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Identification of the Transcription Factor ATF3 as a Direct and Indirect Regulator of the LDLR
- Source :
- Metabolites; Volume 12; Issue 9; Pages: 840, Metabolites 12:840 (2022)
- Publication Year :
- 2021
- Publisher :
- MDPI, 2021.
-
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.
- Subjects :
- ATF3
atherosclerosis
cardiovascular disease
coronary artery disease
gene expression
inflammation
LDLR
lipid metabolism
liver metabolism
LPS
MAFF
transcription factor
Article
Endocrinology, Diabetes and Metabolism
Atf3
Atherosclerosis
Cardiovascular Disease
Coronary Artery Disease
Gene Expression
Inflammation
Ldlr
Lipid Metabolism
Liver Metabolism
Lps
Maff
Transcription Factor
Molecular Biology
Biochemistry
ddc
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Metabolites; Volume 12; Issue 9; Pages: 840, Metabolites 12:840 (2022)
- Accession number :
- edsair.doi.dedup.....0afbb3108de59f43c279eab4a1c21ebb