Cholesterol Modulates Airway Epithelial Cell Differentiation Via Inhibition of P53 Nuclear Translocation

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Abstract Cholesterol is an essential plasma membrane component, crucial for maintaining cellular permeability in the airway. 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. Unbiased proteomic analysis from differentiating primary human bronchial epithelial cells (phBECs) revealed an overall inhibition of the cholesterol biosynthesis pathway. We hypothesized that excess cholesterol affects the differentiation of phBECs into a fully functional bronchial epithelium. PhBECs were differentiated in presence of 80 µM cholesterol for 21 days, the main airway cell type populations were monitored using qRT-PCR and immunofluorescent (IF) stainings, and epithelial barrier integrity was analyzed via transepithelial electrical resistance (TEER) measurements. Chronic cholesterol led to a significant increase of club cells at the expense of ciliated cells. Pathway enrichment analysis of the proteomics data suggested tumor protein p53 as a master regulator of genes involved in the cholesterol biosynthesis pathway during normal differentiation of phBECs. Chronic cholesterol exposure strongly inhibited nuclear translocation of p53 indicating a negative feedback mechanism of extrinsic cholesterol on cholesterol biosynthesis. Given that loss of p53 is known to increase club cell renewal and decrease ciliated cell differentiation, our study suggests that cholesterol-mediated inhibition of p53 nuclear translocation impairs p53-dependent processes of bronchial epithelial cell fate.

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