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IRE1α: from the function to the potential therapeutic target in atherosclerosis

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Abstract

Inositol requiring enzyme 1 (IRE1) is generally thought to control the most conserved pathway in the unfolded protein response (UPR). Two isoforms of IRE1, IRE1α and IRE1β, have been reported in mammals. IRE1α is a ubiquitously expressed protein whose knockout shows marked lethality. In contrast, the expression of IRE1β is exclusively restricted in the epithelial cells of the respiratory and gastrointestinal tracts, and IRE1β-knockout mice are phenotypically normal. As research continues to deepen, IRE1α was showed to be tightly linked to inflammation, lipid metabolism regulation, cell death and so on. Growing evidence also suggests an important role for IRE1α in promoting atherosclerosis (AS) progression and acute cardiovascular events through disrupting lipid metabolism balance, facilitating cells apoptosis, accelerating inflammatory responses and promoting foam cell formation. In addition, IRE1α was recognized as novel potential therapeutic target in AS prevention. This review provides some clues about the relationship between IRE1α and AS, hoping to contribute to further understanding roles of IRE1α in atherogenesis and to be helpful for the design of novel efficacious therapeutics agents targeting IRE1α-related pathways.

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Abbreviations

Acacb:

Acetyl-coenzyme A carboxylase beta

ADPN:

Adiponectin

AMPK:

AMP-activated protein kinase

ANGII:

AngiotensinII

Angptl3:

Angiopoietin-like protein 3

AP1:

Activator protein 1

AS:

Atherosclerosis

ASK1:

Apoptosis signal-regulated kinase 1

ATF6:

Activating transcription factor 6

BAT:

Brown adipose tissue

BAX:

Bcl-2-associated X protein

Bcl:

B-cell lymphoma

BIP:

Binding immunoglobulin protein

CD36:

Cluster of differentiation 36

Ces1:

Carboxylesterase 1

CHOP:

C/EBP homologous protein

Dgat2:

Diacylglycerol O-acyltransferase 2

ER:

Endoplasmic reticulum

ERS:

Endoplasmic reticulum stress

FA:

Fatty acids

FABP4:

Fatty acid binding protein 4

FGF21:

Fibroblast growth factor 21

FMRP:

Fragile X mental retardation protein

Gipie:

GRP78 interacting protein induced by ERS

GRP78:

Glucose regulated protein 78

HFD:

High fat diet

ICAM-1:

Intercellular adhesion molecule-1

IFN-γ:

Interferon-γ

IL:

Interleukin

IKK:

Inhibitor of nuclear factor kappa-B kinase

IRE1:

Inositol requiring enzyme 1

IRE1α:

Inositol requiring enzyme 1α

IκB:

Inhibitor of nuclear factor kappa-B

INPPL1:

Inositol polyphosphate phosphatase like-1

JNK:

C-Jun N-terminal kinase

LC3:

Microtubule-associated protein light chain 3

LDL:

Low-density lipoprotein

MCP-1:

Monocyte chemotactic protein-1

miR:

MicroRNA

mm-LDL:

Minimally modified low-density lipoprotein

mTOR:

Mammalian target of rapamycin

NF-κB:

Nuclear factor kappa-B

ox-LDL:

Oxidized low-density lipoprotein

PBA:

4-Phenylbutyric acid

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

PIP3:

Phosphatidylinositol trisphosphate

PPAR-γ:

Peroxisome proliferator-activated receptor-γ

Ppargc1α:

PPAR-γ coactivator-1 alpha

RIDD:

Regulated inositol requiring enzyme 1-dependent decay

RNase:

Endoribonuclease

Scd1:

Stearoyl-CoA desaturase 1

TLR:

Toll-like receptors

TNF-α:

Tumor necrosis factor-α

TRAF:

Tumor necrosis factor receptor associated factor

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

UPR:

Unfolded protein response

VLDL:

Very low-density lipoprotein

WAT:

White adipose tissue

XBP1:

X-box binding protein 1

XBP1s:

X-box binding protein 1 spliced

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Funding

This work was supported by the Hunan Provincial Natural Science Foundation of China (2021JJ30602), A Project Supported by Scientific Research Fund of Hunan Provincial Education Department (21A0283, 19B478), and Hunan Provincial College Students Research Study and Innovative Experiment Project (2022-3039, 2022-3042, 2022-3205, 2022-3206).

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Author notes

  1. Zheng-Yang Zhou, Li Wu and Yi-Fan Liu have contributed equally to this work.

Authors and Affiliations

  1. The Laboratory of Translational Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Zheng-Yang Zhou, Li Wu, Yi-Fan Liu, Mu-Yao Tang, Jing-Yi Tang, Ya-Qian Deng, Lei Liu, Bin-Bin Nie, Zi-Kai Zou & Liang Huang

  2. Department of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Zheng-Yang Zhou, Li Wu, Mu-Yao Tang, Jing-Yi Tang, Ya-Qian Deng, Lei Liu, Bin-Bin Nie & Zi-Kai Zou

  3. Department of Anaesthesiology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Jing-Yi Tang

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  9. Zi-Kai Zou
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  10. Liang Huang
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Contributions

LH, Z-YZ and LW conceived the theme. Z-YZ, Y-FL wrote original manuscript draft and performed the literature search. Z-YZ and LH involved in preparation of figures. M-YT, J-YT, LL, B-BN and Z-KZ supervised manuscript critically and gave some good suggestions. Z-YZ, LH and Y-QD revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Liang Huang.

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Zhou, ZY., Wu, L., Liu, YF. et al. IRE1α: from the function to the potential therapeutic target in atherosclerosis. Mol Cell Biochem 479, 1079–1092 (2024). https://doi.org/10.1007/s11010-023-04780-6

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