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Pathophysiology

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

  1. Mohamed A. Zayed1,2,3,4⇑,
  2. Xiaohua Jin1,
  3. Chao Yang1,
  4. Larisa Belaygorod1,
  5. Connor Engel1,
  6. Kshitij Desai1,
  7. Nikolai Harroun1,
  8. Omar Saffaf1,
  9. Bruce W. Patterson5,
  10. Fong-Fu Hsu6 and
  11. Clay F. Semenkovich6
  1. 1Section of Vascular Surgery, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO
  2. 2Division of Molecular Cell Biology, Washington University School of Medicine in St. Louis, St. Louis, MO
  3. 3Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO
  4. 4VA St. Louis Health Care System, St. Louis, MO
  5. 5Center for Human Nutrition, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO
  6. 6Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO
  1. Corresponding author: Mohamed A. Zayed, zayedm{at}wustl.edu
Diabetes 2021 Feb; 70(2): 549-561. https://doi.org/10.2337/db20-0635
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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 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 endoribonuclease-prepared siRNA decreased PPARα phosphorylation 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.

Footnotes

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.13229129.

  • Received June 15, 2020.
  • Accepted November 12, 2020.
  • © 2020 by the American Diabetes Association
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CEPT1-Mediated Phospholipogenesis Regulates Endothelial Cell Function and Ischemia-Induced Angiogenesis Through PPARα
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
Diabetes Feb 2021, 70 (2) 549-561; DOI: 10.2337/db20-0635

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CEPT1-Mediated Phospholipogenesis Regulates Endothelial Cell Function and Ischemia-Induced Angiogenesis Through PPARα
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
Diabetes Feb 2021, 70 (2) 549-561; DOI: 10.2337/db20-0635
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