Liver X receptor-alpha gene expression is positively regulated by thyroid hormone.
The nuclear oxysterol receptors, liver X receptors (LXRs), and thyroid hormone receptors (TRs) cross talk mutually in many aspects of transcription, sharing the same DNA binding site (direct repeat-4) with identical geometry and polarity. In the current study, we demonstrated that thyroid hormone (T(3)) up-regulated mouse LXR-alpha, but not LXR-beta, mRNA expression in the liver and that cholesterol administration did not affect the LXR-alpha mRNA levels. Recently, several groups have reported that human LXR-alpha autoregulates its own gene promoter through binding to the LXR response element. Therefore, we examined whether TRs regulate the mouse LXR-alpha gene promoter activity. Luciferase assays showed that TR-beta1 positively regulated the mouse LXR-alpha gene transcription. Analysis of serial deletion mutants of the promoter demonstrated that the positive regulation by TR-beta1 was not observed in the -1240/+30-bp construct. EMSA(s) demonstrated that TR-beta1 or retinoid X receptor-alpha did not bind to the region from -1300 to -1240 bp (site A), whereas chromatin-immunoprecipitation assays revealed that TR-beta1 and retinoid X receptor-alpha were recruited to the site A, indicating the presence of intermediating protein between the nuclear receptors and DNA site. We also showed that human LXR-alpha gene expression and promoter activities were up-regulated by thyroid hormone. These data suggest that LXR-alpha mRNA expression is positively regulated by TR-beta1 and thyroid hormone at the transcriptional level in mammals. This novel insight that thyroid hormone regulates LXR-alpha mRNA levels and promoter activity should shed light on a cross talk between LXR-alpha and TR-beta1 as a new therapeutic target against dyslipidemia and atherosclerosis.
Hashimoto
Koshi
K
Department of Medicine and Molecular Science, Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi Maebashi, Gunma, Japan 371-8511. khashi@med.gunma-u.ac.jp
Matsumoto
Shunichi
S
Yamada
Masanobu
M
Satoh
Teturou
T
Mori
Masatomo
M
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000502:physiology; D047488:Retinoid X Receptors / Q000378:metabolism; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D014284:Triiodothyronine; D002784:Cholesterol