E3 ubiquitin ligase Listerin regulates macrophage cholesterol efflux and atherosclerosis by targeting ABCA1
Lei Cao, Jie Zhang, Liwen Yu, Wei Yang, Wenqian Qi, Ruiqing Ren, Yapeng Liu, Yonghao Hou, Yu Cao, Qian Li, Xiaohong Wang, Zhengguo Zhang, Bo Li, Wenhai Sui, Yun Zhang, Chengjiang Gao, Cheng Zhang, Meng Zhang
Lei Cao, Jie Zhang, Liwen Yu, Wei Yang, Wenqian Qi, Ruiqing Ren, Yapeng Liu, Yonghao Hou, Yu Cao, Qian Li, Xiaohong Wang, Zhengguo Zhang, Bo Li, Wenhai Sui, Yun Zhang, Chengjiang Gao, Cheng Zhang, Meng Zhang
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Research Article Cardiology Metabolism

E3 ubiquitin ligase Listerin regulates macrophage cholesterol efflux and atherosclerosis by targeting ABCA1

Abstract

Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA-Seq, we identified Listerin E3 ubiquitin protein ligase 1 (Listerin) as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific KO mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxidized LDL (oxLDL). ABCA1 agonist erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while KO of ABCA1 abolished Listerin’s effects in Tsuchiya human monocytic leukemia line (THP-1) cells. This study establishes Listerin as a protective factor in atherosclerosis via posttranslational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.

Authors

Lei Cao, Jie Zhang, Liwen Yu, Wei Yang, Wenqian Qi, Ruiqing Ren, Yapeng Liu, Yonghao Hou, Yu Cao, Qian Li, Xiaohong Wang, Zhengguo Zhang, Bo Li, Wenhai Sui, Yun Zhang, Chengjiang Gao, Cheng Zhang, Meng Zhang

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Figure 7

Listerin KO aggravates the development of atherosclerosis in vivo.

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Listerin KO aggravates the development of atherosclerosis in vivo. Male ...
Male ApoE–/– Listerinfl/fl and ApoE–/– Listerinfl/fl Lyz2Cre mice were fed a WD for 16 weeks. (A) The measurement of BW and serum levels of triglycerides (mmol/L), cholesterol (mmol/L), HDL-C (mmol/L), and LDL (mmol/L). n = 8 per group. (B) Representative images and quantitation of aortic arch regions containing white plaques (yellow arrowheads). (C) En face Oil Red O staining and (D) quantitation of atherosclerotic plaques in the whole aorta. n = 8 per group. (E) H&E staining of representative aortic root sections and quantification of lesion area and necrotic core area. n = 8 per group. Scale bar: 200 μm. (F) Oil Red O–stained cross-section images and analysis of atherosclerotic plaques in the aortic root. n = 8 per group. Scale bar: 200 μm. Immunofluorescence staining for (G) CD68 and (H) ABCA1 in the aortic root. n = 8 per group. Scale bars: 200 μm (G) and 100 um (H). (I) Immunoblot images and quantitative analysis of ABCA1 in whole-aorta lysates from ApoE–/– Listerinfl/fl and ApoE–/– Listerinfl/fl Lyz2Cre mice. n = 8 per group. Data are presented as the mean ± SD. The Shapiro-Wilk method was used to test normal distributions. Statistical analysis was performed using an unpaired, 2-tailed Student’s t test. **P < 0.01 and ***P < 0.001.