Identical gene regulation patterns of T3 and selective thyroid hormone receptor modulator gC-1

Yuan, Chaoshen; Lin, Jean Z.H.; Sieglaff, Douglas H.; Ayers, Steven D.; DeNoto-Reynolds, Frances; Baxter, John D.; Webb, Paul

doi:10.1210/en.2011-1325

Cited by 70Thyroid Disorders and TreatmentsEstrogen and related hormone effectsPeroxisome Proliferator-Activated Receptors

Identical gene regulation patterns of T3 and selective thyroid hormone receptor modulator gC-1

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Yuan, Chaoshen, Lin, Jean Z.H., Sieglaff, Douglas H., Ayers, Steven D., DeNoto-Reynolds, Frances, Baxter, John D., Webb, Paul·2012·Endocrinology

DOI 10.1210/en.2011-1325PMC PMC3249679

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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.

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Selective modulation of THR-β1 allows targeting hepatic genes without cardiac side effects.
“Selective modulation of THR-β1 allows targeting hepatic genes without cardiac side effects.181 182”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [181]

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Authors: Yuan, C., Lin, J. Z. H., Sieglaff, D. H., Ayers, S. D., DeNoto-Reynolds, F., Baxter, J. D., & Webb, P.
Affiliations: Houston Methodist (US)
Diabetes Center and Department of Medicine (C.Y., F.D.R., J.D.B.), University of California, San Francisco, California 94122
Corresponding author: Webb, Paul
ORCID: Lin, Jean Z.H.
Baxter, John D.
Webb, Paul
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2012-01-01
Volume: 153
Issue: 1
Pages: 501-511
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2011-1325
PMC: PMC3249679
OpenAlex: W2075858435
Cited by: 70
References: 35
Citations by year: 2025: 26 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 5 · 2020: 2 · 2018: 1 · 2017: 5 · 2016: 4 · 2015: 2 · 2014: 7 · 2013: 10 · 2012: 3
FWCI: 5.51
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Endocrinology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (NIH-R01)
National Institute of Diabetes and Digestive and Kidney Diseases (RC4DK090849, DK61468, DK090849-01)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: GC-1, triiodothyronine, thyroid hormone receptor beta, hepatic gene expression, HepG2 cells, hypothyroidism, dyslipidemia, nuclear receptor ligands
MeSH terms: Angiopoietin-Like Protein 4, Acetates, Animals, Binding Sites, Gene Expression Regulation, Humans, Liver, Male, Mice, Inbred C57BL, Phenols, Receptors, Thyroid Hormone, Triiodothyronine, RNA, Small Interfering, Thyroid Hormone Receptors alpha, Thyroid Hormone Receptors beta, Angiopoietins, Mice, Hep G2 Cells

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Identical gene regulation patterns of T3 and selective thyroid hormone receptor modulator gC-1

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