Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR

Sabine Bauer; Jana Eigenmann; Yuqi Zhao; Julia Fleig; Johann S Hawe; Calvin Pan; Dario Bongiovanni; Simon Wengert; Angela Ma; Aldons J Lusis; Jason C Kovacic; Johan L M Björkegren; Lars Maegdefessel; Heribert Schunkert; Moritz von Scheidt

doi:10.3390/metabo12090840

Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR

Metabolites. 2022 Sep 6;12(9):840. doi: 10.3390/metabo12090840.

Authors

Sabine Bauer^{1

2}, Jana Eigenmann¹, Yuqi Zhao³, Julia Fleig¹, Johann S Hawe¹, Calvin Pan⁴, Dario Bongiovanni^{2

5}, Simon Wengert^{6

7}, Angela Ma⁸, Aldons J Lusis⁴, Jason C Kovacic^{9

10

11}, Johan L M Björkegren^{8

12

13}, Lars Maegdefessel^{2

14

15}, Heribert Schunkert^{1

2}, Moritz von Scheidt^{1

2}

Affiliations

¹ Department of Cardiology, German Heart Centre Munich, Technical University Munich, 80636 Munich, Germany.
² DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, 80802 Munich, Germany.
³ Department of Integrative Biology and Physiology, Institute for Quantitative and Computational Biosciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁴ Departments of Medicine, Human Genetics, Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁵ Division of Cardiology, Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, 6900 Lugano, Switzerland.
⁶ Helmholtz Pioneer Campus, Helmholtz Center Munich, 85764 Neuherberg, Germany.
⁷ Institute of Computational Biology, Helmholtz Center Munich, 85764 Oberschleißheim, Germany.
⁸ Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW 2010, Australia.
¹⁰ St. Vincent's Clinical School, University of New South Wales, Darlinghurst, Sydney, NSW 2010, Australia.
¹¹ Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, New York, NY 10029, USA.
¹² Clinical Gene Networks AB, 114 44 Stockholm, Sweden.
¹³ Integrated Cardio Metabolic Centre, Karolinska Institutet, Novum, Huddinge, 171 77 Stockholm, Sweden.
¹⁴ Department of Vascular and Endovascular Surgery, Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany.
¹⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.

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.

Keywords: ATF3; LDLR; LPS; MAFF; atherosclerosis; cardiovascular disease; coronary artery disease; gene expression; inflammation; lipid metabolism; liver metabolism; transcription factor.

Abstract

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