M Croyal1, Z Kaabia2, L León3, S Ramin-Mangata4, T Baty2, F Fall2, S Billon-Crossouard5, A Aguesse5, T Hollstein6, D R Sullivan7, E Nobecourt8, G Lambert9, M Krempf10. 1. INRA, UMR 1280, physiologie des adaptations nutritionnelles, 44000 Nantes, France; CRNHO, West human nutrition research center, CHU, 44000 Nantes, France. Electronic address: mikael.croyal@univ-nantes.fr. 2. CRNHO, West human nutrition research center, CHU, 44000 Nantes, France. 3. INRA, UMR 1280, physiologie des adaptations nutritionnelles, 44000 Nantes, France; Programa de Biotecnología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional, 06600 México City, Mexico. 4. INSERM, UMR 1188 DéTROI, 97400 Sainte-Clotilde, France; Faculté de médecine, université de La Réunion, 97400 Saint-Denis, France. 5. INRA, UMR 1280, physiologie des adaptations nutritionnelles, 44000 Nantes, France; CRNHO, West human nutrition research center, CHU, 44000 Nantes, France. 6. Interdisziplinäres Stoffwechsel Centrum Arbeitsbereich Lipidstoffwechsel, Charité Campus Wirchow Klinikum, 1000 Berlin, Germany. 7. The Royal Prince Alfred Hospital, 2006 Sydney, Australia. 8. INSERM, UMR 1188 DéTROI, 97400 Sainte-Clotilde, France; Faculté de médecine, université de La Réunion, 97400 Saint-Denis, France; CHU de la Réunion, 97400 Saint-Pierre, France. 9. INSERM, UMR 1188 DéTROI, 97400 Sainte-Clotilde, France; Faculté de médecine, université de La Réunion, 97400 Saint-Denis, France. Electronic address: gilles.lambert@univ-reunion.fr. 10. INRA, UMR 1280, physiologie des adaptations nutritionnelles, 44000 Nantes, France; CRNHO, West human nutrition research center, CHU, 44000 Nantes, France; Department of endocrinology, metabolic diseases and nutrition, G. and R. Laennec hospital, 44000 Nantes, France.
Abstract
AIM: The benefit of the lipid-lowering drug fenofibrate on cardiovascular outcomes is controversial. Our aim was to find new circulating markers to identify those patients most likely to benefit from fenofibrate prescription. METHODS: Analyses were conducted of plasma samples collected from 102 patients with type 2 diabetes, enrolled in the FIELD trial, before and afterfenofibrate treatment (200mg/day). Non-targeted and targeted lipid analyses and apolipoprotein measurements were made using mass spectrometry methods. RESULTS: Lipidomics revealed a global decrease in ceramide after fenofibrate treatment confirmed by quantitative analysis (-18.2%, P<0.001). These changes were strongly associated with those found for plasma sphingomyelin (r=0.80, P<0.001) and, to a lesser extent, for sphingosine-1-phosphate (r=0.34, P<0.001). Ceramide levels decreased in 73.5% of patients. In addition to the expected lipid changes (decreases in triglycerides, total cholesterol and LDL cholesterol, and increase in HDL cholesterol), fenofibrate also lowered plasma apoC-II (-11.1%, P<0.01), apoC-III (-24.6%; P<0.001), apoB100 (-27.0%, P<0.01) and sphingomyelinase (-7.6%, P<0.001), and increased plasma apoA-II (22.4%, P<0.001) as well as adiponectin (11.4%, P<0.001). No significant association was found between ceramide decrease and these modulations except for total cholesterol (r=0.20, P=0.047) and HDL protein components. At baseline, only elevated sphingolipid levels were significantly associated with ceramide reduction after fenofibrate treatment. CONCLUSION:Fenofibrate lowers plasma ceramide independently of the usual lipid parameters. As ceramide is a strong marker of atherosclerosis, our study underpins the need to further evaluate its contribution to cardiovascular events in fenofibrate-treated patients. Crown
RCT Entities:
AIM: The benefit of the lipid-lowering drug fenofibrate on cardiovascular outcomes is controversial. Our aim was to find new circulating markers to identify those patients most likely to benefit from fenofibrate prescription. METHODS: Analyses were conducted of plasma samples collected from 102 patients with type 2 diabetes, enrolled in the FIELD trial, before and after fenofibrate treatment (200mg/day). Non-targeted and targeted lipid analyses and apolipoprotein measurements were made using mass spectrometry methods. RESULTS: Lipidomics revealed a global decrease in ceramide after fenofibrate treatment confirmed by quantitative analysis (-18.2%, P<0.001). These changes were strongly associated with those found for plasma sphingomyelin (r=0.80, P<0.001) and, to a lesser extent, for sphingosine-1-phosphate (r=0.34, P<0.001). Ceramide levels decreased in 73.5% of patients. In addition to the expected lipid changes (decreases in triglycerides, total cholesterol and LDL cholesterol, and increase in HDL cholesterol), fenofibrate also lowered plasma apoC-II (-11.1%, P<0.01), apoC-III (-24.6%; P<0.001), apoB100 (-27.0%, P<0.01) and sphingomyelinase (-7.6%, P<0.001), and increased plasma apoA-II (22.4%, P<0.001) as well as adiponectin (11.4%, P<0.001). No significant association was found between ceramide decrease and these modulations except for total cholesterol (r=0.20, P=0.047) and HDL protein components. At baseline, only elevated sphingolipid levels were significantly associated with ceramide reduction after fenofibrate treatment. CONCLUSION:Fenofibrate lowers plasma ceramide independently of the usual lipid parameters. As ceramide is a strong marker of atherosclerosis, our study underpins the need to further evaluate its contribution to cardiovascular events in fenofibrate-treated patients. Crown
Authors: Andreas Hober; Fredrik Edfors; Maria Ryaboshapkina; Jonas Malmqvist; Louise Rosengren; Andrew J Percy; Lars Lind; Björn Forsström; Mathias Uhlén; Jan Oscarsson; Tasso Miliotis Journal: Mol Cell Proteomics Date: 2019-10-07 Impact factor: 5.911