Regulation of thyroid hormone activation via the liver X-receptor/retinoid X-receptor pathway

Abstract

Thyroid hormone receptor (TR) and liver X-receptor (LXR) are the master regulators of lipid metabolism. Remarkably, a mouse with a targeted deletion of both LXRa and LXRb is resistant to western diet-induced obesity, and exhibits ectopic liver expression of the thyroid hormone activating type 2 deiodinase (D2). We hypothesized that LXR/retinoid X-receptor (RXR) signaling inhibits hepatic D2 expression, and studied this using a luciferase reporter containing the human DIO2 (hDIO2) promoter in HepG2 cells. Given that, in contrast to mammals, the chicken liver normally expresses D2, the chicken DIO2 (cDIO2) promoter was also studied. 22(R)-OH-cholesterol negatively regulated hDIO2 in a dose-dependent manner (100 mM, approximately twofold), while it failed to affect the cDIO2 promoter. Truncations in the hDIO2 promoter identified the region K901 to K584 bp as critical for negative regulation. We also investigated if 9-cis retinoic acid (9-cis RA), the ligand for the heterodimeric partner of TR and LXR, RXR, could regulate the hDIO2 promoter. Notably, 9-cis RA repressed the hDIO2 luciferase reporter (1 mM, approximately fourfold) in a dose-dependent manner, while coexpression of an inactive mutant RXR abolished this effect. However, it is unlikely that RXR homodimers mediate the repression of hDIO2 since mutagenesis of a DR-1 at K506 bp did not interfere with 9-cis RA-mediated repression. Our data indicate that hDIO2 transcription is negatively regulated by both 22(R)-OH-cholesterol and 9-cis RA, which is consistent with LXR/RXR involvement. In vivo, the inhibition of D2-mediated tri-iodothyronine (T 3 ) production by cholesterol/9-cis RA could function as a feedback loop, given that T 3 decreases hepatic cholesterol levels.

Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

“…Recently, Christoffolete et al (42) showed that LXR stimulation negatively regulates Dio2 transcription in human liver. In our study, Dio2 expression is sixfold and eightfold higher in LXRα −/− and LXRβ −/− mice, respectively, compared with WT mice.…”

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

“…Administration of 22(R)-OH-cholesterol, an LXR agonist, and 9-cis retinoic acid (9-cis RA), a ligand for the heterodimeric partner of TR and LXR, RXR, negatively regulate the activity of human DIO2 (hDIO2) gene promoter. In vivo, cholesterol/9-cis RA inhibits DIO2 activity that mediates T3 production [73]. This is another type of TR-LXR crosstalk by which LXRs regulate the metabolism of thyroid hormone.…”

Liver X receptor β: new player in the regulatory network of thyroid hormone and ‘browning’ of white fat

“…Christoffolete et al demonstrated that LXR/ RXR signaling inhibits hepatic DIO2 expression and activity both in vivo and in vitro. 23 One of the most surprising and significant findings from this study was the over-active HPT axis identified in LXR KO mice, which suggested to us that the regulation of TH feedback by LXR in the hypothalamus significantly contributed to the increased TH synthesis in the LXR KO mice. Neurons that express thyrotropin releasing hormone (TRH) in PVN project to the portal system, through which they reach the thyrotropin producing cells of the anterior pituitary.…”