Liver X receptors regulate adrenal steroidogenesis and hypothalamic-pituitary-adrenal feedback.
The nuclear hormone receptors liver X receptor alpha (LXRalpha) (NR1H3) and LXRbeta (NR1H2) are established regulators of cholesterol, lipid, and glucose metabolism and are attractive drug targets for the treatment of diabetes and cardiovascular disease. Adrenal steroid hormones including glucocorticoids and mineralocorticoids are known to interfere with glucose metabolism, insulin signaling, and blood pressure regulation. Here we present genome-wide expression profiles of LXR-responsive genes in both the adrenal and the pituitary gland. LXR activation in cultured adrenal cells inhibited expression of multiple steroidogenic genes and consequently decreased adrenal steroid hormone production. In addition, LXR agonist treatment elevated ACTH mRNA expression and hormone secretion from pituitary cells both in vitro and in vivo. Reduced expression of the glucocortioid-activating enzyme 11beta-hydroxysteroid dehydrogenase 1 in pituitary cells upon LXR activation suggests blunting of the negative feedback of glucocorticoids by LXRs. In conclusion, LXRs independently interfere with the hypothalamic-pituitary-adrenal axis regulation at the level of the pituitary and the adrenal gland.
Nilsson
Maria
M
Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge, Sweden.
Stulnig
Thomas M
TM
Lin
Chin-Yo
CY
Yeo
Ai Li
AL
Nowotny
Peter
P
Liu
Edison T
ET
Steffensen
Knut R
KR
D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D057093:Orphan Nuclear Receptors; D010902:Pituitary Gland / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism*
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D000071518:Liver X Receptors; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; C000605211:Nr1h2 protein, mouse; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids