PLK1 promotes cholesterol efflux and alleviates atherosclerosis by up-regulating ABCA1 and ABCG1 expression via the AMPK/PPARγ/LXRα pathway

Hu, Heng‐Jing; Wang, Xiuheng; Zhang, Tianqing; Liu, Yao; Zhang, Zhi-Zhu; Hong, Hui; Tang, Huifang; Jiang, Zhisheng

doi:10.1016/j.bbalip.2022.159221

Cited by 8 publications

(6 citation statements)

References 46 publications

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“…explore the mechanisms of CYP4A11regulating ABCA1, we screened the cholesterol-dependent signaling pathways that regulate ABCA1 expression, including PPARγ/LXRα, PPARα, LXRβ, and SREBP2. [34][35][36][37] We found that CYP4A11 promoted the activation and nuclear translocation of the transcription factor SREBP2 and thus promoted the binding of SREBP2 to the ABCA1 promoter. SREBP2 was confirmed to bind to the promoter of ABCA1 to suppress its transcriptional activity in THP-1 macrophage, asthma smooth muscle cells, vascular ECs, and hepatoma cell lines [62][63][64][65] but there are no reports in vascular SMCs.…”

Section: Discussionmentioning

confidence: 74%

“…To explore the mechanism of ABCA1 downregulation by CYP4A11–20‐HETE axis, we screened classic signaling pathways that were reported to regulate ABCA1 expression, including PPARγ/LXRα, PPARα, LXRβ, and SREBP2 34–37 . Therein, SREBP2 is restrained in the endoplasmic reticulum (ER) as an inactive precursor (pre‐SREBP2; ~130 kDa), which can be cleaved and activated under the action of various endogenous factors or chaperone proteins to downregulate ABCA1 expression 37 .…”

Section: Resultsmentioning

confidence: 99%

“…To further explore the mechanisms of CYP4A11‐regulating ABCA1, we screened the cholesterol‐dependent signaling pathways that regulate ABCA1 expression, including PPARγ/LXRα, PPARα, LXRβ, and SREBP2 34–37 . We found that CYP4A11 promoted the activation and nuclear translocation of the transcription factor SREBP2 and thus promoted the binding of SREBP2 to the ABCA1 promoter.…”

Section: Discussionmentioning

confidence: 99%

“…To explore the mechanism of ABCA1 downregulation by CYP4A11-20-HETE axis, we screened classic signaling pathways that were reported to regulate ABCA1 expression, including PPARγ/LXRα, PPARα, LXRβ, and SREBP2. [34][35][36][37] Therein, SREBP2 is restrained in the endoplasmic reticulum (ER) as an inactive precursor (pre-SREBP2; ~130 kDa), which can be cleaved and activated under the action of various endogenous factors or chaperone proteins to downregulate ABCA1 expression. 37 Immunoblot analysis showed that CYP4A11 knockdown blocked-while CYP4A11 overexpression enhanced-the nuclear/activated isoform of SREBP2 (n-SREBP2; ~70 kDa); however, this did not affect the PPARγ/LXRα, PPARα, and LXRβ signaling pathways (Figure 6A-C).…”

Section: Cyp4a11-20-hete Inhibits Abca1 Expression By Promoting Srebp...mentioning

confidence: 99%

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Dickkopf‐1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1

Li,

Zheng,

Zhang

et al. 2023

The FASEB Journal

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Vascular smooth muscle cells (VSMCs) are considered to be a crucial source of foam cells in atherosclerosis due to their low expression level of cholesterol exporter ATP‐binding cassette transporter A1 (ABCA1) intrinsically. While the definite regulatory mechanisms are complicated and have not yet been fully elucidated, we previously reported that Dickkopf‐1 (DKK1) mediates endothelial cell (EC) dysfunction, thereby aggravating atherosclerosis. However, the role of smooth muscle cell (SMC) DKK1 in atherosclerosis and foam cell formation remains unknown. In this study, we established SMC‐specific DKK1‐knockout (DKK1SMKO) mice by crossbreeding DKK1flox/flox mice with TAGLN‐Cre mice. Then, DKK1SMKO mice were crossed with APOE−/− mice to generate DKK1SMKO/APOE−/− mice, which exhibited milder atherosclerotic burden and fewer SMC foam cells. In vitro loss‐ and gain‐of‐function studies of DKK1 in primary human aortic smooth muscle cells (HASMCs) have proven that DKK1 prevented oxidized lipid‐induced ABCA1 upregulation and cholesterol efflux and promoted SMC foam cell formation. Mechanistically, RNA‐sequencing (RNA‐seq) analysis of HASMCs as well as chromatin immunoprecipitation (ChIP) experiments showed that DKK1 mediates the binding of transcription factor CCAAT/enhancer‐binding protein delta (C/EBPδ) to the promoter of cytochrome P450 epoxygenase 4A11 (CYP4A11) to regulate its expression. In addition, CYP4A11 as well as its metabolite 20‐HETE‐promoted activation of transcription factor sterol regulatory element‐binding protein 2 (SREBP2) mediated the DKK1 regulation of ABCA1 in SMC. Furthermore, HET0016, the antagonist of CYP4A11, has also shown an alleviating effect on atherosclerosis. In conclusion, our results demonstrate that DKK1 promotes SMC foam cell formation during atherosclerosis via a reduction in CYP4A11‐20‐HETE/SREBP2‐mediated ABCA1 expression.

