Abstract：
Apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia in mice and humans. For years, the cause remained a mystery, but the mechanisms have now come into focus. Here, we review progress in defining APOA5\'s function in plasma triglyceride metabolism. Biochemical studies revealed that APOA5 binds to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppresses its ability to inhibit the activity of lipoprotein lipase (LPL). Thus, APOA5 deficiency is accompanied by increased ANGPTL3/8 activity and lower levels of LPL activity. APOA5 deficiency also reduces amounts of LPL in capillaries of oxidative tissues (e.g., heart, brown adipose tissue). Cell culture experiments revealed the likely explanation: ANGPTL3/8 detaches LPL from its binding sites on the surface of cells, and that effect is blocked by APOA5. Both the low intracapillary LPL levels and the high plasma triglyceride levels in Apoa5-/- mice are normalized by recombinant APOA5. Carboxyl-terminal sequences in APOA5 are crucial for its function; a mutant APOA5 lacking 40-carboxyl-terminal residues cannot bind to ANGPTL3/8 and lacks the ability to change intracapillary LPL levels or plasma triglyceride levels in Apoa5-/- mice. Also, an antibody against the last 26 amino acids of APOA5 reduces intracapillary LPL levels and increases plasma triglyceride levels in wild-type mice. An inhibitory ANGPTL3/8-specific antibody functions as an APOA5-mimetic reagent, increasing intracapillary LPL levels and lowering plasma triglyceride levels in both Apoa5-/- and wild-type mice. That antibody is a potentially attractive strategy for treating elevated plasma lipid levels in human patients.
摘要：
载脂蛋白AV(APOA5)缺乏导致小鼠和人的高甘油三酯血症。多年来,原因仍然是个谜,但是这些机制现在已经成为焦点。这里,我们综述了APOA5在血浆甘油三酯代谢中功能的定义进展。生化研究表明，APOA5与血管生成素样蛋白3/8复合物（ANGPTL3/8）结合，并抑制其抑制脂蛋白脂肪酶（LPL）活性的能力。因此，APOA5缺乏伴随着增加的ANGPTL3/8活性和较低水平的LPL活性。APOA5缺乏也会降低氧化组织毛细血管中LPL的含量(例如，心,棕色脂肪组织）。细胞培养实验揭示了可能的解释：ANGPTL3/8将LPL从其在细胞表面的结合位点上分离，这种影响被APOA5阻止了。Apoa5-/-小鼠的低毛细管内LPL水平和高血浆甘油三酯水平均通过重组APOA5标准化。APOA5中的羧基末端序列对于其功能至关重要；缺少40个羧基末端残基的突变APOA5不能结合ANGPTL3/8，并且缺乏改变Apoa5-/-小鼠中毛细血管内LPL水平或血浆甘油三酯水平的能力。此外，在野生型小鼠中,针对APOA5最后26个氨基酸的抗体可降低毛细血管内LPL水平并增加血浆甘油三酯水平.抑制性ANGPTL3/8特异性抗体作为APOA5模拟试剂，在Apoa5-/-和野生型小鼠中增加毛细管内LPL水平并降低血浆甘油三酯水平。该抗体是治疗人类患者血浆脂质水平升高的潜在有吸引力的策略。
