Cao Lei, Zhang Jie, Yu Liwen, Yang Wei, Qi Wenqian, Ren Ruiqing, Liu Yapeng, Hou Yonghao, Cao Yu, Li Qian, Wang Xiaohong, Zhang Zhengguo, Li Bo, Sui Wenhai, Zhang Yun, Gao Chengjiang, Zhang Cheng, Zhang Meng
State Key Laboratory for Innovation and Transformation of Luobing Theory, K, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
Organ Procurement Organizations, Qilu Hospital of Shandong University, Jinan, China.
J Clin Invest. 2025 Jun 17;135(16). doi: 10.1172/JCI186509.
Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified 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 knockout 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 oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.
动脉粥样硬化源于胆固醇代谢紊乱，尤其是巨噬细胞胆固醇外流受损导致泡沫细胞形成。通过单细胞和大量RNA测序，我们确定李斯特菌素是巨噬细胞胆固醇代谢的调节因子。在人类和啮齿动物的动脉粥样硬化进展过程中，李斯特菌素的表达增加。在巨噬细胞特异性敲除小鼠中，其缺乏会抑制胆固醇外流，促进泡沫细胞形成，并加剧斑块特征（巨噬细胞浸润、脂质沉积、坏死核心）。相反，李斯特菌素过表达减轻了这些动脉粥样硬化表现。从机制上讲，李斯特菌素通过催化K1884/K1957残基处的K63连接多聚泛素化来稳定关键的胆固醇外流介质ABCA1，对抗氧化型低密度脂蛋白（oxLDL）诱导的ESCRT介导的ABCA1溶酶体降解。ABCA1激动剂赤藓二醇恢复了李斯特菌素缺陷巨噬细胞中的胆固醇外流，而ABCA1敲除消除了李斯特菌素在THP-1细胞中的作用。本研究通过ABCA1的翻译后稳定作用将李斯特菌素确立为动脉粥样硬化的保护因子，提供了一种靶向ABCA1泛素化以增强胆固醇外流的潜在治疗策略。
