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Androgen-dependent tissue factor pathway inhibitor regulating protein: a review of its peripheral actions and association with cardiometabolic diseases

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Abstract

The first genome-wide association study on coronary artery disease (CAD) in the Han Chinese population identified C6orf105 as a susceptibility gene. The C6orf105 gene was later found to encode for a protein that regulates tissue factor pathway inhibitor (TFPI) expression in endothelial cells in an androgen-dependent manner, and the novel protein was thus termed androgen-dependent TFPI-regulating protein (ADTRP). Since the identification of ADTRP, there have been several studies associating genetic variants on the ADTRP gene with CAD risk, as well as research providing mechanistic insights on this novel protein and its functional role. ADTRP is a membrane protein, whose expression is upregulated by androgen, GATA-binding protein 2, oxidized low-density lipoprotein, peroxisome proliferator‐activated receptors, and low-density lipoprotein receptors. ADTRP regulates multiple downstream targets involved in coagulation, inflammation, endothelial function, and vascular integrity. In addition, ADTRP functions as a fatty acid esters of hydroxy fatty acid (FAHFA)-specific hydrolase that is involved in energy metabolism. Current evidence suggests that ADTRP may play a role in the pathogenesis of atherosclerosis, CAD, obesity, and metabolic disorders. This review summarizes the current literature on ADTRP, with a focus on the peripheral actions of ADTRP, including expression, genetic variations, signaling pathways, and function. The evidence linking ADTRP and cardiometabolic diseases will also be discussed.

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Abbreviations

ABPP:

Activity-based protein profiling

ADTRP:

Androgen-dependent tissue factor pathway inhibitor regulating protein

AIG1:

Androgen-induced gene 1

AKT:

AKT serine/threonine kinase

ApoB:

Apolipoprotein B

ARE:

Androgen response element

BAT:

Brown adipose tissue

CAD:

Coronary artery disease

CASP7:

Caspase 7

CCND1:

Cyclin D1

CDK4:

Cyclin-dependent kinase 4

CDKN1A:

Cyclin-dependent kinase inhibitor 1A

CD36:

Cluster of differentiation 36

ChIP-seq:

Chromatin immunoprecipitation-sequencing

CI:

Confidence interval

FAHFA:

Fatty acid esters of hydroxy fatty acid

FP:

Fluorophosphonate

FVIIc:

Factor VII coagulant activity

FXa:

Factor Xa

GATA2:

GATA-binding protein 2

GLP-1:

Glucagon-like peptide 1

GWAS:

Genome-wide association study

HUVEC:

Human umbilical vein endothelial cell

KO:

Knockout

LDL:

Low-density lipoprotein

LDLR:

Low-density lipoprotein receptor

LOX-1:

Lectin-like oxidized low-density lipoprotein receptor-1

LRP6:

Low-density lipoprotein receptor related protein 6

MI:

Myocardial infarction

MIA3/TANGO1:

Melanoma inhibitory activity protein 3/Transport and Golgi organization protein 1

MMP9:

Matrix metallopeptidase 9

myrAKT1:

Myristoylated human AKT1

NF-κB:

Nuclear factor kappa B

OR:

Odds ratio

ox-LDL:

Oxidized low-density lipoprotein

PAHSA:

Palmitic acid hydroxy stearic acid

PBMC:

Peripheral blood mononuclear cell

PDCD2:

Programmed cell death 2

PI3K:

Phosphatidylinositol 3-kinase

PI3KR3:

Phosphatidylinositol 3-kinase regulatory subunit gamma

POU1F1:

POU domain class 1 transcription factor 1

PPAR:

Peroxisome proliferator‐activated receptor

qRT-PCR:

Quantitative reverse transcription-polymerase chain reaction

shRNA:

Short hairpin ribonucleic acid

siRNA:

Small interfering ribonucleic acid

SNP:

Single-nucleotide polymorphism

TF-FVIIa:

Tissue factor-factor VIIa

TFPI:

Tissue factor pathway inhibitor

WAT:

White adipose tissue

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Authors and Affiliations

  1. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block Level 12, 1E Kent Ridge Road, 119228, Singapore

    Zizheng Kee, Sze Min Ong, Chew-Kiat Heng & Delicia Shu Qin Ooi

  2. Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Kent Ridge, Singapore

    Zizheng Kee, Sze Min Ong, Chew-Kiat Heng & Delicia Shu Qin Ooi

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  1. Zizheng Kee
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Conceptualization: Delicia Shu Qin Ooi; Literature search and analysis: Zizheng Kee, Sze Min Ong; Writing—original draft preparation: Zizheng Kee, Sze Min Ong; Writing—review and editing: Chew-Kiat Heng, Delicia Shu Qin Ooi.

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Kee, Z., Ong, S.M., Heng, CK. et al. Androgen-dependent tissue factor pathway inhibitor regulating protein: a review of its peripheral actions and association with cardiometabolic diseases. J Mol Med 100, 185–196 (2022). https://doi.org/10.1007/s00109-021-02160-5

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