Journal Article

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

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

2022

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Activating transcription factor 3 / Animal models / Arteriosclerosis / Article ; ATF3 ; atherosclerosis ; cardiovascular disease ; coronary artery disease ; gene expression ; inflammation ; LDLR ; lipid metabolism ; liver metabolism ; LPS ; MAFF ; transcription factor / ATF3 / ATF3; atherosclerosis; cardiovascular disease; coronary artery disease; gene expression; inflammation; LDLR; lipid metabolism; liver metabolism; LPS; MAFF; transcription factor / 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 / Medicine, Experimental / Metabolism / Microbiology / Physiological aspects / QR1-502 / Receptor density / siRNA / Smooth muscle / Transcription factors / Transcriptomes