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.

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…192 FXR may also mediate tumor effects through destabilization of hypoxia-inducible factor-1 alpha (HIF1-α), a master regulator that reprograms cancer cell metabolism and increases growth factors. [193][194][195] In addition, secondary BAs such as LCA also appear to be cytostatic through TGR5dependent effects on cancer cell metabolism, lipogenesis, epithelial mesenchymal transition (EMT), pro-and anti-apoptotic signaling, and anti-tumor immunity in vitro and in vivo. 186,196,197 Furthermore, FXR and TGR5 also inhibit COX2 and NFκB, which are both important to cancer biology.…”

Metabolomic Analysis Points to Bioactive Lipid Species and Acireductone Dioxygenase 1 (ADI1) as Potential Therapeutic Targets in Poor Prognosis Endometrial Cancer

“…Among the lipid species with increased levels in SC, the presence of two bile acids is noteworthy. It is well known that bile acids, which are also bioactive lipids, regulate different nuclear receptors including HIF-1alpha [ 36 ]. Within the lipid species with decreased levels in SC, we detected signalling molecules such as fatty acids and conjugates, eicosanoids, monoacylglycerols, diacylglycerols (DAG), lysophosphatidic acids, phosphatidic acids (PA), phosphatidylinositols (PI) and derivatives as well as one bile acid.…”

Oxidized low‐density lipoprotein suppresses mouse granulosa cell differentiation through disruption of the hypoxia‐inducible factor 1 pathway

“…We correctly hypothesized that the attenuated differentiation of granulosa cells by oxLDL may affect HIF1α signaling in mouse luteinized granulosa cells. Furthermore, treatment of granulose cells with MG‐132, an inhibitor of the 26S proteasome that is responsible for degrading ubiquitinated HIF1α protein (Moon et al, ), reversed the oxLDL‐dependent down‐regulation of HIF1α, suggesting that oxLDL post‐translationally affects HIF1α abundance in mouse granulosa cells. Significantly, MG‐132 also partially restored the oxLDL‐attenuated differentiation of the luteinized granulosa cells.…”