Center for Cell Structure and Function, Haihe Laboratory of Cell Ecosystem, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, 250014, Jinan, China.
Metabolism and Disease Research Centre, Central Hospital Affiliated to Shandong First Medical University, 250013, Jinan, China.
Nat Commun. 2024 Sep 27;15(1):8273. doi: 10.1038/s41467-024-52621-x.
Disruption of ciliary homeostasis in vascular endothelial cells has been implicated in the development of atherosclerosis. However, the molecular basis for the regulation of endothelial cilia during atherosclerosis remains poorly understood. Herein, we provide evidence in male mice that the accumulation of lipid droplets in vascular endothelial cells induces ciliary loss and contributes to atherosclerosis. Triglyceride accumulation in vascular endothelial cells differentially affects the abundance of free fatty acid species in the cytosol, leading to stimulated lipid droplet formation and suppressed protein S-palmitoylation. Reduced S-palmitoylation of ciliary proteins, including ADP ribosylation factor like GTPase 13B, results in the loss of cilia. Restoring palmitic acid availability, either through pharmacological inhibition of stearoyl-CoA desaturase 1 or a palmitic acid-enriched diet, significantly restores endothelial cilia and mitigates the progression of atherosclerosis. These findings thus uncover a previously unrecognized role of lipid droplets in regulating ciliary homeostasis and provide a feasible intervention strategy for preventing and treating atherosclerosis.
血管内皮细胞纤毛稳态的破坏与动脉粥样硬化的发生有关。然而，动脉粥样硬化过程中内皮纤毛调控的分子机制仍知之甚少。本研究在雄性小鼠中提供证据表明，血管内皮细胞中脂质滴的积累诱导纤毛丧失，并促进动脉粥样硬化的发生。血管内皮细胞中甘油三酯的积累会使细胞质中游离脂肪酸的丰度产生差异，从而刺激脂质滴的形成并抑制蛋白 S-棕榈酰化。纤毛蛋白的 S-棕榈酰化减少，包括 ADP 核糖基化因子样 GTP 酶 13B，导致纤毛丧失。通过药理学抑制硬脂酰辅酶 A 去饱和酶 1 或富含棕榈酸的饮食增加棕榈酸的可用性，可显著恢复内皮细胞纤毛，减轻动脉粥样硬化的进展。这些发现揭示了脂质滴在调节纤毛稳态中的先前未被认识的作用，并为预防和治疗动脉粥样硬化提供了可行的干预策略。
