Fappi_2025_Cell.Rep.Med__102152

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.