缺乏中性胆固醇酯水解酶 1（NCEH1）可损害饮食诱导的糖尿病小鼠的内皮功能。
Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice.
机构信息
Department of Physiology, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, 210009, China.
出版信息
Cardiovasc Diabetol. 2024 Apr 25;23(1):138. doi: 10.1186/s12933-024-02239-6.
BACKGROUND
Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored.
METHODS
The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured.
RESULTS
Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1.
CONCLUSIONS
NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.
背景
中性胆固醇酯水解酶 1（NCEH1）在胆固醇酯代谢调节中发挥着关键作用。NCEH1 的缺乏会加速小鼠动脉粥样硬化病变的形成。然而，NCEH1 在与糖尿病相关的内皮功能障碍中的作用尚未得到探索。本研究旨在探讨 NCEH1 是否能改善糖尿病患者的内皮功能，并探讨其潜在机制。
方法
通过高脂肪饮食（HFD）喂养肥胖小鼠、高葡萄糖（HG）诱导的小鼠主动脉或原代内皮细胞（ECs）来确定 NCEH1 的表达和活性。测量主动脉对乙酰胆碱（Ach）反应的内皮依赖性松弛（EDR）。
结果
结果表明，在 HFD 诱导的小鼠主动脉、HG 暴露的小鼠主动脉离体和 HG 孵育的原代 ECs 中，NCEH1 的表达和活性均降低。HG 暴露降低了小鼠主动脉的 EDR，内皮特异性缺乏 NCEH1 会使 EDR 进一步恶化，而过表达 NCEH1 则恢复了受损的 EDR。在 HFD 小鼠中也观察到了类似的结果。机制上，NCEH1 通过将内皮型一氧化氮合酶（eNOS）从 caveolin-1（Cav-1）上解离，改善了破坏的 EDR，从而激活 eNOS 并释放一氧化氮（NO）。此外，NCEH1 与 E3 泛素蛋白连接酶 ZNRF1 的相互作用导致 Cav-1 通过泛素化途径降解。沉默 Cav-1 和上调 ZNRF1 足以改善糖尿病主动脉的 EDR，而过表达 Cav-1 和下调 ZNRF1 则消除了 NCEH1 对糖尿病内皮功能的影响。因此，NCEH1 通过破坏糖尿病小鼠内皮细胞中 Cav-1/eNOS 复合物，增加 NO 生物利用度来维持内皮功能，这依赖于 ZNRF1 诱导的 Cav-1 泛素化。
结论
NCEH1 可能是预防和治疗糖尿病血管并发症的有前途的候选药物。
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