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Chakraborty, A. ; Giraldo-Arias, J. ; Merl-Pham, J. ; Dick, E. ; Mastalerz, M. ; Zöller, M. ; Marchi, H. ; Le Gleut, R. ; Hatz, R.* ; Behr, J.* ; Hilgendorff, A. ; Hauck, S.M. ; Staab-Weijnitz, C.A.

Cholesterol regulates airway epithelial cell differentiation by inhibiting p53 nuclear translocation.

Int. J. Mol. Sci. 26, 8324 - 8324 (2025)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Cholesterol is an essential plasma membrane component, and altered cholesterol metabolism has been linked to cholesterol accumulation in the airways of COPD and cystic fibrosis patients. However, its role in airway epithelial differentiation is not well understood. Tandem mass spectrometry-based proteomic analysis of differentiating primary human bronchial epithelial cells (phBECs) revealed an overall inhibition of the cholesterol biosynthesis pathway. We hypothesized that excess cholesterol impairs the differentiation of phBECs into a fully functional bronchial epithelium. PhBECs were differentiated in the presence of 80 µM cholesterol for 21 days, the main airway cell type populations monitored using qRT-PCR and immunofluorescent stainings, and epithelial barrier integrity was analyzed via transepithelial electrical resistance measurements. Chronic cholesterol exposure led to a significant increase in CC10+ secretory cells at the expense of ciliated cells. Pathway enrichment analysis suggested the tumor protein p53 as a master regulator of genes during normal differentiation of phBECs. Chronic cholesterol exposure drastically impaired the nuclear translocation of p53. Our findings suggest that this inhibition underlies the cholesterol-induced expansion of CC10+ secretory cell populations at the expense of ciliated cells. In conclusion, we identify cholesterol as an important regulator of normal bronchial epithelial cell differentiation through inhibition of p53 nuclear translocation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Ingenuity Pathway Analysis ; Cholesterol ; P53 ; Primary Human Bronchial Epithelial Cells; Label-free; Proteome; Notch; Homeostasis; Models; Blood
ISSN (print) / ISBN 1661-6596
e-ISSN 1422-0067
Journal International Journal of Molecular Sciences
Quellenangaben Volume: 26, Issue: 17, Pages: 8324 - 8324 Article Number: , Supplement: ,
Publisher MDPI
Publishing Place Basel
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
CF Metabolomics & Proteomics (CF-MPC)
CF Statistical Consulting (CF-STATCON)
Grants University of Colorado School of Medicine, Anschutz Medical Campus
Deutsches Zentrum für Lungenforschung