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载脂蛋白 A5 基因敲除小鼠的高甘油三酯血症是由于毛细血管腔中脂蛋白脂酶含量减少所致。

Hypertriglyceridemia in Apoa5-/- mice results from reduced amounts of lipoprotein lipase in the capillary lumen.

机构信息

Department of Medicine and.

Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.

出版信息

J Clin Invest. 2023 Dec 1;133(23):e172600. doi: 10.1172/JCI172600.

DOI:10.1172/JCI172600
PMID:37824203
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10688983/
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

载脂蛋白 AV（APOA5）缺乏导致高甘油三酯血症的原因仍不清楚，但我们怀疑其根本原因是毛细血管中的脂蛋白脂肪酶（LPL）含量减少。通过常规免疫组织化学染色，我们观察到 Apoa5-/- 小鼠心脏和棕色脂肪组织（BAT）毛细血管中的 LPL 染色减少。此外，在静脉注射 LPL、CD31 和 GPIHBP1 特异性 mAb 后，LPL Ab 与心脏和 BAT 毛细血管的结合（相对于 CD31 或 GPIHBP1 Ab）在 Apoa5-/- 小鼠中减少。Apoa5-/- 小鼠肝素后血浆中的 LPL 水平也较低。我们怀疑最近的生化观察结果——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 LPL 水平低有关。我们表明，一种 ANGPTL3/8 特异性 mAb（IBA490）和 APOA5 可使 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。我们还表明，ANGPTL3/8 将 LPL 从细胞表面的肝素硫酸蛋白聚糖和 GPIHBP1 上脱离，IBA490 和 APOA5 可阻止 LPL 脱离。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。

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