Liver X receptor-alpha regulates proopiomelanocortin (POMC) gene transcription in the pituitary.
The liver X receptors (LXR-alpha and -beta) 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-alpha 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-alpha mRNA expression in GH3 cells with small interfering RNA specific to LXR-alpha caused a loss of promoter activity induced by the LXR ligand, suggesting that LXR-alpha directly regulates the POMC gene promoter. EMSAs also demonstrated that the retinoid X receptor-alpha/LXR-alpha 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-alpha positively regulates the POMC gene promoter at the transcriptional level and suggest LXR-alpha to be a coordinator for cross talk between lipid metabolism and neuroendocrinology.
Matsumoto
Shunichi
S
Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, 3-39-15 Showa-machi Maebashi, Gunma 371-8511, Japan.
Hashimoto
Koshi
K
Yamada
Masanobu
M
Satoh
Teturou
T
Hirato
Junko
J
Mori
Masatomo
M
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003345:Corticosterone / Q000097:blood; D004268:DNA-Binding Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D019281:Dimerization; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000324:Adrenocorticotropic Hormone; D002784:Cholesterol; D002791:Cholesterol, Dietary; D003345:Corticosterone; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011333:Pro-Opiomelanocortin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D047490:Retinoid X Receptor alpha; D013449:Sulfonamides; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides