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CEPT1-Mediated Phospholipogenesis Regulates Endothelial Cell Function and Ischemia-Induced Angiogenesis Through PPARα.

Citation
Zayed, M. A., et al. “Cept1-Mediated Phospholipogenesis Regulates Endothelial Cell Function And Ischemia-Induced Angiogenesis Through Pparα.”. Diabetes, pp. 549-561.
Center Washington University in St Louis
Author Mohamed A Zayed, Xiaohua Jin, Chao Yang, Larisa Belaygorod, Connor Engel, Kshitij Desai, Nikolai Harroun, Omar Saffaf, Bruce W Patterson, Fong-Fu Hsu, Clay F Semenkovich
Abstract

De novo phospholipogenesis, mediated by choline-ethanolamine phosphotransferase 1 (CEPT1), is essential for phospholipid activation of transcription factors such as peroxisome proliferator-activated receptor α (PPARα) in the liver. Fenofibrate, a PPARα agonist and lipid-lowering agent, decreases amputation incidence in patients with diabetes. Because we previously observed that CEPT1 is elevated in carotid plaque of patients with diabetes, we evaluated the role of CEPT1 in peripheral arteries and PPARα phosphorylation (Ser12). CEPT1 was found to be elevated in diseased lower-extremity arterial intima of individuals with peripheral arterial disease and diabetes. To evaluate the role of in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of via induced ---mediated recombination (/). / ECs demonstrated decreased proliferation, migration, and tubule formation, and / mice had reduced perfusion and angiogenesis in ischemic hind limbs. Peripheral ischemic recovery and PPARα signaling were further compromised by streptozotocin-induced diabetes and ameliorated by feeding fenofibrate. endoribonuclease-prepared siRNA decreased PPARα phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike / mice, / mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate. Therefore, we demonstrate that CEPT1 is essential for EC function and tissue recovery after ischemia and that fenofibrate rescues CEPT1-mediated activation of PPARα.

Year of Publication
2021
Journal
Diabetes
Volume
70
Issue
2
Number of Pages
549-561
Date Published
02/2021
ISSN Number
1939-327X
DOI
10.2337/db20-0635
Alternate Journal
Diabetes
PMID
33214136
PMCID
PMC7881870
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