Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans
The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, th...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227522001493 |
| _version_ | 1797944111170322432 |
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| author | Mathieu R. Brodeur David Rhainds Daniel Charpentier Marie Boulé Téodora Mihalache-Avram Mélanie Mecteau Geneviève Brand Valérie Pedneault-Gagnon Annik Fortier Eric J. Niesor Eric Rhéaume Cyrille Maugeais Jean-Claude Tardif |
| author_facet | Mathieu R. Brodeur David Rhainds Daniel Charpentier Marie Boulé Téodora Mihalache-Avram Mélanie Mecteau Geneviève Brand Valérie Pedneault-Gagnon Annik Fortier Eric J. Niesor Eric Rhéaume Cyrille Maugeais Jean-Claude Tardif |
| author_sort | Mathieu R. Brodeur |
| collection | DOAJ |
| description | The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport. |
| first_indexed | 2024-04-10T20:34:30Z |
| format | Article |
| id | doaj.art-f4c2963532d24b62b4094a8ce7f0e3c8 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-04-10T20:34:30Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-f4c2963532d24b62b4094a8ce7f0e3c82023-01-25T04:14:40ZengElsevierJournal of Lipid Research0022-22752023-01-01641100316Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humansMathieu R. Brodeur0David Rhainds1Daniel Charpentier2Marie Boulé3Téodora Mihalache-Avram4Mélanie Mecteau5Geneviève Brand6Valérie Pedneault-Gagnon7Annik Fortier8Eric J. Niesor9Eric Rhéaume10Cyrille Maugeais11Jean-Claude Tardif12Montreal Heart Institute, Montreal, Quebec, CanadaMontreal Heart Institute, Montreal, Quebec, CanadaMontreal Heart Institute, Montreal, Quebec, CanadaMontreal Heart Institute, Montreal, Quebec, CanadaMontreal Heart Institute, Montreal, Quebec, CanadaMontreal Heart Institute, Montreal, Quebec, CanadaMontreal Heart Institute, Montreal, Quebec, CanadaMontreal Heart Institute, Montreal, Quebec, CanadaMontreal Health Innovations Coordinating Center, Montreal, Quebec, CanadaF. Hoffmann-La Roche Ltd., Basel, SwitzerlandMontreal Heart Institute, Montreal, Quebec, Canada; Faculty of Medicine, Université de Montréal, Montreal, Quebec, CanadaF. Hoffmann-La Roche Ltd., Basel, SwitzerlandMontreal Heart Institute, Montreal, Quebec, Canada; Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; For correspondence: Jean-Claude TardifThe large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport.http://www.sciencedirect.com/science/article/pii/S0022227522001493CETPcholesteryl ester transfer protein inhibitorsapolipoprotein compositionlow-density lipoprotein receptoratorvastatindal-PLAQUE-2 study |
| spellingShingle | Mathieu R. Brodeur David Rhainds Daniel Charpentier Marie Boulé Téodora Mihalache-Avram Mélanie Mecteau Geneviève Brand Valérie Pedneault-Gagnon Annik Fortier Eric J. Niesor Eric Rhéaume Cyrille Maugeais Jean-Claude Tardif Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans Journal of Lipid Research CETP cholesteryl ester transfer protein inhibitors apolipoprotein composition low-density lipoprotein receptor atorvastatin dal-PLAQUE-2 study |
| title | Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans |
| title_full | Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans |
| title_fullStr | Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans |
| title_full_unstemmed | Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans |
| title_short | Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans |
| title_sort | dalcetrapib and anacetrapib increase apolipoprotein e containing hdl in rabbits and humans |
| topic | CETP cholesteryl ester transfer protein inhibitors apolipoprotein composition low-density lipoprotein receptor atorvastatin dal-PLAQUE-2 study |
| url | http://www.sciencedirect.com/science/article/pii/S0022227522001493 |
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