Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5^–/– mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific mAbs, the binding of LPL Abs to heart and BAT capillaries (relative to CD31 or GPIHBP1 Abs) was reduced in Apoa5^–/– mice. LPL levels in the postheparin plasma were also lower in Apoa5^–/– mice. We suspected that a recent biochemical observation — that APOA5 binds to the ANGPTL3/8 complex and suppresses its capacity to inhibit LPL catalytic activity — could be related to the low intracapillary LPL levels in Apoa5^–/– mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in Apoa5^–/– mice. We also showed that ANGPTL3/8 detached LPL from heparan sulfate proteoglycans and GPIHBP1 on the surface of cells and that the LPL detachment was blocked by IBA490 and APOA5. Our studies explain the hypertriglyceridemia in Apoa5^–/– mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism.

中文翻译：

---

Apoa5–/– 小鼠的高甘油三酯血症是由于毛细血管腔中脂蛋白脂肪酶含量减少所致

为什么载脂蛋白 AV (APOA5) 缺乏会导致高甘油三酯血症仍不清楚，但我们怀疑根本原因是毛细血管中脂蛋白脂肪酶 (LPL) 的数量减少。通过常规免疫组织化学，我们观察到Apoa5 ^–/–小鼠心脏和棕色脂肪组织 (BAT) 毛细血管的 LPL 染色减少。此外，静脉注射 LPL、CD31 和 GPIHBP1 特异性单克隆抗体后， Apoa5 ^–/–小鼠中 LPL 抗体与心脏和 BAT 毛细血管的结合（相对于 CD31 或 GPIHBP1 抗体）减少。Apoa5 ^–/–小鼠肝素后血浆中的 LPL 水平也较低。我们怀疑最近的一项生化观察——APOA5 与 ANGPTL3/8 复合物结合并抑制其抑制 LPL 催化活性的能力——可能与Apoa5 ^–/–小鼠毛细血管内低 LPL 水平有关。我们发现 ANGPTL3/8 特异性单克隆抗体 (IBA490) 和 APOA5 可以使Apoa5 ^–/–小鼠的血浆甘油三酯 (TG) 水平和毛细血管内 LPL 水平正常化。我们还发现ANGPTL3/8使LPL与细胞表面的硫酸乙酰肝素蛋白聚糖和GPIHBP1分离，并且LPL分离被IBA490和APOA5阻断。我们的研究解释了Apoa5 ^–/–小鼠的高甘油三酯血症，并进一步阐明了调节血浆 TG 代谢的分子机制。