TY - JOUR
T1 - CEPT1-Mediated Phospholipogenesis Regulates Endothelial Cell Function and Ischemia-Induced Angiogenesis Through PPARα
AU - Zayed, Mohamed A.
AU - Jin, Xiaohua
AU - Yang, Chao
AU - Belaygorod, Larisa
AU - Engel, Connor
AU - Desai, Kshitij
AU - Harroun, Nikolai
AU - Saffaf, Omar
AU - Patterson, Bruce W.
AU - Hsu, Fong Fu
AU - Semenkovich, Clay F.
N1 - Funding Information:
Acknowledgments. The authors thank Amanda Penrose, Section of Vascular Surgery at Washington University, for assistance with collection, preparation, and processing of Biobank Core Facility research samples and Susan Grathwohl, Section of Vascular Surgery at Washington University, for mouse colony maintenance and independent review of peripheral murine angiograms. The authors thank Dr. Chenglong Li, Section of Vascular Surgery at Washington University, for assistance with Ppara−/−murine HLI operations. VE-Cadherin-CreERT2 mice were a gift from the laboratory of Dr. Ralf Adams, Max Planck Institute for Molecular Biomedicine, Germany. The authors also thank Dr. Xiaochao Wei, Division of Endocrinology, Metabolism, and Lipid Research at Washington University, and Dr. Rithwick Rajagopal, Division of Endocrinology, Metabolism, and Lipid Research at Washington University, for their critical suggestions and critiques. Funding. This work was supported by the Washington University School of Medicine Vascular Surgery Biobank Core Facility and by the Vascular Cures Foundation Wylie Scholar Award (M.A.Z.), the American Surgical Association Research Fellowship Award (M.A.Z.), the Society for Vascular Surgery Foundation Research Investigator Award (M.A.Z.), Washington University School of Medicine Diabetes Research Center National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants P30 DK020589 (M.A.Z.), NIH/National Heart, Lung, and Blood Institute grant K08 HL132060 (M.A.Z.), Nutrition Obesity Research Center NIH/NIDDK grant P30 DK056341 (B.W.P.), and NIH/NIDDK grant R01 DK101392 (C.F.S.). The Washington University School of Medicine Mass Spectrometry Facility is supported by U.S. Public Health Service grants P41-GM103422 and P60-DK-20579. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. M.A.Z. and C.F.S. were responsible for conception and design. M.A.Z., X.J., C.Y., L.B., K.D., N.H., O.S., B.W.P., and C.F.S. analyzed and interpreted data. X.J., C.Y., L.B., K.D., N.H., O.S., B.W.P., and F.-F.H. collected data. M.A.Z., X.J., and C.F.S. wrote the manuscript. M.A.Z. and C.F.S. critically revised the manuscript. M.A.Z., X.J., C.Y., L.B., K.D., N.H., O.S., B.W.P., F.-F.H., and C.F.S. provided final approval of the manuscript. M.A.Z., X.J., C.Y., K.D., and C.F.S. performed statistical analysis. M.A.Z. obtained funding and had overall responsibility. C.E. contributed to analysis and interpretation, collection of data, and provided final approval of the manuscript. M.A.Z. is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2020 by the American Diabetes Association.
PY - 2021/2
Y1 - 2021/2
N2 - 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 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 were further compromised by streptozotocin-induced diabetes and ameliorated by feeding fenofibrate. Cept1 endoribo-nuclease-prepared siRNA decreased PPARα phosphor-ylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike Cept1Lp/LpCre+ mice, 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 after ischemia and that fenofibrate rescues CEPT1-mediated activation of PPARα.
AB - 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 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 were further compromised by streptozotocin-induced diabetes and ameliorated by feeding fenofibrate. Cept1 endoribo-nuclease-prepared siRNA decreased PPARα phosphor-ylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike Cept1Lp/LpCre+ mice, 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 after ischemia and that fenofibrate rescues CEPT1-mediated activation of PPARα.
UR - http://www.scopus.com/inward/record.url?scp=85100279595&partnerID=8YFLogxK
U2 - 10.2337/DB20-0635
DO - 10.2337/DB20-0635
M3 - Article
C2 - 33214136
AN - SCOPUS:85100279595
SN - 0012-1797
VL - 70
SP - 549
EP - 561
JO - Diabetes
JF - Diabetes
IS - 2
ER -