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Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR
Coronary artery disease (CAD) is a complex, multifactorial disease caused, in particular, by inflammation and cholesterol metabolism. At the molecular level, the role of tissue-specific signaling pathways leading to CAD is still largely unexplored. This study relied on two main resources: (1) genes...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9504235/ https://www.ncbi.nlm.nih.gov/pubmed/36144244 http://dx.doi.org/10.3390/metabo12090840 |
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author | Bauer, Sabine Eigenmann, Jana Zhao, Yuqi Fleig, Julia Hawe, Johann S. Pan, Calvin Bongiovanni, Dario Wengert, Simon Ma, Angela Lusis, Aldons J. Kovacic, Jason C. Björkegren, Johan L. M. Maegdefessel, Lars Schunkert, Heribert von Scheidt, Moritz |
author_facet | Bauer, Sabine Eigenmann, Jana Zhao, Yuqi Fleig, Julia Hawe, Johann S. Pan, Calvin Bongiovanni, Dario Wengert, Simon Ma, Angela Lusis, Aldons J. Kovacic, Jason C. Björkegren, Johan L. M. Maegdefessel, Lars Schunkert, Heribert von Scheidt, Moritz |
author_sort | Bauer, Sabine |
collection | PubMed |
description | Coronary artery disease (CAD) is a complex, multifactorial disease caused, in particular, by inflammation and cholesterol metabolism. At the molecular level, the role of tissue-specific signaling pathways leading to CAD is still largely unexplored. This study relied on two main resources: (1) genes with impact on atherosclerosis/CAD, and (2) liver-specific transcriptome analyses from human and mouse studies. The transcription factor activating transcription factor 3 (ATF3) was identified as a key regulator of a liver network relevant to atherosclerosis and linked to inflammation and cholesterol metabolism. ATF3 was predicted to be a direct and indirect (via MAF BZIP Transcription Factor F (MAFF)) regulator of low-density lipoprotein receptor (LDLR). Chromatin immunoprecipitation DNA sequencing (ChIP-seq) data from human liver cells revealed an ATF3 binding motif in the promoter regions of MAFF and LDLR. siRNA knockdown of ATF3 in human Hep3B liver cells significantly upregulated LDLR expression (p < 0.01). Inflammation induced by lipopolysaccharide (LPS) stimulation resulted in significant upregulation of ATF3 (p < 0.01) and subsequent downregulation of LDLR (p < 0.001). Liver-specific expression data from human CAD patients undergoing coronary artery bypass grafting (CABG) surgery (STARNET) and mouse models (HMDP) confirmed the regulatory role of ATF3 in the homeostasis of cholesterol metabolism. This study suggests that ATF3 might be a promising treatment candidate for lowering LDL cholesterol and reducing cardiovascular risk. |
format | Online Article Text |
id | pubmed-9504235 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95042352022-09-24 Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR Bauer, Sabine Eigenmann, Jana Zhao, Yuqi Fleig, Julia Hawe, Johann S. Pan, Calvin Bongiovanni, Dario Wengert, Simon Ma, Angela Lusis, Aldons J. Kovacic, Jason C. Björkegren, Johan L. M. Maegdefessel, Lars Schunkert, Heribert von Scheidt, Moritz Metabolites Article Coronary artery disease (CAD) is a complex, multifactorial disease caused, in particular, by inflammation and cholesterol metabolism. At the molecular level, the role of tissue-specific signaling pathways leading to CAD is still largely unexplored. This study relied on two main resources: (1) genes with impact on atherosclerosis/CAD, and (2) liver-specific transcriptome analyses from human and mouse studies. The transcription factor activating transcription factor 3 (ATF3) was identified as a key regulator of a liver network relevant to atherosclerosis and linked to inflammation and cholesterol metabolism. ATF3 was predicted to be a direct and indirect (via MAF BZIP Transcription Factor F (MAFF)) regulator of low-density lipoprotein receptor (LDLR). Chromatin immunoprecipitation DNA sequencing (ChIP-seq) data from human liver cells revealed an ATF3 binding motif in the promoter regions of MAFF and LDLR. siRNA knockdown of ATF3 in human Hep3B liver cells significantly upregulated LDLR expression (p < 0.01). Inflammation induced by lipopolysaccharide (LPS) stimulation resulted in significant upregulation of ATF3 (p < 0.01) and subsequent downregulation of LDLR (p < 0.001). Liver-specific expression data from human CAD patients undergoing coronary artery bypass grafting (CABG) surgery (STARNET) and mouse models (HMDP) confirmed the regulatory role of ATF3 in the homeostasis of cholesterol metabolism. This study suggests that ATF3 might be a promising treatment candidate for lowering LDL cholesterol and reducing cardiovascular risk. MDPI 2022-09-06 /pmc/articles/PMC9504235/ /pubmed/36144244 http://dx.doi.org/10.3390/metabo12090840 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bauer, Sabine Eigenmann, Jana Zhao, Yuqi Fleig, Julia Hawe, Johann S. Pan, Calvin Bongiovanni, Dario Wengert, Simon Ma, Angela Lusis, Aldons J. Kovacic, Jason C. Björkegren, Johan L. M. Maegdefessel, Lars Schunkert, Heribert von Scheidt, Moritz Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR |
title | Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR |
title_full | Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR |
title_fullStr | Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR |
title_full_unstemmed | Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR |
title_short | Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR |
title_sort | identification of the transcription factor atf3 as a direct and indirect regulator of the ldlr |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9504235/ https://www.ncbi.nlm.nih.gov/pubmed/36144244 http://dx.doi.org/10.3390/metabo12090840 |
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