Effect of complete, lifelong ANGPTL3 deficiency on triglyceride-rich lipoprotein kinetics

Abstract

Angiopoietin-like 3 (ANGPTL3) inhibits lipases that hydrolyze triglycerides (TGs) in TG-rich lipoproteins (TRLs). We evaluated TRL-TGs, TRL particle (apolipoprotein B), palmitate, and glucose kinetics during a mixed-meal test that included intravenous and oral tracer administrations in people with extremely rare compound heterozygous ANGTPL3 loss-of-function mutations (ANGPTL3^-/- group, n = 3) and matched control participants (n = 7). Multi-organ (liver, muscle, and adipose tissue) insulin sensitivity was evaluated with a two-step hyperinsulinemic-euglycemic clamp procedure and glucose and palmitate tracer infusions. We find that plasma TG and TRL particle concentrations are more than 10-fold lower in the ANGPTL3^-/- than in the control group due to both markedly reduced liver-derived TRL particle and TG secretion rates combined with increased plasma clearance of both liver- and gut-derived TRLs. Palmitate and glucose kinetics during the meal test are not different between the groups. We conclude that the biological function of ANGPTL3 reaches beyond inhibiting intravascular lipase activity.

Keywords: ANGPTL3; TG secretion; angiopoietin; hypolipidemia; lipoprotein kinetics; lipoprotein turnover; plasma TG clearance.

Graphical abstract

Figure 1

Outline of the study protocols (A) Mixed-meal test with tracers administered intravenously and orally, as part of the meal that served as the first meal during the 24-h metabolic profiling protocol. (B) Two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with tracer infusions. Both the meal test and the clamp procedure were initiated in the morning after participants fasted overnight. Abbreviation: BSA, body surface area.

Figure 2

Basal lipoprotein particle size profile (A–E) Basal (overnight fasted condition) particle concentrations, assessed by using differential ion mobility analysis, in the ANGPTL3^−/− group (n = 3) and the control group (n = 3). Data are shown as mean ± SEM (bars and error bars) values for each group and individual participants’ values (circles). Abbreviations: ANGPTL, angiopoietin-like protein; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; TRL, triglyceride-rich lipoprotein; VLDL, very low-density lipoprotein.

Figure 3

Triglyceride-rich lipoprotein triglyceride and apolipoprotein concentrations during the mixed-meal test Triglyceride concentration in the chylomicron (A) and total triglyceride-rich lipoprotein (B) fraction, apolipoprotein B-48 concentration in the chylomicron (C) and total triglyceride-rich lipoprotein (D) fraction, and apoB-100 in the total triglyceride-rich lipoprotein fraction (E) in the ANGPTL3^−/− group (n = 3) and the control group (n = 7) immediately before starting the meal (time = 0) and for 300 min after ingesting the meal. Circles and vertical bars represent mean ± SEM for each group. Abbreviations: apo, apolipoprotein; ANGPTL, angiopoietin-like protein; TG, triglyceride; TRL, triglyceride-rich lipoprotein.

Figure 4

Lipid kinetics during the mixed-meal test Plasma palmitate concentration (A) and appearance rate in the systemic circulation (B), triglyceride enrichment with the intravenously infused palmitate tracer in the chylomicron (C) and total triglyceride-rich lipoprotein (D) fractions, triglyceride enrichment with the orally administered palmitate (tripalmitin) tracer in the chylomicron (E) and total triglyceride-rich lipoprotein (F) fractions immediately before starting the meal (time = 0) and for 300 min after ingesting the meal, and the average proportion of total palmitate in triglycerides in the chylomicron (G) and total triglyceride-rich lipoprotein (H) fractions that was derived from meal palmitate in the ANGPTL3^−/− group (n = 3) and the control group (n = 7). Circles and vertical bars represent mean ± SEM for each group. Abbreviations: ANGPTL, angiopoietin-like protein; Ra, rate of appearance; TG, triglyceride; TRL, triglyceride-rich lipoprotein; TTR, tracer-to-tracee ratio.