Cargando…
Inhibition of pulmonary β-carotene 15, 15’-oxygenase expression by glucocorticoid involves PPARα
β-carotene 15,15’-oxygenase (BCO1) catalyzes the first step in the conversion of dietary provitamin A carotenoids to vitamin A. This enzyme is expressed in a variety of developing and adult tissues, suggesting that its activity may regulate local retinoid synthesis. Vitamin A and related compounds (...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521778/ https://www.ncbi.nlm.nih.gov/pubmed/28732066 http://dx.doi.org/10.1371/journal.pone.0181466 |
_version_ | 1783252036692738048 |
---|---|
author | Gong, Xiaoming Marisiddaiah, Raju Rubin, Lewis P. |
author_facet | Gong, Xiaoming Marisiddaiah, Raju Rubin, Lewis P. |
author_sort | Gong, Xiaoming |
collection | PubMed |
description | β-carotene 15,15’-oxygenase (BCO1) catalyzes the first step in the conversion of dietary provitamin A carotenoids to vitamin A. This enzyme is expressed in a variety of developing and adult tissues, suggesting that its activity may regulate local retinoid synthesis. Vitamin A and related compounds (retinoids) are critical regulators of lung epithelial development, integrity, and injury repair. A balance between the actions of retinoids and glucocorticoids (GCs) promotes normal lung development and, in particular, alveolarization. Alterations in this balance, including vitamin A deficiency and GC excess, contribute to the development of chronic lung disorders. Consequently, we investigated if GCs counteract retinoid effects in alveolar epithelial cells by mechanisms involving BCO1-dependent local vitamin A metabolism. We demonstrate that BCO1 is expressed in human fetal lung tissue and human alveolar epithelial-like A549 cells. Our results indicate A549 cells metabolize β-carotene to retinal and retinoic acid (RA). GCs exposure using dexamethasone (DEX) decreases BCO1 mRNA and protein levels in A549 cells and reduces BCO1 promoter activity via inhibiting peroxisome proliferator-activated receptor γ (PPARγ) DNA binding. DEX also induces expression of PPARα, which in turn most likely causes a decrease in PPARγ/RXRα heterodimer binding to the bco1 gene promoter and consequent inhibition of bco1 gene expression. PPARα knockdown with siRNA abolishes DEX-induced suppression of BCO1 expression, confirming the requirement for PPARα in this DEX-mediated BCO1 mechanism. Taken together, these findings provide the first evidence that GCs regulate vitamin A (retinoid) signaling via inhibition of bco1 gene expression in a PPARα-dependent manner. These results explicate novel aspects of local GC:retinoid interactions that may contribute to alveolar tissue remodeling in chronic lung diseases that affect children and, possibly, adults. |
format | Online Article Text |
id | pubmed-5521778 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-55217782017-08-07 Inhibition of pulmonary β-carotene 15, 15’-oxygenase expression by glucocorticoid involves PPARα Gong, Xiaoming Marisiddaiah, Raju Rubin, Lewis P. PLoS One Research Article β-carotene 15,15’-oxygenase (BCO1) catalyzes the first step in the conversion of dietary provitamin A carotenoids to vitamin A. This enzyme is expressed in a variety of developing and adult tissues, suggesting that its activity may regulate local retinoid synthesis. Vitamin A and related compounds (retinoids) are critical regulators of lung epithelial development, integrity, and injury repair. A balance between the actions of retinoids and glucocorticoids (GCs) promotes normal lung development and, in particular, alveolarization. Alterations in this balance, including vitamin A deficiency and GC excess, contribute to the development of chronic lung disorders. Consequently, we investigated if GCs counteract retinoid effects in alveolar epithelial cells by mechanisms involving BCO1-dependent local vitamin A metabolism. We demonstrate that BCO1 is expressed in human fetal lung tissue and human alveolar epithelial-like A549 cells. Our results indicate A549 cells metabolize β-carotene to retinal and retinoic acid (RA). GCs exposure using dexamethasone (DEX) decreases BCO1 mRNA and protein levels in A549 cells and reduces BCO1 promoter activity via inhibiting peroxisome proliferator-activated receptor γ (PPARγ) DNA binding. DEX also induces expression of PPARα, which in turn most likely causes a decrease in PPARγ/RXRα heterodimer binding to the bco1 gene promoter and consequent inhibition of bco1 gene expression. PPARα knockdown with siRNA abolishes DEX-induced suppression of BCO1 expression, confirming the requirement for PPARα in this DEX-mediated BCO1 mechanism. Taken together, these findings provide the first evidence that GCs regulate vitamin A (retinoid) signaling via inhibition of bco1 gene expression in a PPARα-dependent manner. These results explicate novel aspects of local GC:retinoid interactions that may contribute to alveolar tissue remodeling in chronic lung diseases that affect children and, possibly, adults. Public Library of Science 2017-07-21 /pmc/articles/PMC5521778/ /pubmed/28732066 http://dx.doi.org/10.1371/journal.pone.0181466 Text en © 2017 Gong et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Gong, Xiaoming Marisiddaiah, Raju Rubin, Lewis P. Inhibition of pulmonary β-carotene 15, 15’-oxygenase expression by glucocorticoid involves PPARα |
title | Inhibition of pulmonary β-carotene 15, 15’-oxygenase expression by glucocorticoid involves PPARα |
title_full | Inhibition of pulmonary β-carotene 15, 15’-oxygenase expression by glucocorticoid involves PPARα |
title_fullStr | Inhibition of pulmonary β-carotene 15, 15’-oxygenase expression by glucocorticoid involves PPARα |
title_full_unstemmed | Inhibition of pulmonary β-carotene 15, 15’-oxygenase expression by glucocorticoid involves PPARα |
title_short | Inhibition of pulmonary β-carotene 15, 15’-oxygenase expression by glucocorticoid involves PPARα |
title_sort | inhibition of pulmonary β-carotene 15, 15’-oxygenase expression by glucocorticoid involves pparα |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521778/ https://www.ncbi.nlm.nih.gov/pubmed/28732066 http://dx.doi.org/10.1371/journal.pone.0181466 |
work_keys_str_mv | AT gongxiaoming inhibitionofpulmonarybcarotene1515oxygenaseexpressionbyglucocorticoidinvolvesppara AT marisiddaiahraju inhibitionofpulmonarybcarotene1515oxygenaseexpressionbyglucocorticoidinvolvesppara AT rubinlewisp inhibitionofpulmonarybcarotene1515oxygenaseexpressionbyglucocorticoidinvolvesppara |