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Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes

This study evaluated HIF-1α inhibitors under different hypoxic conditions, physiological hypoxia (5% O(2)) and severe hypoxia (0.1% O(2)). We found that chenodeoxy cholic acid (CDCA) reduced the amount of HIF-1α protein only under physiological hypoxia but not under severe hypoxia without decreasing...

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Autores principales: Moon, Yunwon, Choi, Su Mi, Chang, Soojeong, Park, Bongju, Lee, Seongyeol, Lee, Mi-Ock, Choi, Hueng-Sik, Park, Hyunsung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476666/
https://www.ncbi.nlm.nih.gov/pubmed/26098428
http://dx.doi.org/10.1371/journal.pone.0130911
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author Moon, Yunwon
Choi, Su Mi
Chang, Soojeong
Park, Bongju
Lee, Seongyeol
Lee, Mi-Ock
Choi, Hueng-Sik
Park, Hyunsung
author_facet Moon, Yunwon
Choi, Su Mi
Chang, Soojeong
Park, Bongju
Lee, Seongyeol
Lee, Mi-Ock
Choi, Hueng-Sik
Park, Hyunsung
author_sort Moon, Yunwon
collection PubMed
description This study evaluated HIF-1α inhibitors under different hypoxic conditions, physiological hypoxia (5% O(2)) and severe hypoxia (0.1% O(2)). We found that chenodeoxy cholic acid (CDCA) reduced the amount of HIF-1α protein only under physiological hypoxia but not under severe hypoxia without decreasing its mRNA level. By using a proteasome inhibitor MG132 and a translation inhibitor cyclohexamide, we showed that CDCA reduced HIF-1α protein by decreasing its translation but not by enhancing its degradation. The following findings indicated that farnesoid X receptor (FXR), a CDCA receptor and its target gene, Small heterodimer partner (SHP) are not involved in this effect of CDCA. Distinctly from CDCA, MG132 prevented SHP and an exogenous FXR agonist, GW4064 from reducing HIF-1α protein. Furthermore a FXR antagonist, guggulsterone failed to prevent CDCA from decreasing HIF-1α protein. Furthermore, guggulsterone by itself reduced HIF-1α protein even in the presence of MG132. These findings suggested that CDCA and guggulsterone reduced the translation of HIF-1α in a mechanism which FXR and SHP are not involved. This study reveals novel therapeutic functions of traditional nontoxic drugs, CDCA and guggulsterone, as inhibitors of HIF-1α protein.
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spelling pubmed-44766662015-06-25 Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes Moon, Yunwon Choi, Su Mi Chang, Soojeong Park, Bongju Lee, Seongyeol Lee, Mi-Ock Choi, Hueng-Sik Park, Hyunsung PLoS One Research Article This study evaluated HIF-1α inhibitors under different hypoxic conditions, physiological hypoxia (5% O(2)) and severe hypoxia (0.1% O(2)). We found that chenodeoxy cholic acid (CDCA) reduced the amount of HIF-1α protein only under physiological hypoxia but not under severe hypoxia without decreasing its mRNA level. By using a proteasome inhibitor MG132 and a translation inhibitor cyclohexamide, we showed that CDCA reduced HIF-1α protein by decreasing its translation but not by enhancing its degradation. The following findings indicated that farnesoid X receptor (FXR), a CDCA receptor and its target gene, Small heterodimer partner (SHP) are not involved in this effect of CDCA. Distinctly from CDCA, MG132 prevented SHP and an exogenous FXR agonist, GW4064 from reducing HIF-1α protein. Furthermore a FXR antagonist, guggulsterone failed to prevent CDCA from decreasing HIF-1α protein. Furthermore, guggulsterone by itself reduced HIF-1α protein even in the presence of MG132. These findings suggested that CDCA and guggulsterone reduced the translation of HIF-1α in a mechanism which FXR and SHP are not involved. This study reveals novel therapeutic functions of traditional nontoxic drugs, CDCA and guggulsterone, as inhibitors of HIF-1α protein. Public Library of Science 2015-06-22 /pmc/articles/PMC4476666/ /pubmed/26098428 http://dx.doi.org/10.1371/journal.pone.0130911 Text en © 2015 Moon 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Moon, Yunwon
Choi, Su Mi
Chang, Soojeong
Park, Bongju
Lee, Seongyeol
Lee, Mi-Ock
Choi, Hueng-Sik
Park, Hyunsung
Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes
title Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes
title_full Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes
title_fullStr Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes
title_full_unstemmed Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes
title_short Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes
title_sort chenodeoxycholic acid reduces hypoxia inducible factor-1α protein and its target genes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476666/
https://www.ncbi.nlm.nih.gov/pubmed/26098428
http://dx.doi.org/10.1371/journal.pone.0130911
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