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.
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, 2300 RA Leiden, The Netherlands. hoekstra@lacdr.leidenuniv.nl
Menno
M
Hoekstra
Ronald J
RJ
van der Sluis
Zhaosha
Z
Li
Maaike H
MH
Oosterveer
Albert K
AK
Groen
Theo J C
TJ
Van Berkel
D000311:Adrenal Glands / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D003345:Corticosterone / Q000097:blood*; D005260:Female; D005938:Glucocorticoids / Q000097:blood*; D007555:Isoxazoles / Q000494:pharmacology*; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D011375:Progesterone Reductase / Q000235:genetics / Q000378:metabolism; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000235:genetics / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D000324:Adrenocorticotropic Hormone; D001054:Apolipoproteins A; D002786:Cholesterol Side-Chain Cleavage Enzyme; D003345:Corticosterone; D005938:Glucocorticoids; D007555:Isoxazoles; D008055:Lipids; D026901:Membrane Transport Proteins; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D011375:Progesterone Reductase; D044103:Receptor, Melanocortin, Type 2; D018160:Receptors, Cytoplasmic and Nuclear; D051122:Scavenger Receptors, Class B; D013252:Steroid 11-beta-Hydroxylase; D013255:Steroid 21-Hydroxylase; D014366:Tryptophan Oxygenase; D000099150:Receptor, Farnesoid X-Activated; C454739:Scarb1 protein, mouse; C022205:apolipoprotein A-IV; C476578:organic solute transporter beta, mouse; C533068:3 beta-hydroxysteroid dehydrogenase type II; C531511:Cyp21a1 protein, mouse; C412815:GW 4064