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Section: Discussionmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cyp4a11-20-hete Inhibits Abca1 Expression By Promoting Srebp...mentioning

confidence: 99%

See 2 more Smart Citations

Dickkopf‐1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1

Li,

Zheng,

Zhang

et al. 2023

The FASEB Journal

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show abstract

“…ABCA1 and ABCG1 are involved in the reverse transport of intracellular cholesterol. Phospholipids and cholesterol mediated by ABCA1 actively flow from cells to apoA-1, and cholesterol mediated by ABCG1 flows from cells to HDL (Hu et al, 2022;Ogura, 2022). HDL and apoA-1 mediated cholesterol efflux experiments were carried out to study whether PC can promote the cholesterol efflux from foam cells induced by ox-LDL.…”

Section: Pc Promote Cholesterol Efflux From Raw2647 Macrophagesmentioning

confidence: 99%

Pomegranate punicalagin inhibits the foam cells formation in Raw264.7 macrophages

Zhao

ZHANG

et al. 2023

Food Sci. Technol

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In order to reveal the inhibitory effect of pomegranate punicalagin on macrophage foam cell formation and its possible mechanism, Raw264.7 macrophages were as the experimental carrier to detect the effect of punicalagin on macrophage cholesterol accumulation and outflow, and evaluate the regulation of punicalagin on cholesterol accumulation related genes CD36, PPARγ and outflow related genes ABCA1/G1, LXRα by Western-Blot method. The results showed that punicalagin can inhibit the cholesterol accumulation in raw264.7 macrophages due to restraining the PPARγ-CD36 expression, and meanwhile it could also promote macrophage cholesterol efflux by regulating LXRα-ABCA1/G1 pathway.

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Protein posttranslational modifications in metabolic diseases: basic concepts and targeted therapies

Yang,

Wu,

Zhou

et al. 2024

MedComm

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Metabolism‐related diseases, including diabetes mellitus, obesity, hyperlipidemia, and nonalcoholic fatty liver disease, are becoming increasingly prevalent, thereby posing significant threats to human health and longevity. Proteins, as the primary mediators of biological activities, undergo various posttranslational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, methylation, and SUMOylation, among others, which substantially diversify their functions. These modifications are crucial in the physiological and pathological processes associated with metabolic disorders. Despite advancements in the field, there remains a deficiency in contemporary summaries addressing how these modifications influence processes of metabolic disease. This review aims to systematically elucidate the mechanisms through which PTM of proteins impact the progression of metabolic diseases, including diabetes, obesity, hyperlipidemia, and nonalcoholic fatty liver disease. Additionally, the limitations of the current body of research are critically assessed. Leveraging PTMs of proteins provides novel insights and therapeutic targets for the prevention and treatment of metabolic disorders. Numerous drugs designed to target these modifications are currently in preclinical or clinical trials. This review also provides a comprehensive summary. By elucidating the intricate interplay between PTMs and metabolic pathways, this study advances understanding of the molecular mechanisms underlying metabolic dysfunction, thereby facilitating the development of more precise and effective disease management strategies.

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PLK1 promotes cholesterol efflux and alleviates atherosclerosis by up-regulating ABCA1 and ABCG1 expression via the AMPK/PPARγ/LXRα pathway

Cited by 8 publications

References 46 publications

Dickkopf‐1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1

Dickkopf‐1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1

Pomegranate punicalagin inhibits the foam cells formation in Raw264.7 macrophages

Protein posttranslational modifications in metabolic diseases: basic concepts and targeted therapies

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