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

Abstract

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.

Thyroid Hormone Receptor β (TRβ) and Liver X Receptor (LXR) Regulate Carbohydrate-response Element-binding Protein (ChREBP) Expression in a Tissue-selective Manner

“…Cross-talk between TR␤ and LXR Signaling for the Regulation of ChREBP Expression-Published work described the LXR␣ gene as a TH target in mouse liver (20). In the present study, no significant regulation of LXR␣ expression by TH or T3 was detected in the different models and experiments performed (Fig.…”

“…Two hypotheses were proposed in the literature to document the mechanisms of these common functions. First, LXR␣ has been described as a TH target in mouse liver (20,21). Second, these two transcription factors can recognize and bind as RXR heterodimers to a similar response element in vitro and thus might control the same target set.…”

“…Different levels of potential cross-talk between LXRs and TR␤ have indeed been described (19). For instance, LXR␣ expression has been previously described to be regulated by TH in mouse liver (20). At a functional level, LXRs and TR␤ regulate a common set of events especially in the liver, where both receptors stimulate lipogenesis and cholesterol disposal.…”

Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond [Review]

“…Thyroid hormone up-regulates mRNA expression of mouse LXR-α, but not LXR-β, in the liver, but cholesterol administration does not affect the LXR-α mRNA levels [65]. The…”

“…The type of TR-LXR crosstalk is complicated for this human LXR-α gene promoter contains three cognitive LXREs, whereas neither half-sites of TREs nor those of LXREs are found in the mouse [24]. Although the positive TRE is located between -1300 bp and -1240 bp in the mouse promoter, where TR or LXR does not bind directly to Site A, TR-β is recruited to Site A, suggesting the presence of a protein complexed to intermediate TR-β to Site A [65] (Fig. 2B).…”