FXR agonist GW4064 increases plasma glucocorticoid levels in C57BL/6 mice

Since high expression of farnesoid X receptor (FXR) has been detected in glucocorticoid-producing adrenocortical cells, we evaluated the potential role of FXR in adrenal glucocorticoid production.FXR agonist GW4064 increased fasting plasma corticosterone levels (+45%; P < 0.01) in C57BL/6 mice, indicative of enhanced adrenal steroidogenesis. GW4064 treatment did not affect plasma ACTH levels, adrenal weight, or adrenal expression of steroidogenic genes. Scavenger receptor BI (SR-BI) mRNA and protein expression, respectively, increased 1.9-fold (P < 0.01) and 1.5-fold, which suggests a stimulated lipoprotein-associated cholesterol uptake into the adrenals upon GW4064 treatment. In line with an enhanced flux of cellular cholesterol into the steroidogenic pathway, adrenal unesterified and esterified cholesterol stores were 21–41% decreased (P < 0.01) upon GW4064 treatment.In conclusion, we have shown that the FXR agonist GW4064 stimulates plasma corticosterone levels in C57BL/6 mice. Our findings suggest a novel role for FXR in the modulation of adrenal cholesterol metabolism and glucocorticoid synthesis in mice.

► The FXR agonist GW4064 increases fasting plasma corticosterone levels. ► GW4064 activates FXR locally within the adrenals. ► GW4064 does not directly affect adrenal steroidogenic gene expression. ► GW4064 stimulates the adrenal gene expression of the HDL receptor SR-BI.