Liver X Receptor-α 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 (T3) up-regulated mouse LXR-α, but not LXR-β, mRNA expression in the liver and that cholesterol administration did not affect the LXR-α mRNA levels. Recently, several groups have reported that human LXR-α autoregulates its own gene promoter through binding to the LXR response element. Therefore, we examined whether TRs regulate the mouse LXR-α gene promoter activity. Luciferase assays showed that TR-β1 positively regulated the mouse LXR-α gene transcription. Analysis of serial deletion mutants of the promoter demonstrated that the positive regulation by TR-β1 was not observed in the −1240/+30-bp construct. EMSA(s) demonstrated that TR-β1 or retinoid X receptor-α did not bind to the region from −1300 to −1240 bp (site A), whereas chromatin-immunoprecipitation assays revealed that TR-β1 and retinoid X receptor-α 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-α gene expression and promoter activities were up-regulated by thyroid hormone. These data suggest that LXR-α mRNA expression is positively regulated by TR-β1 and thyroid hormone at the transcriptional level in mammals. This novel insight that thyroid hormone regulates LXR-α mRNA levels and promoter activity should shed light on a cross talk between LXR-α and TR-β1 as a new therapeutic target against dyslipidemia and atherosclerosis.