Chenodeoxycholic acid reduces hypoxia inducible factor-1α protein and its target genes

Yunwon Moon, Su Mi Choi, Soojeong Chang, Bongju Park, Seongyeol Lee, Mi Ock Lee, Hueng Sik Choi, Hyunsung Park

Research output: Contribution to journalArticle

Abstract

This study evaluated HIF-1α inhibitors under different hypoxic conditions, physiological hypoxia (5% O2) and severe hypoxia (0.1% O2). 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.

Original languageEnglish (US)
Article numbere0130911
JournalPloS one
Volume10
Issue number6
DOIs
StatePublished - Jun 22 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Moon, Y., Choi, S. M., Chang, S., Park, B., Lee, S., Lee, M. O., Choi, H. S., & Park, H. (2015). Chenodeoxycholic acid reduces hypoxia inducible factor-1α protein and its target genes. PloS one, 10(6), [e0130911]. https://doi.org/10.1371/journal.pone.0130911