Abstract
Background and AimsBile 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 (TGR5) and the sphingosine‐1‐phosphate receptor 2 (S1PR2). We aimed to determine the effects of cholestasis and more specifically of bile acids on cortisol production.Methods FXR and TGR5 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.ResultsWe 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 TGR5. 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 TGR5 agonists failed to induce cortisol secretion in H295R cells. S1PR2 inhibition significantly abolished TCDCA‐induced cortisol secretion, lowered phosphorylation of ERK and abrogated enhanced transcription of steroidogenesis‐related genes in H295R cells. Likewise, siRNA S1PR2 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 AC45594 also reduced TCDCA‐induced steroidogenesis.ConclusionsOur findings indicate that supraphysiological bile acid levels as observed in cholestasis stimulate steroidogenesis via an S1PR2‐ERK‐SF‐1 signalling pathway.
Highlights
Bile acids are a heterogeneous family of complex molecules with steroidal structure and are actively secreted along with cholesterol and phospholipids into bile.[1]. In addition to their major function of facilitating digestion and absorption of nutrient lipids, bile acids are considered as signalling molecules and their receptors are en vogue targets for drug development. This is primarily related to the fact that bile acids are known to regulate amino acid, lipid and glucose metabolism and energy homoeostasis which are mainly mediated by bile acids’ characterized receptors: the farnesoid X receptor (FXR), the G protein‐coupled bile acid recep‐ tor (TGR5) and the sphingosine‐1‐phosphate receptor 2 (S1PR2).[2-4]
H295R cells pretreated with the PKA inhibitor Rp‐isomer neither showed substantial reduction in cortisol secretion induced by Taurine‐conjugated CDCA (TCDCA) nor did PKA inhibition in‐ terfere with the TCDCA's effects on mRNA expression of STAR, CYP21A2 and hydroxy‐delta‐5‐steroid dehydrogenase (HSD3B2) (Figure S5)
We hypothesized that bile acids regulate adrenocorti‐ cal steroid synthesis and secretion in an FXR‐ or transmembrane G protein‐coupled receptor (TGR5)‐dependent manner
Summary
Bile acids are a heterogeneous family of complex molecules with steroidal structure and are actively secreted along with cholesterol and phospholipids into bile.[1]. In addition to their major function of facilitating digestion and absorption of nutrient lipids, bile acids are considered as signalling molecules and their receptors are en vogue targets for drug development. There is numerous clinical and experimental evidence tempting to hypothesize that bile acids at high concentrations stimulate adre‐ nal cortex function: (a) cholestatic patients with significantly elevated serum bile acid levels showed significantly increased cortisol serum
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