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Title: Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes

Abstract

Apolipoprotein E (apoE), a protein mainly involved in lipid metabolism, is associated with several neurodegenerative disorders including Alzheimer's disease. Despite numerous attempts to elucidate apoE gene regulation in the brain, the exact mechanism is still uncovered. The mechanism of apoE gene regulation in the brain involves the proximal promoter and multienhancers ME.1 and ME.2, which evolved by gene duplication. Herein we questioned whether thyroid hormones and their nuclear receptors have a role in apoE gene regulation in astrocytes. Our data showed that thyroid hormones increase apoE gene expression in HTB14 astrocytes in a dose-dependent manner. This effect can be intermediated by the thyroid receptor β (TRβ) which is expressed in these cells. In the presence of triiodothyronine (T3) and 9-cis retinoic acid, in astrocytes transfected to overexpress TRβ and retinoid X receptor α (RXRα), apoE promoter was indirectly activated through the interaction with ME.2. To determine the location of TRβ/RXRα binding site on ME.2, we performed DNA pull down assays and found that TRβ/RXRα complex bound to the region 341–488 of ME.2. This result was confirmed by transient transfection experiments in which a series of 5′- and 3′-deletion mutants of ME.2 were used. These data support the existence of amore » biologically active TRβ binding site starting at 409 in ME.2. In conclusion, our data revealed that ligand-activated TRβ/RXRα heterodimers bind with high efficiency on tissue-specific distal regulatory element ME.2 and thus modulate apoE gene expression in the brain. - Highlights: • T3 induce a dose-dependent increase of apoE expression in astrocytes. • Thyroid hormones activate apoE promoter in a cell specific manner. • Ligand activated TRβ/RXRα bind on the distal regulatory element ME.2 to modulate apoE. • The binding site of TRβ/RXRα heterodimer is located at 409 bp on ME.2.« less

Authors:
; ;  [1];  [2];  [1];  [1]
  1. Institute of Cellular Biology and Pathology “Nicolae Simionescu”, Bucharest (Romania)
  2. University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Crete (Greece)
Publication Date:
OSTI Identifier:
22594122
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 468; Journal Issue: 1-2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; APOLIPOPROTEINS; BRAIN; DNA; GENE REGULATION; LIGANDS; LIVER; METABOLISM; MUTANTS; NERVOUS SYSTEM DISEASES; PROMOTERS; RECEPTORS; RETINOIC ACID; THYROID; TRIIODOTHYRONINE

Citation Formats

Roman, Corina, Fuior, Elena V., Trusca, Violeta G., Kardassis, Dimitris, Simionescu, Maya, and Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro. Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2015.10.132.
Roman, Corina, Fuior, Elena V., Trusca, Violeta G., Kardassis, Dimitris, Simionescu, Maya, & Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro. Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes. United States. doi:10.1016/J.BBRC.2015.10.132.
Roman, Corina, Fuior, Elena V., Trusca, Violeta G., Kardassis, Dimitris, Simionescu, Maya, and Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro. Fri . "Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes". United States. doi:10.1016/J.BBRC.2015.10.132.
@article{osti_22594122,
title = {Thyroid hormones upregulate apolipoprotein E gene expression in astrocytes},
author = {Roman, Corina and Fuior, Elena V. and Trusca, Violeta G. and Kardassis, Dimitris and Simionescu, Maya and Gafencu, Anca V., E-mail: anca.gafencu@icbp.ro},
abstractNote = {Apolipoprotein E (apoE), a protein mainly involved in lipid metabolism, is associated with several neurodegenerative disorders including Alzheimer's disease. Despite numerous attempts to elucidate apoE gene regulation in the brain, the exact mechanism is still uncovered. The mechanism of apoE gene regulation in the brain involves the proximal promoter and multienhancers ME.1 and ME.2, which evolved by gene duplication. Herein we questioned whether thyroid hormones and their nuclear receptors have a role in apoE gene regulation in astrocytes. Our data showed that thyroid hormones increase apoE gene expression in HTB14 astrocytes in a dose-dependent manner. This effect can be intermediated by the thyroid receptor β (TRβ) which is expressed in these cells. In the presence of triiodothyronine (T3) and 9-cis retinoic acid, in astrocytes transfected to overexpress TRβ and retinoid X receptor α (RXRα), apoE promoter was indirectly activated through the interaction with ME.2. To determine the location of TRβ/RXRα binding site on ME.2, we performed DNA pull down assays and found that TRβ/RXRα complex bound to the region 341–488 of ME.2. This result was confirmed by transient transfection experiments in which a series of 5′- and 3′-deletion mutants of ME.2 were used. These data support the existence of a biologically active TRβ binding site starting at 409 in ME.2. In conclusion, our data revealed that ligand-activated TRβ/RXRα heterodimers bind with high efficiency on tissue-specific distal regulatory element ME.2 and thus modulate apoE gene expression in the brain. - Highlights: • T3 induce a dose-dependent increase of apoE expression in astrocytes. • Thyroid hormones activate apoE promoter in a cell specific manner. • Ligand activated TRβ/RXRα bind on the distal regulatory element ME.2 to modulate apoE. • The binding site of TRβ/RXRα heterodimer is located at 409 bp on ME.2.},
doi = {10.1016/J.BBRC.2015.10.132},
journal = {Biochemical and Biophysical Research Communications},
number = 1-2,
volume = 468,
place = {United States},
year = {Fri Dec 04 00:00:00 EST 2015},
month = {Fri Dec 04 00:00:00 EST 2015}
}