title: Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes.
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.
authors.affiliation: Department of Life Science, University of Seoul, Seoul, Korea.
authors.forename: Yunwon
authors.initials: Y
authors.lastname: Moon
authors.affiliation: Department of Life Science, University of Seoul, Seoul, Korea.
authors.forename: Su Mi
authors.initials: SM
authors.lastname: Choi
authors.affiliation: Department of Life Science, University of Seoul, Seoul, Korea.
authors.forename: Soojeong
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Life Science, University of Seoul, Seoul, Korea.
authors.forename: Bongju
authors.initials: B
authors.lastname: Park
authors.affiliation: Department of Life Science, University of Seoul, Seoul, Korea.
authors.forename: Seongyeol
authors.initials: S
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Korea.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Department of Life Science, University of Seoul, Seoul, Korea.
authors.forename: Hyunsung
authors.initials: H
authors.lastname: Park
mesh_terms: D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology*; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007555:Isoxazoles; D007976:Leupeptins; D011282:Pregnenediones / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D017931:DNA Primers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007555:Isoxazoles; D007976:Leupeptins; D011282:Pregnenediones; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C023617:pregna-4,17-diene-3,16-dione; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C412815:GW 4064