Fappi Alan, Patterson Bruce W, Burks Kendal H, Davidson Nicholas O, Vaisar Tomas, Kanter Jenny E, Bornfeldt Karin E, Fisher Edward A, Goldberg Ira J, Stitziel Nathan O, Mittendorfer Bettina
Center for Human Nutrition, Washington University, St. Louis, MO, USA; Departments of Medicine and Nutrition & Exercise Physiology, University of Missouri School of Medicine, Columbia, MO, USA.
Center for Human Nutrition, Washington University, St. Louis, MO, USA.
Cell Rep Med. 2025 Jun 17;6(6):102152. doi: 10.1016/j.xcrm.2025.102152. Epub 2025 May 29.
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.
血管生成素样3（ANGPTL3）可抑制水解富含甘油三酯（TG）的脂蛋白（TRL）中甘油三酯的脂肪酶。我们在一项混合餐试验中评估了TRL-TG、TRL颗粒（载脂蛋白B）、棕榈酸酯和葡萄糖的动力学，该试验包括对具有极其罕见的复合杂合ANGTPL3功能丧失突变的人群（ANGPTL3组，n = 3）和匹配的对照参与者（n = 7）进行静脉和口服示踪剂给药。采用两步高胰岛素-正常血糖钳夹程序以及葡萄糖和棕榈酸酯示踪剂输注来评估多器官（肝脏、肌肉和脂肪组织）的胰岛素敏感性。我们发现，由于肝脏来源的TRL颗粒和TG分泌率显著降低，同时肝脏和肠道来源的TRL的血浆清除率增加，ANGPTL3组的血浆TG和TRL颗粒浓度比对照组低10倍以上。两组在餐试验期间的棕榈酸酯和葡萄糖动力学无差异。我们得出结论，ANGPTL3的生物学功能超出了抑制血管内脂肪酶活性的范围。
