Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E[S]
Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-06-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520310130 |
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| author | John S. Millar Michael E. Lassman Tiffany Thomas Rajasekhar Ramakrishnan Patricia Jumes Richard L. Dunbar Emil M. deGoma Amanda L. Baer Wahida Karmally Daniel S. Donovan Hashmi Rafeek John A. Wagner Stephen Holleran Joseph Obunike Yang Liu Soumia Aoujil Taylor Standiford David E. Gutstein Henry N. Ginsberg Daniel J. Rader Gissette Reyes-Soffer |
| author_facet | John S. Millar Michael E. Lassman Tiffany Thomas Rajasekhar Ramakrishnan Patricia Jumes Richard L. Dunbar Emil M. deGoma Amanda L. Baer Wahida Karmally Daniel S. Donovan Hashmi Rafeek John A. Wagner Stephen Holleran Joseph Obunike Yang Liu Soumia Aoujil Taylor Standiford David E. Gutstein Henry N. Ginsberg Daniel J. Rader Gissette Reyes-Soffer |
| author_sort | John S. Millar |
| collection | DOAJ |
| description | Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; P = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; P = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; P = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR. |
| first_indexed | 2024-12-14T03:16:04Z |
| format | Article |
| id | doaj.art-519f42374d614106b1158dd25fc71604 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-14T03:16:04Z |
| publishDate | 2017-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-519f42374d614106b1158dd25fc716042022-12-21T23:19:07ZengElsevierJournal of Lipid Research0022-22752017-06-0158612141220Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E[S]John S. Millar0Michael E. Lassman1Tiffany Thomas2Rajasekhar Ramakrishnan3Patricia Jumes4Richard L. Dunbar5Emil M. deGoma6Amanda L. Baer7Wahida Karmally8Daniel S. Donovan9Hashmi Rafeek10John A. Wagner11Stephen Holleran12Joseph Obunike13Yang Liu14Soumia Aoujil15Taylor Standiford16David E. Gutstein17Henry N. Ginsberg18Daniel J. Rader19Gissette Reyes-Soffer20To whom correspondence should be addressed. J.S.M.); (G.R.-S.); University of Pennsylvania, Philadelphia, PA 19104Merck & Co., Inc., Kenilworth, NJ 07033Columbia University, New York, NY 10032Columbia University, New York, NY 10032Merck & Co., Inc., Kenilworth, NJ 07033University of Pennsylvania, Philadelphia, PA 19104University of Pennsylvania, Philadelphia, PA 19104University of Pennsylvania, Philadelphia, PA 19104Columbia University, New York, NY 10032Columbia University, New York, NY 10032University of Pennsylvania, Philadelphia, PA 19104Merck & Co., Inc., Kenilworth, NJ 07033Columbia University, New York, NY 10032New York City College of Technology, CUNY, Brooklyn, NY 11201Merck & Co., Inc., Kenilworth, NJ 07033University of Pennsylvania, Philadelphia, PA 19104University of Pennsylvania, Philadelphia, PA 19104Merck & Co., Inc., Kenilworth, NJ 07033Columbia University, New York, NY 10032University of Pennsylvania, Philadelphia, PA 19104To whom correspondence should be addressed. J.S.M.); (G.R.-S.); Columbia University, New York, NY 10032Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; P = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; P = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; P = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR.http://www.sciencedirect.com/science/article/pii/S0022227520310130lipoprotein metabolismplasma lipid transfer proteinsdrug therapykineticsstatinscholesteryl ester transfer protein |
| spellingShingle | John S. Millar Michael E. Lassman Tiffany Thomas Rajasekhar Ramakrishnan Patricia Jumes Richard L. Dunbar Emil M. deGoma Amanda L. Baer Wahida Karmally Daniel S. Donovan Hashmi Rafeek John A. Wagner Stephen Holleran Joseph Obunike Yang Liu Soumia Aoujil Taylor Standiford David E. Gutstein Henry N. Ginsberg Daniel J. Rader Gissette Reyes-Soffer Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E[S] Journal of Lipid Research lipoprotein metabolism plasma lipid transfer proteins drug therapy kinetics statins cholesteryl ester transfer protein |
| title | Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E[S] |
| title_full | Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E[S] |
| title_fullStr | Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E[S] |
| title_full_unstemmed | Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E[S] |
| title_short | Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E[S] |
| title_sort | effects of cetp inhibition with anacetrapib on metabolism of vldl tg and plasma apolipoproteins c ii c iii and e s |
| topic | lipoprotein metabolism plasma lipid transfer proteins drug therapy kinetics statins cholesteryl ester transfer protein |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520310130 |
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