Plasma kinetics of apoC-III and apoE in normolipidemic and hypertriglyceridemic subjects

Rami Batal,Michel Tremblay,P Hugh R Barrett,Hélène Jacques,Alexandre Fredenrich,Orval Mamer,Jean Davignon,Jeffrey S Cohn

doi:10.1016/s0022-2275(20)32379-8

Rami Batal, Michel Tremblay + Show 6 more

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https://doi.org/10.1016/s0022-2275(20)32379-8

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Abstract

Apolipoprotein (apo) C-III and apoE play a central role in controlling the plasma metabolism of triglyceride-rich lipoproteins (TRL). We have investigated the plasma kinetics of total, very low density lipoprotein (VLDL) and high density lipoprotein (HDL) apoC-III and apoE in normolipidemic (NL) (n = 5), hypertriglyceridemic (HTG, n = 5), and Type III hyperlipoproteinemic (n = 2) individuals. Apolipoprotein kinetics were investigated using a primed constant (12 h) infusion of deuterium-labeled leucine. HTG and Type III patients had reduced rates of VLDL apoB-100 catabolism and no evidence of VLDL apoB-100 overproduction. Elevated (3- to 12-fold) total plasma and VLDL apoC-III levels in HTG and Type III patients, although associated with reduced apoC-III catabolism (i.e., increased residence times (RTs)), were mainly due to increased apoC-III production (plasma apoC-III transport rates (TRs, mean ± SEM): (NL) 2.05 ± 0.22 (HTG) 4.90 ± 0.81 (P < 0.01), and (Type III) 8.78 mg·kg−1·d−1; VLDL apoC-III TRs: (NL) 1.35 ± 0.23 (HTG) 5.35 ± 0.85 (P < 0.01), and (Type III) 7.40 mg·kg−1·d−1). Elevated total plasma and VLDL apoE levels in HTG (2- and 6-fold, respectively) and in Type III (9- and 43-fold) patients were associated with increased VLDL apoE RTs (0.21 ± 0.02, 0.46 ± 0.05 (P < 0.01), and 1.21 days, NL vs. HTG vs. Type III, respectively), as well as significantly increased apoE TRs (plasma: (NL) 2.94 ± 0.78 (HTG) 5.80 ± 0.59 (P < 0.01) and (Type III) 11.80 mg·kg−1·d−1; VLDL: (NL) 1.59 ± 0.18 (HTG) 4.52 ± 0.61 (P < 0.01) and (Type III) 11.95 mg·kg−1·d−1).These results demonstrate that hypertriglyceridemic patients, having reduced VLDL apoB-100 catabolism (including patients with type III hyperlipoproteinemia) are characterized by overproduction of plasma and VLDL apoC-III and apoE.—Batal, R., M. Tremblay, P. H. R. Barrett, H. Jacques, A. Fredenrich, O. Mamer, J. Davignon, and J. S. Cohn. Plasma kinetics of apoC-III and apoE in normolipidemic and hypertriglyceridemic subjects. J. Lipid Res. 2000. 41: 706–718.

Highlights

ApoC-III and apoE are proteins that play a central role in controlling the plasma metabolism of triglyceride-rich lipoproteins (TRL)
Total plasma apoC-III transport rate (TR) were 2-fold higher and very low density lipoprotein (VLDL) apoC-III TRs were 4-fold higher in HTG compared to NL subjects, whereas there was no significant difference in apoC-III Residence time (RT) (Table 3)
VLDL apoC-III and apoE overproduction was a characteristic feature of these hypertriglyceridemic patients, which occurred in the absence of increased VLDL apoB-100 production (Table 2)

Summary

Introduction

ApoC-III and apoE are proteins that play a central role in controlling the plasma metabolism of triglyceride-rich lipoproteins (TRL). The importance of apoC-III in regulating plasma TRL metabolism is demonstrated by the fact that: 1) in the general population, total plasma triglyceride levels are strongly correlated with the concentration of total plasma and TRL apoC-III [4]; 2) individuals with certain apoC-III gene polymorphisms have increased susceptibility to hypertriglyceridemia [5,6,7]; 3) patients with an inherited deficiency of apoC-III have low plasma triglyceride levels [8, 9]; 4) overexpression of the human apoC-III gene in transgenic mice results in hypertriglyceridemia [10], whereas apoC-III gene knockout mice are hypotriglyceridemic [11]; and 5) in vitro evidence demonstrates that apoC-III has the capacity to inhibit: a) the activity of lipoprotein lipase (LPL) [12], b) the capacity of TRL to bind to LPL [13], and c) the uptake of TRL by the liver [14] through reduced binding of TRL and their remnants to the LDL receptor (LDL-R) [15], the lipolysis-stimulated receptor (LSR) [16], and cell-surface glycosaminoglycans [17], (though not the LDL receptor-related protein (LRP) [18]). Our objective was to determine whether increased levels of plasma apoC-III and apoE in HTG and Type III patients (both having increased levels of very low density lipoprotein (VLDL) apoB-100, due to reduced rates of VLDL apoB-100 catabolism) were due to an increase in their rates of apoC-III and apoE production or a decrease in their rates of catabolism

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