DOCUMENT
DOCUMENT
1/1
CEPT1-Mediated Phospholipogenesis Regulates Endothelial Cell Function and Ischemia-Induced Angiogenesis Through PPARα
figure
posted on 2020-11-19, 16:09 authored by Ada AdminAda 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. SemenkovichDe 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.