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

Abstract

BackgroundApolipoprotein 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.MethodsWe 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.ResultsCompared 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.ConclusionThese 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 registrationClinicalTrials.gov NCT04209816 and NCT01445730.FundingSwedish 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.

Keywords: Lipoproteins; Metabolism.

Figures

Figure 1. Enrichment curves for VLDL1, VLDL2, IDL, and LDL apoB100 in patients with APOC3 LOF variants and nonvariant carriers.

Tracer/tracee ratios (data points are means and vertical lines represent standard deviations) are presented for apoB100 in each lipoprotein density range. Time in hours is from tracer administration. Solid line refers to the mean of the model fits.

Figure 2. Postprandial lipemia responses in patients with APOC3 LOF variants and nonvariant carriers.

Data show the rise in plasma apoB48 and plasma TG after a standard fat-rich meal (data points are mean values and vertical bars present standard deviations). Time in hours is from tracer administration. The standard fat-rich meal was consumed at the 2-hour time point after tracer administration. Turquoise color refers to the nonvariant carrier group, and red color refers to the APOC3 LOF carriers.

Figure 3. Flowchart showing key kinetic parameter differences in APOC3 LOF carriers and nonvariant carriers.

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.