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

doi:10.3390/metabo12090840

journal article

Title:: Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR.
Document type:: Journal Article
Author(s):: 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
Abstract:: 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.
Journal title abbreviation:: Metabolites
Year:: 2022
Journal volume:: 12
Journal issue:: 9
Fulltext / DOI:: doi:10.3390/metabo12090840
Pubmed ID:: http://view.ncbi.nlm.nih.gov/pubmed/36144244
TUM Institution:: Klinik für Herz- und Kreislauferkrankungen im Erwachsenenalter (DHM) (Prof. Schunkert); Professur für Vaskuläre Biologie (Prof. Maegdefessel)
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Lehr- und Forschungskooperationen mit den Kliniken und Instituten am Deutschen Herzzentrum Klinik für Herz- und Kreislauferkrankungen im Erwachsenenalter (DHM) (Prof. Schunkert)2022

mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Klinik und Poliklinik für Vaskuläre und Endovaskuläre Chirurgie (Prof. Eckstein)Professur für Vaskuläre Biologie (Prof. Maegdefessel)2022