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Bauer, S.* ; Eigenmann, J.* ; Zhao, Y.* ; Fleig, J.* ; Hawe, J.S.* ; Pan, C.* ; Bongiovanni, D.* ; Wengert, S. ; Ma, A.E.* ; Lusis, A.J.* ; Kovacic, J.C.* ; Bjoerkegren, J.L.M.* ; Maegdefessel, L.* ; Schunkert, H.* ; von Scheidt, M.*

Identification of the transcription factor ATF3 as a direct and indirect regulator of the LDLR.

Metabolites 12:840 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Atf3 ; Atherosclerosis ; Cardiovascular Disease ; Coronary Artery Disease ; Gene Expression ; Inflammation ; Ldlr ; Lipid Metabolism ; Liver Metabolism ; Lps ; Maff ; Transcription Factor
ISSN (print) / ISBN 2218-1989
e-ISSN 2218-1989
Journal Metabolites
Quellenangaben Volume: 12, Issue: 9, Pages: , Article Number: 840 Supplement: ,
Publisher MDPI
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Helmholtz Pioneer Campus (HPC)
Institute of Computational Biology (ICB)
Grants NHLBI NIH HHS
NIDDK NIH HHS