NDLI: Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice

Content Provider	Springer Nature : BioMed Central
Author	Sun, Hai-Jian Ni, Zhang-Rong Liu, Yao Fu, Xiao Liu, Shi-Yi Hu, Jin-Yi Sun, Qing-Yi Li, Yu-Chao Hou, Xiao-Hui Zhang, Ji-Ru Zhu, Xue-Xue Lu, Qing-Bo
Abstract	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.
Related Links	https://cardiab.biomedcentral.com/counter/pdf/10.1186/s12933-024-02239-6.pdf
Ending Page	19
Page Count	19
Starting Page	1
File Format	HTM / HTML
ISSN	14752840
DOI	10.1186/s12933-024-02239-6
Journal	Cardiovascular Diabetology
Issue Number	1
Volume Number	23
Language	English
Publisher	BioMed Central
Publisher Date	2024-04-25
Access Restriction	Open
Subject Keyword	Diabetes Angiology Cardiology Endothelial dysfunction Nitric oxide NCEH1 eNOS
Content Type	Text
Resource Type	Article
Subject	Cardiology and Cardiovascular Medicine Internal Medicine Endocrinology, Diabetes and Metabolism
Journal Impact Factor	8.5/2023
5-Year Journal Impact Factor	8.9/2023

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