TIGAR mitigates atherosclerosis by promoting cholesterol efflux from macrophages

Zhen-Wang Zhao; Min Zhang; Jin Zou; Xiang-Jun Wan; Li Zhou; Yao Wu; Shang-Ming Liu; Ling-Xiao Liao; Heng Li; Yu-Sheng Qin; Xiao-Hua Yu; Chao-Ke Tang

doi:10.1016/j.atherosclerosis.2021.04.002

TIGAR mitigates atherosclerosis by promoting cholesterol efflux from macrophages

Atherosclerosis. 2021 Jun:327:76-86. doi: 10.1016/j.atherosclerosis.2021.04.002. Epub 2021 Apr 20.

Authors

Zhen-Wang Zhao¹, Min Zhang¹, Jin Zou², Xiang-Jun Wan¹, Li Zhou¹, Yao Wu¹, Shang-Ming Liu¹, Ling-Xiao Liao³, Heng Li¹, Yu-Sheng Qin¹, Xiao-Hua Yu⁴, Chao-Ke Tang⁵

Affiliations

¹ Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
² Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, 421001, Hunan, China.
³ Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, 421001, China.
⁴ Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, China. Electronic address: yxh167@qq.com.
⁵ Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: tangchaoke@qq.com.

PMID: 33994201
DOI: 10.1016/j.atherosclerosis.2021.04.002

Abstract

Background and aims: TP53-induced glycolysis and apoptosis regulator (TIGAR) is now characterized as a fructose-2,6-bisphosphatase to reduce glycolysis and protect against oxidative stress. Recent studies have demonstrated that TIGAR is associated with cardiovascular disease. However, little is known about its role in atherosclerogenesis. In this study, we aimed to investigate the effect of TIGAR on atherosclerosis and explore the underlying molecular mechanism.

Methods: The Gene Expression Omnibus (GEO) datasets were used to analyze the differential expression of relative proteins. THP-1-derived macrophages were used as an in vitro model and apolipoprotein E-deficient (Apoe^-/^-) mice were used as an in vivo model. [³H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). Both qPCR and Western blot were used to evaluate the mRNA and protein expression, respectively. Lentiviral vectors were used to disturb the expression of TIGAR in vitro and in vivo. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaques in Apoe^-/^- mice fed a Western diet. Conventional assay kits were used to measure the levels of reactive oxygen species (ROS), plasma lipid profiles and 27-hydroxycholesterol (27-HC).

Results: Our results showed that TIGAR is increased upon the formation of macrophage foam cells and atherosclerosis. TIGAR knockdown markedly promoted lipid accumulation in macrophages. Silencing of TIGAR impaired cholesterol efflux and down-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 by interfering with liver X receptor α (LXRα) expression and activity, but did not influence cholesterol uptake by macrophages. Additionally, this inhibitory effect of TIGAR deficiency on cholesterol metabolism was mediated through the ROS/CYP27A1 pathway. In vivo experiments revealed that TIGAR deficiency decreased the levels of ABCA1 and ABCG1 in plaques and aorta and impaired the capacity of RCT, thereby leading to the progression of atherosclerosis in Apoe^-/^- mice.

Conclusions: TIGAR mitigates the development of atherosclerosis by up-regulating ABCA1 and ABCG1 expression via the ROS/CYP27A1/LXRα pathway.

Keywords: ABCA1; ABCG1; Atherosclerosis; CYP27A1; ROS; TIGAR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter 1 / metabolism
Animals
Apoptosis Regulatory Proteins*
Atherosclerosis*
Cholesterol / metabolism*
Foam Cells / metabolism
Glycolysis
Liver X Receptors / metabolism
Macrophages* / metabolism
Mice
Mice, Knockout, ApoE
Phosphoric Monoester Hydrolases*

Substances

ATP Binding Cassette Transporter 1
Apoptosis Regulatory Proteins
Liver X Receptors
Cholesterol
Phosphoric Monoester Hydrolases
TIGAR protein, mouse