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Liver X receptor-alpha regulates proopiomelanocortin (POMC) gene transcription in the pituitary.

ABSTRACT: 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.

SUBMITTER: Matsumoto S

PROVIDER: S-EPMC5419326 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Liver X receptor-alpha regulates proopiomelanocortin (POMC) gene transcription in the pituitary.

Matsumoto Shunichi S Hashimoto Koshi K Yamada Masanobu M Satoh Teturou T Hirato Junko J Mori Masatomo M

Molecular endocrinology (Baltimore, Md.) 20081126 1

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 ...[more]

PMID: 19036902

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Project description:The proopiomelanocortin (POMC) molecule has been implicated in models of self-injurious behavior (SIB) in neurodevelopmental disorders, but it has never been specifically sequenced in search of base specific polymorphisms. The empirical focus of this preliminary study was to sequence the POMC gene in 11 children (mean age = 41.8 months, range = 12-60 months; 73% male) with clinical concerns regarding global developmental delay, 5 with reported self-injury. Genomic DNA was extracted from blood samples, and the POMC gene was amplified by specific oligonucleotide primers via polymerase chain reaction. The amplified gene products were sequenced by the University of Minnesota Genomic Center, and the results were analyzed using Sequencher software. A single nucleotide polymorphism (SNP), 1130 C>T, was found in the 3' untranslated region (UTR) of two samples (one of whom had SIB). The program TargetScanHuman was used to predict the function of this mutation. Variant c.1130 C<T was predicted to be located in the target site of two microRNAs (miRNAs; hsa-mir-3715 and hsa-mir-1909), and the variant allele T may result in an increased minimum free energy for the two miRNAs. Further work with much larger samples is needed to continue the investigation of POMC's possible function as a risk factor for the development of SIB in children with developmental delay/disability. The findings presented in this study show that the SNP found in the 3' UTR could alter the binding of miRNAs to POMC 3'UTR, thus, increasing POMC expression and affecting several biological systems with high relevance to the biology of self-injury. There was a significant difference in ?-endorphin levels between SIB (M = 169.25 pg/mL) and no SIB (M = 273.5 pg/mL, SD = 15.2) cases (p < .01). Intervention implications are tied to prior observations of individual differences among SIB responders and nonresponders to treatment with the opioid antagonist naltrexone. Stratifying individuals with SIB by POMC mutation status may provide a potential tailoring-like variable to guide the selection of who is more (or less) likely to respond to opiate antagonist treatment. Currently, opioid antagonistic treatment for SIB is empiric (trial and error).

Dataset Information

Liver X receptor-alpha regulates proopiomelanocortin (POMC) gene transcription in the pituitary.

Publications

Liver X receptor-alpha regulates proopiomelanocortin (POMC) gene transcription in the pituitary.

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