PDF(Pubmed)
Abstract：
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.
摘要：
为什么载脂蛋白AV（APOA5）缺乏导致高甘油三酯血症仍不清楚，但是我们怀疑根本原因是毛细血管中脂蛋白脂肪酶（LPL）的减少。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-后，CD31-,和GPIHBP1特异性单克隆抗体，在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-/-小鼠血浆中的LPL水平也较低。我们怀疑最近的生化观察-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-/-小鼠的低毛细管内LPL水平有关。我们表明，ANGPTL3/8特异性单克隆抗体（IBA490）和APOA5使Apoa5-/-小鼠的血浆甘油三酯水平和毛细血管内LPL水平正常化。我们还表明，ANGPTL3/8使LPL与细胞表面的HSPG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甘油三酯代谢的分子机制。
