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

posted on 19.11.2020, 16:09 by Ada Admin, 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
De novo phosopholipogenesis, 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. Since 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 Cept1 in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of Cept1 via induced VE-cadherin-CreERT2 mediated recombination (Cept1Lp/LpCre+). Cept1Lp/LpCre+ ECs demonstrated decreased proliferation, migration, and tubule formation, and Cept1Lp/LpCre+ mice had reduced perfusion and angiogenesis in ischemic hind-limbs. Peripheral ischemic recovery and PPARα signaling was further compromised by Streptozotocin-induced diabetes, and ameliorated by feeding fenofibrate. Cept1 esiRNA decreased PPARα-phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike Cept1Lp/LpCre+, Cept1Lp/LpCre+Ppara-/- mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate. Therefore we demonstrate that CEPT1 is essential for EC function and tissue recovery following ischemia, and that fenofibrate rescues CEPT1-mediated activation of PPARα.


This work was supported by grants from the Vascular Cures Foundation Wylie Scholar Award (MAZ), American Surgical Association Research Fellowship Award (MAZ), Society for Vascular Surgery Foundation Research Investigator Award (MAZ), Washington University School of Medicine Diabetes Research Center NIH/NIDDK P30 DK020589 (MAZ), NIH/NHLBI K08 HL132060 (MAZ), Nutrition Obesity Research Center NIH/NIDDK P30 DK056341 (BWP), and NIH/NIDDK R01 DK101392 (CFS). The Washington University School of Medicine Mass Spectrometry Facility is supported by US Public Health Service Grants P41-GM103422 and P60-DK-20579.