Differential Feedback Regulation of Δ4-3-Oxosteroid 5β-Reductase Expression by Bile Acids

Abstract

Δ4-3-oxosteroid 5β-reductase is member D1 of the aldo-keto reductase family 1 (AKR1D1), which catalyzes 5β-reduction of molecules with a 3-oxo-4-ene structure. Bile acid intermediates and most of the steroid hormones carry the 3-oxo-4-ene structure. Therefore, AKR1D1 plays critical roles in both bile acid synthesis and steroid hormone metabolism. Currently our understanding on transcriptional regulation of AKR1D1 under physiological and pathological conditions is very limited. In this study, we investigated the regulatory effects of primary bile acids, chenodeoxycholic acid (CDCA) and cholic acid (CA), on AKR1D1 expression. The expression levels of AKR1D1 mRNA and protein in vitro and in vivo following bile acid treatments were determined by real-time PCR and Western blotting. We found that CDCA markedly repressed AKR1D1 expression in vitro in human hepatoma HepG2 cells and in vivo in mice. On the contrary, CA significantly upregulated AKR1D1 expression in HepG2 cells and in mice. Further mechanistic investigations revealed that the farnesoid x receptor (FXR) signaling pathway was not involved in regulating AKR1D1 by bile acids. Instead, CDCA and CA regulated AKR1D1 through the mitogen-activated protein kinases/c-Jun N-terminal kinases (MAPK/JNK) signaling pathway. Inhibition of the MAPK/JNK pathway effectively abolished CDCA and CA-mediated regulation of AKR1D1. It was thus determined that AKR1D1 expression was regulated by CDCA and CA through modulating the MAPK/JNK signaling pathway. In conclusion, AKR1D1 expression was differentially regulated by primary bile acids through negative and positive feedback mechanisms. The findings indicated that both bile acid concentrations and compositions play important roles in regulating AKR1D1 expression, and consequently bile acid synthesis and steroid hormone metabolism.

Dysregulation of Δ 4 -3-oxosteroid 5β-reductase in diabetic patients: Implications and mechanisms

“…Anti-GAPDH antibodies (G9545) were obtained from Sigma-Aldrich (St. Louis, MO, USA). The specificity of those antibodies against the target proteins was demonstrated and reported previously (Valanejad et al, 2017; Song et al, 2014; He et al, 2011; Bellet et al, 2016). The specificity of AKR1D1 antibodies was evaluated with recombinant human AKR1D1 protein and the results were presented in Supplemental Fig.…”

“…As a key player in bile acid synthesis and steroid hormone metabolism, our current understanding on AKR1D1’s roles in metabolic disease and diabetes is limited (Valanejad et al, 2017). In this study, we found that AKR1D1 expression was markedly repressed in diabetic patients.…”

Secondary Unconjugated Bile Acids Induce Hepatic Stellate Cell Activation

“…Regarding the degree of involvement of BAs in organs, excluding the liver, G protein-coupled receptor (TGR5) was reported as membrane-type BA receptor that is activated by BAs in the order of LCA > DCA > CDCA > CA in intestinal neuroendocrine cells, as well as the gall bladder, spleen, brown adipose tissue, macrophages, and cholangiocytes [ 40 , 41 ]. Therefore, BAs are pivotal signaling molecules stimulating FXR or TGR5 in many organs [ 15 , 42 , 43 , 44 , 45 , 46 , 47 ]. Additionally, HSCs activated in response to liver injury express TLR4, which promotes the activation of IκB kinase/NF-κB and JNK pathways in addition to the secretion of IL-6, transforming growth factor-β (TGF-β1), and monocyte chemoattractant protein 1 (MCP-1) [ 48 ]; however, it is unclear how these processes can be inhibited, which requires future studies.…”

Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo

“…GCs are known to increase 11β-HSD1 activity and expression and this has been postulated as a mechanism driving local GC excess and fueling an adverse metabolic phenotype (Jamieson et al 1995, Dube et al 2015. While the differential feedback of BAs to regulate AKR1D1 expression has been previously described (Valanejad et al 2017), to date, the interplay between GCs and AKR1D1 expression and activity has not been explored.…”