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...

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Bibliographic Details
Published in:	Metabolites Vol. 12; no. 9; p. 840
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-09-2022 MDPI
Subjects:	Activating transcription factor 3 Animal models Arteriosclerosis ATF3 Atherosclerosis Binding sites Bioinformatics Cardiovascular disease Cardiovascular diseases Cholesterol Chromatin Coronary artery coronary artery disease Coronary vessels Development and progression DNA sequencing Gene expression Genetic aspects Health aspects Heart diseases Hepatocytes Homeostasis Identification and classification Immunoprecipitation Inflammation Lipid metabolism Lipopolysaccharides Liver Low density lipoprotein Low density lipoprotein receptors Medical research Medicin och hälsovetenskap Medicine, Experimental Metabolism Physiological aspects Receptor density siRNA Smooth muscle Transcription factors Transcriptomes Germany atherosclerosis coronary artery disease cardiovascular disease transcription factor inflammation MAFF lipid metabolism liver metabolism LDLR ATF3 LPS gene expression
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2218-1989 2218-1989
DOI:	10.3390/metabo12090840