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Liver X Receptor- Regulates Proopiomelanocortin (POMC) Gene Transcription in the Pituitary

Department of Medicine and Molecular Science (S.M., K.H., M.Y., T.S., M.M.) and Department of Human Pathology (J.H.), Graduate School of Medicine, Gunma University, Maebashi, Gunma, 371-8511, Japan

Address all correspondence and requests for reprints to: Koshi Hashimoto, M.D., Ph.D., Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, 3-39-15 Showa-machi Maebashi, Gunma 371-8511, Japan. E-mail: khashi{at}med.gunma-u.ac.jp.

The liver X receptors (LXR- and -β) are nuclear oxysterol receptors that play pivotal roles in regulating the expression of genes involved in cholesterol transport and metabolism. Recently, several groups have reported that the LXRs also regulate adrenal steroidogenesis. However, the roles of LXRs in the hypothalami-pituitary-adrenal axis, especially whether they regulate proopiomelanocortin (POMC) gene expression in the pituitary, remain to be elucidated. In this report, we demonstrate that LXR mRNA is expressed in the pituitary and that at the protein level, LXR- is dominantly expressed. Next, we show that the LXR agonist TO901317 (TO) increased POMC mRNA levels and the number of cells immunostained with anti-ACTH antibody in the mouse pituitary. We also confirmed that TO elevated plasma ACTH and serum corticosterone levels in vivo and increased the total tissue content of immunoreactive ACTH in the pituitary. TO activated the rat POMC gene promoter (–706/+64 bp) in GH3 and AtT-20 cells. Silencing of LXR- mRNA expression in GH3 cells with small interfering RNA specific to LXR- caused a loss of promoter activity induced by the LXR ligand, suggesting that LXR- directly regulates the POMC gene promoter. EMSAs also demonstrated that the retinoid X receptor-/LXR- heterodimer bound to the region between –73 and –52 bp in the rat POMC gene promoter, and this site was responsible for the induction by TO, as confirmed by chromatin immunoprecipitation assays using AtT-20 cells. Our findings provide the first evidence that LXR- positively regulates the POMC gene promoter at the transcriptional level and suggest LXR- to be a coordinator for cross talk between lipid metabolism and neuroendocrinology.

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRβ  |  LXRα

Ligands:   22α-Hydroxycholesterol  |  T0901317