Postprandial metabolism of apolipoproteins B48, B100, C-III, and E in humans with APOC3 loss-of-function mutations
Marja-Riitta Taskinen, Elias Björnson, Niina Matikainen, Sanni Söderlund, Joel Rämö, Mari-Mia Ainola, Antti Hakkarainen, Carina Sihlbom, Annika Thorsell, Linda Andersson, Per-Olof Bergh, Marcus Henricsson, Stefano Romeo, Martin Adiels, Samuli Ripatti, Markku Laakso, Chris J. Packard, Jan Borén
Marja-Riitta Taskinen, Elias Björnson, Niina Matikainen, Sanni Söderlund, Joel Rämö, Mari-Mia Ainola, Antti Hakkarainen, Carina Sihlbom, Annika Thorsell, Linda Andersson, Per-Olof Bergh, Marcus Henricsson, Stefano Romeo, Martin Adiels, Samuli Ripatti, Markku Laakso, Chris J. Packard, Jan Borén
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Clinical Research and Public Health Metabolism

Postprandial metabolism of apolipoproteins B48, B100, C-III, and E in humans with APOC3 loss-of-function mutations

Abstract

Background Apolipoprotein C-III (apoC-III) is a regulator of triglyceride (TG) metabolism, and due to its association with risk of cardiovascular disease, is an emergent target for pharmacological intervention. The impact of substantially lowering apoC-III on lipoprotein metabolism is not clear.Methods We investigated the kinetics of apolipoproteins B48 and B100 (apoB48 and apoB100) in chylomicrons, VLDL1, VLDL2, IDL, and LDL in patients heterozygous for a loss-of-function (LOF) mutation in the APOC3 gene. Studies were conducted in the postprandial state to provide a more comprehensive view of the influence of this protein on TG transport.Results Compared with non-LOF variant participants, a genetically determined decrease in apoC-III resulted in marked acceleration of lipolysis of TG-rich lipoproteins (TRLs), increased removal of VLDL remnants from the bloodstream, and substantial decrease in circulating levels of VLDL1, VLDL2, and IDL particles. Production rates for apoB48-containing chylomicrons and apoB100-containing VLDL1 and VLDL2 were not different between LOF carriers and noncarriers. Likewise, the rate of production of LDL was not affected by the lower apoC-III level, nor were the concentration and clearance rate of LDL-apoB100.Conclusion These findings indicate that apoC-III lowering will have a marked effect on TRL and remnant metabolism, with possibly significant consequences for cardiovascular disease prevention.Trial registration ClinicalTrials.gov NCT04209816 and NCT01445730.Funding Swedish Heart-Lung Foundation, Swedish Research Council, ALF grant from the Sahlgrenska University Hospital, Novo Nordisk Foundation, Sigrid Juselius Foundation, Helsinki University Hospital Government Research funds, Finnish Heart Foundation, and Finnish Diabetes Research Foundation.

Authors

Marja-Riitta Taskinen, Elias Björnson, Niina Matikainen, Sanni Söderlund, Joel Rämö, Mari-Mia Ainola, Antti Hakkarainen, Carina Sihlbom, Annika Thorsell, Linda Andersson, Per-Olof Bergh, Marcus Henricsson, Stefano Romeo, Martin Adiels, Samuli Ripatti, Markku Laakso, Chris J. Packard, Jan Borén

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Figure 3

Flowchart showing key kinetic parameter differences in APOC3 LOF carriers and nonvariant carriers.

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Flowchart showing key kinetic parameter differences in APOC3 LOF carrier...
Data are mean values for each group of patients. Production rates are given in mg/d and FTRs and FDCRs in pools/d. The plasma pool of each apoB100-containing lipoprotein class (VLDL1, VLDL2, IDL, and LDL) is given (mg) within the appropriate circle. ApoB48 and apoB100 kinetic rate constants are in upright text; kinetic rate constants for TG are in italics. The mean transit time was calculated as the sum of the residence times for VLDL1, VLDL2, and IDL apoB-containing particles. Residence time is the reciprocal of the overall FCR; e.g., for VLDL1 apoB100 in nonvariant carriers the FCR is 13.1 pools/24 hours (Table 2), which gives a residence time of 24/13.1 = 1.83 hours. Asterisks indicate significant differences between APOC3 LOF variants versus nonvariant carriers. P values are from group comparison using Mann-Whitney U test.