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.
Chronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease. It is estimated that 60% of all nontraumatic lower-extremity amputations performed annually in the United States are in patients with diabetes and CLTI. The consequences of this condition are extraordinary, with substantial patient morbidity and mortality and high socioeconomic costs. Strategies that optimize the success of arterial revascularization in this unique patient population can have a substantial public health impact and improve patient outcomes. This article provides an up-to-date comprehensive assessment of management strategies for patients afflicted by both diabetes and CLTI.
<i>De novo</i> 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).<b> </b>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 <i>Cept1</i> in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of <i>Cept1</i> via induced <i>VE-cadherin-CreERT2 </i>mediated recombination (<i>Cept1Lp/LpCre+</i>). <i>Cept1Lp/LpCre+</i> ECs demonstrated decreased proliferation, migration, and tubule formation, and <i>Cept1Lp/LpCre+</i> 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. <i>Cept1</i> esiRNA decreased PPARα-phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike <i>Cept1Lp/LpCre+</i>, <i>Cept1Lp/LpCre+Ppara-/-</i> mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate.<b> </b>Therefore we demonstrate that CEPT1 is essential for EC function and tissue recovery following ischemia, and that fenofibrate rescues CEPT1-mediated activation of PPARα.
Fenofibrate, a proliferator-activated receptor (PPAR)α agonist, is the only oral medication demonstrated to prevent lower extremity amputations in diabetic patients. Phosphatidylcholines, generated by choline-ethanolamine phosphotransferase 1 (CEPT1) via the Kennedy Pathway, also induce PPARα activation, but their metabolism is altered in the setting of diabetes. It is unknown whether CEPT1 is essential for fenofibrate-mediated endothelial cell (EC) function. To evaluate this, we generated a murine model for conditional knockdown of Cept1 in the endothelium ( Cept1EC KO). Heart ECs (MHECs) were harvested from 6wk old Cept1EC KO and wildtype (WT) littermates, and cultured in vitro on growth factor-reduced Matrigel. Cultures were then supplemented with VEGF (50ng/mL), bFGF (50ng/mL), and fenofibrate (25uM), then assessed longitudinally at 0, 4, and 6 hours. We observed that compared to WT, Cept1EC KO MHECs had significantly less tubule formation (p < 0.0001). VEGF and bFGF failed to rescue Cept1EC KO MHECs, but demonstrated a robust agonist response in WT MHECs (bFGF: p=0.003; VEGF: p=0.0002). Interestingly, fenofibrate demonstrated complete rescue of Cept1EC KO MHECs at 4 and 6 hours of culture. This finding demonstrates that fenofibrate restores EC function even in the setting of impaired phospholipid biosynthesis. This observation may partially explain how fenofibrate confers added benefits in subjects with diabetic and peripheral arterial disease. Future work will further elucidate this mechanism of action in diabetic subjects.
<i>De novo</i> 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).<b> </b>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 <i>Cept1</i> in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of <i>Cept1</i> via induced <i>VE-cadherin-CreERT2 </i>mediated recombination (<i>Cept1Lp/LpCre+</i>). <i>Cept1Lp/LpCre+</i> ECs demonstrated decreased proliferation, migration, and tubule formation, and <i>Cept1Lp/LpCre+</i> 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. <i>Cept1</i> esiRNA decreased PPARα-phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike <i>Cept1Lp/LpCre+</i>, <i>Cept1Lp/LpCre+Ppara-/-</i> mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate.<b> </b>Therefore we demonstrate that CEPT1 is essential for EC function and tissue recovery following ischemia, and that fenofibrate rescues CEPT1-mediated activation of PPARα.
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