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Trimethylamine N-oxide promotes oxidative stress and lipid accumulation in macrophage foam cells via the Nrf2/ABCA1 pathway

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Abstract

Recently, trimethylamine N-oxide (TMAO) has been considered a risk factor for cardiovascular disease and has a proatherogenic effect. Many studies have found that TMAO is involved in plaque oxidative stress and lipid metabolism, but the specific mechanism is still unclear. In our study, meta-analysis and bioinformatic analysis were firstly conducted in the database, and found that the effect of high plasma TMAO levels on promoting atherosclerotic plaque may be related to the expression of key antioxidant genes nuclear factor erytheroid-derived-2-like 2 (NFE2L2/Nrf2) decreased. Next, we assessed the role of Nrf2-mediated signaling pathway in TMAO-treated foam cells. Our results showed that TMAO can inhibit the expression of Nrf2 and its downstream antioxidant response element such as heme oxygenase-1 (HO-1) and glutathione peroxidase4 (GPX4), resulting in increased production of reactive oxygen species and decreased activity of superoxide dismutase, promoting oxidative stress. And TMAO can also promote lipid accumulation in foam cells by inhibiting cholesterol efflux protein expression. In addition, upregulation of Nrf2 expression partially rescues TMAO-induced oxidative stress and reduces ATP-binding cassette A1 (ABCA1)–mediated lipid accumulation. Therefore, TMAO promotes oxidative stress and lipid accumulation in macrophage foam cells through the Nrf2/ABCA1 pathway, which may provide a potential mechanism for the proatherogenic effect of TMAO.

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Data availability

All data used to support the current study are available from the corresponding author on reasonable request. The links for the database included in the study are as follows: GEO database (http://www.ncbi.nlm.nih.gov/geo); Genecard database (http://www.genecards.org/).

Abbreviations

ABCA1:

ATP-binding cassette A1

ARE:

Antioxidant response element

AS:

Atherosclerosis

CVD:

Cardiovascular diseases

GPX4:

Glutathione peroxidase4

GEO:

Gene Expression Omnibus

HO-1:

Heme oxygenase-1

NFE2L2/Nrf2:

Nuclear factor erytheroid–derived-2-like 2

Ox-LDL:

Oxidized low-density lipoprotein

ROS:

Reactive oxygen species

SOD:

Super oxide dismutase

tBHQ:

Tert-butylhydroquinone

TMAO:

Trimethylamine N-oxide

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Funding

This study was supported by the grants from the National Natural Science Foundation of China (No. 81672084).

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Authors and Affiliations

  1. Department of Laboratory Diagnostics, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, NanGang, Harbin, Heilongjiang, 150001, People’s Republic of China

    ZhiSheng Luo, XiaoChen Yu, Chao Wang, HaiYan Zhao, Xinming Wang & XiuRu Guan

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  1. ZhiSheng Luo
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First author: do experiments, write articles, participate in part of the experimental design. Second, third, and fourth authors: assist in completing the experiment. Corresponding author: participate in article revision, experimental design and supervision, financial support. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to XiuRu Guan.

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Key Points

•The proatherogenic effect of high plasma TMAO level might be associated with the differential expression of NFE2L2 decreased by meta-analysis and bioinformatic analysis.

•TMAO promotes oxidative stress by inhibiting Nrf2/ARE signaling axis in macrophage foam cell.

•TMAO induces lipid accumulation by inhibiting cholesterol efflux protein expression in foam cell which partially alleviated by upregulation of Nrf2.

Supplementary information

ESM 1

Supplementary Table 1 Characteristics of the Included Studies. Abbreviations: M, male; CVD, cardiovascular disease; STEMI, ST-segment elevation myocardial infarction; ACS, Acute coronary syndromes. Data of TMAO Levels are expressed as medians (interquartile ranges) or means ± standard deviations. (DOCX 61 kb)

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Luo, Z., Yu, X., Wang, C. et al. Trimethylamine N-oxide promotes oxidative stress and lipid accumulation in macrophage foam cells via the Nrf2/ABCA1 pathway. J Physiol Biochem 80, 67–79 (2024). https://doi.org/10.1007/s13105-023-00984-y

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