posted on 2020-11-19, 16:09authored byAda 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. 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.
Funding
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.