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Liver X Receptors Regulate Adrenal Steroidogenesis and Hypothalamic-Pituitary-Adrenal Feedback

Department of Biosciences and Nutrition (M.N., K.R.S.), Karolinska Institutet, 14157 Huddinge, Sweden; Genome Institute of Singapore (C.-Y.L., A.L.Y., E.T.L.), Singapore 138672; Division of Endocrinology and Metabolism (T.M.S., P.N.), Department of Internal Medicine III, University of Vienna, 1090 Vienna, Austria

Address all correspondence and requests for reprints to: Knut R. Steffensen, Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge, Sweden. E-mail: knut.steffensen{at}biosci.ki.se.

The nuclear hormone receptors liver X receptor (LXR) (NR1H3) and LXRß (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 11ß-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.

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRβ  |  LXRα

Ligands:   T0901317

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