Bile acids increase steroidogenesis in cholemic mice and induce cortisol secretion in adrenocortical H295R cells via S1 PR PR 2, ERK ERK and SF SF ‐1

摘要

Abstract Background and Aims Bile acids are now accepted as central signalling molecules for the regulation of glucose, amino acid and lipid metabolism. Adrenal gland cortex cells express the bile acid receptors farnesoid X receptor ( FXR ), the G protein‐coupled bile acid receptor ( TGR 5) and the sphingosine‐1‐phosphate receptor 2 (S1 PR 2). We aimed to determine the effects of cholestasis and more specifically of bile acids on cortisol production. Methods FXR and TGR 5 knockout mice and controls were subjected to common bile duct ligation ( CBDL ) or chenodeoxycholic acid ( CDCA ) feeding to model cholestasis. Human adrenocortical H295R cells were challenged with bile acids for mechanistic studies. Results We found that CBDL and CDCA feeding increased the levels of corticosterone, the rodent equivalent to human cortisol and mRNA and protein levels of steroidogenesis‐related enzymes in adrenals independent of FXR and TGR 5. Taurine‐conjugated CDCA ( TCDCA ) significantly stimulated cortisol secretion, phosphorylation of extracellular signal‐regulated kinase ( ERK ) and expression of steroidogenesis‐related genes in human adrenocortical H295R cells. FXR and TGR 5 agonists failed to induce cortisol secretion in H295R cells. S1 PR 2 inhibition significantly abolished TCDCA ‐induced cortisol secretion, lowered phosphorylation of ERK and abrogated enhanced transcription of steroidogenesis‐related genes in H295R cells. Likewise, si RNA S1 PR 2 treatment reduced the phosphorylation of ERK and cortisol secretion. Steroidogenic factor‐1 ( SF ‐1) transactivation activity was increased upon TCDCA treatment suggesting that bile acid signalling is linked to SF ‐1. Treatment with SF ‐1 inverse agonist AC 45594 also reduced TCDCA ‐induced steroidogenesis. Conclusions Our findings indicate that supraphysiological bile acid levels as observed in cholestasis stimulate steroidogenesis via an S1 PR 2‐ ERK ‐ SF ‐1 signalling pathway.