Medizinische Universität Graz - Research portal
Selected Publication:
Striessnig-Bina, I.
The role of Adipose TriGlyceride Lipase (ATGL) in lung cancer and regeneration of bronchiolar epithelia
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp. 95
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- Authors Med Uni Graz:
- Advisor:
- Birner-Grünberger Ruth
- Höfler Gerald
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- Abstract:
- Metabolic reprogramming represents a hallmark of malignant cell transformation. Rapidly proliferating cancer cells exhibit high rates of de novo lipogenesis. The role of the lipolytic cascade and its rate-limiting enzyme adipocyte triglyceride lipase (ATGL) in cancer development and progression, however, has not been sufficiently investigated so far. Our group has previously reported that mice lacking ATGL (AKO/cTg), develop lung adenocarcinoma. Lung characterization revealed that AKO/cTg mice show decreased lung function and massive lipid accumulation, especially in bronchiolar epithelial club cells. Moreover, we found that ATGL is not only an important TG hydrolase in the lung, but has also prominent retinylester hydrolase activity as seen by deregulated Vitamin A signaling. In addition, AKO/cTg club cells are incapable of producing the most abundant secreted protein in the lung, namely the club cell secretory protein (CCSP). Besides having less secretory vesicles, the main sites for CCSP storage, they have also reduced numbers of mitochondria, indicating an energetic imbalance. Moreover, RNA expression analyses pointed to impaired PPAR signaling and oxygen measurements confirmed reduced mitochondrial respiration in AKO/cTg club cells. Assessment of club cell functionality in vivo by using the club cell toxin NA revealed that AKO/cTg club cells have defective regeneration and are not able to fully repair NA induced bronchial epithelial damage. Additionally, we observe increased pro-oncogenic, inflammatory STAT3 signaling, which might promote bronchial epithelial proliferation. Interestingly, ATRA supplementation intended to rescue defective vitamin A signaling, was able to restore bronchial epithelial regeneration after NA challenge. Taken together these results indicate that lipid accumulation and/or energetic imbalance impair bronchoprotective club cell functions. This could trigger enhanced repair/inflammatory processes in the bronchiolar epithelium leading to neoplasia development.