not known how bronchiolar club cell energy metabolism contributes to this process. Here, we show that adipose triglyceride lipase (ATGL), the rate-limiting enzyme for intracellular lipolysis, is critical for normal club cell function in mice. Deletion of the gene encoding ATGL, Pnpla2 (also known as Atgl), induced substantial triglyceride accumulation, decreased mitochondrial numbers, and decreased mitochondrial respiration in club cells. This defect manifested as bronchiolar epithelial thickening and increased airway resistance under baseline conditions. After naphthalene‑induced epithelial denudation, a regenerative defect was apparent. Mechanistically, dysfunctional PPARα lipid-signaling underlies this phenotype because (a) ATGL was needed for PPARα lipid-signaling in regenerating bronchioles and (b) administration of the specific PPARα agonist WY14643 restored normal bronchiolar club cell ultrastructure and regenerative potential. Our data emphasize the importance of the cellular energy metabolism for lung epithelial regeneration and highlight the significance of ATGL-mediated lipid catabolism for lung health.

Authors

Manu Manjunath Kanti, Isabelle Striessnig-Bina, Beatrix Irene Wieser, Silvia Schauer, Gerd Leitinger, Thomas O. Eichmann, Martina Schweiger, Margit Winkler, Elke Winter, Andrea Lana, Iris Kufferath, Leigh Matthew Marsh, Grazyna Kwapiszewska, Rudolf Zechner, Gerald Hoefler, Paul Willibald Vesely

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Figure 2

Atgl‑KO/cTg club cells contain lipid droplets and show mitochondrial impairments.

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Atgl‑KO/cTg club cells contain lipid droplets and show mitochondrial im...
(A) Double IF micrographs of lung sections stained with Abs against club cell marker CYP2F2 (green) and ciliated cell marker ac‑αTUB (red). Nuclear staining was with DAPI (blue). Representative images are shown. The WB shows lung extracts blotted with Abs, as indicated. (B) TEM images of representative stretches of bronchiolar epithelium showing club and ciliated cells. Scatter plots report data on club and ciliated cell numbers per basement membrane length and club cell cross-sectional area, as depicted. n = 6 control mice and n = 4 Atgl-KO/cTg mice. (C) Mitochondria (M) and lipid droplets (LD) visualized by TEM. Scatter plots report organelle numbers per cross-sectional area, as depicted. n = 6 control mice and n = 4 Atgl-KO/cTg mice. (A–C) All animals were aged 6 to 9 months. (D) Mitochondrial respiration of isolated club cells was measured by oxygraph respirometry. Specific substrates for respective mitochondrial complexes were added sequentially, as depicted. n = 3 experiments/group. Mice were aged 3 to 4 months. Error bars depict SEM. Statistical analysis was performed using Student’s 2-tailed t test. Scale bars: 5 μm. Detailed information on animals is provided in Supplemental Table 1. ADP, adenosine diphosphate; Antimyc., antimycin; Oct. Car., octenoylcarnitine.