title: Identical gene regulation patterns of T3 and selective thyroid hormone receptor modulator GC-1.
abstract: Synthetic selective thyroid hormone (TH) receptor (TR) modulators (STRM) exhibit beneficial effects on dyslipidemias in animals and humans and reduce obesity, fatty liver, and insulin resistance in preclinical animal models. STRM differ from native TH in preferential binding to the TRβ subtype vs. TRα, increased uptake into liver, and reduced uptake into other tissues. However, selective modulators of other nuclear receptors exhibit important gene-selective actions, which are attributed to differential effects on receptor conformation and dynamics and can have profound influences in animals and humans. Although there are suggestions that STRM may exhibit such gene-specific actions, the extent to which they are actually observed in vivo has not been explored. Here, we show that saturating concentrations of the main active form of TH, T(3), and the prototype STRM GC-1 induce identical gene sets in livers of euthyroid and hypothyroid mice and a human cultured hepatoma cell line that only expresses TRβ, HepG2. We find one case in which GC-1 exhibits a modest gene-specific reduction in potency vs. T(3), at angiopoietin-like factor 4 in HepG2. Investigation of the latter effect confirms that GC-1 acts through TRβ to directly induce this gene but this gene-selective activity is not related to unusual T(3)-response element sequence, unlike previously documented promoter-selective STRM actions. Our data suggest that T(3) and GC-1 exhibit almost identical gene regulation properties and that gene-selective actions of GC-1 and similar STRM will be subtle and rare.
authors: Methodist Hospital Research Institute, F8-045, 6565 Fannin Street, Houston, Texas 77030, USA.
authors: Chaoshen
authors: C
authors: Yuan
authors: Jean Z H
authors: JZ
authors: Lin
authors: Douglas H
authors: DH
authors: Sieglaff
authors: Steven D
authors: SD
authors: Ayers
authors: Frances
authors: F
authors: Denoto-Reynolds
authors: John D
authors: JD
authors: Baxter
authors: Paul
authors: P
authors: Webb
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: C474772:ANGPTL4 protein, human; D000085:Acetates; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C413355:GC 1 compound; D010636:Phenols; D034741:RNA, Small Interfering; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine