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Liver X Receptor- Gene Expression Is Positively Regulated by Thyroid Hormone

Department of Medicine and Molecular Science, 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, 3-39-22 Showa-machi Maebashi, Gunma, Japan 371-8511. E-mail: khashi{at}med.gunma-u.ac.jp.

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-, but not LXR-ß, mRNA expression in the liver and that cholesterol administration did not affect the LXR- mRNA levels. Recently, several groups have reported that human LXR- autoregulates its own gene promoter through binding to the LXR response element. Therefore, we examined whether TRs regulate the mouse LXR- gene promoter activity. Luciferase assays showed that TR-ß1 positively regulated the mouse LXR- gene transcription. Analysis of serial deletion mutants of the promoter demonstrated that the positive regulation by TR-ß1 was not observed in the –1240/+30-bp construct. EMSA(s) demonstrated that TR-ß1 or retinoid X receptor- did not bind to the region from –1300 to –1240 bp (site A), whereas chromatin-immunoprecipitation assays revealed that TR-ß1 and retinoid X receptor- 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- gene expression and promoter activities were up-regulated by thyroid hormone. These data suggest that LXR- mRNA expression is positively regulated by TR-ß1 and thyroid hormone at the transcriptional level in mammals. This novel insight that thyroid hormone regulates LXR- mRNA levels and promoter activity should shed light on a cross talk between LXR- and TR-ß1 as a new therapeutic target against dyslipidemia and atherosclerosis.

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