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

Marcelo A. Christoffolete, Márton Doleschall, Péter Egri, Zsolt Liposits, Ann Marie Zavacki, Antonio C. Bianco, Balázs Gereben

Research output: Article

22 Citations (Scopus)

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. LXRα and LXRβ 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 DI02 (hD/02) promoter in HepG2 cells. Given that, in contrast to mammals, the chicken liver normally expresses D2, the chicken DI02 (cDI02) promoter was also studied. 22(R)-QH-cholesterol negatively regulated hDI02 in a dose-dependent manner (100 μM, approximately twofold), while it failed to affect the cDI02 promoter. Truncations in the hDI02 promoter identified the region - 901 to - 584 bp as critical for negative regulation. We also investigated if 9-cir retinoic acid (9-cis RA), the ligand for the heterodimeric partner of TR and LXR, RXR, could regulate the hDI02 promoter. Notably, 9-cis RA repressed the hDI02 luciferase reporter (1 μM, 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 hDI02 since mutagenesis of a DR-1 at - 506 bp did not interfere with 9-cis RA-mediated repression. Our data indicate that hDI02 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 (T3) production by cholesterol/9-cis RA could function as a feedback loop, given that T3 decreases hepatic cholesterol levels.

Original languageEnglish
Pages (from-to)179-186
Number of pages8
JournalJournal of Endocrinology
Volume205
Issue number2
DOIs
Publication statusPublished - máj. 1 2010

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ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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