Nilsson Maria, Stulnig Thomas M, Lin Chin-Yo, Yeo Ai Li, Nowotny Peter, Liu Edison T, Steffensen Knut R
Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge, Sweden.
Mol Endocrinol. 2007 Jan;21(1):126-37. doi: 10.1210/me.2006-0187. Epub 2006 Sep 14.
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.
核激素受体肝X受体α（LXRα，NR1H3）和肝X受体β（LXRβ，NR1H2）是胆固醇、脂质和葡萄糖代谢的既定调节因子，是治疗糖尿病和心血管疾病的有吸引力的药物靶点。已知包括糖皮质激素和盐皮质激素在内的肾上腺类固醇激素会干扰葡萄糖代谢、胰岛素信号传导和血压调节。在此，我们展示了肾上腺和垂体中LXR反应性基因的全基因组表达谱。培养的肾上腺细胞中的LXR激活抑制了多个类固醇生成基因的表达，从而降低了肾上腺类固醇激素的产生。此外，LXR激动剂治疗在体外和体内均提高了垂体细胞中促肾上腺皮质激素（ACTH）mRNA的表达和激素分泌。LXR激活后垂体细胞中糖皮质激素激活酶11β-羟基类固醇脱氢酶1的表达降低，提示LXRs减弱了糖皮质激素的负反馈作用。总之，LXRs在垂体和肾上腺水平独立干扰下丘脑-垂体-肾上腺轴的调节。
