Heparin binding triggers human VLDL remodeling by circulating lipoprotein lipase: Relevance to VLDL functionality in health and disease.
Heparin binding triggers human VLDL remodeling by circulating lipoprotein lipase: Relevance to VLDL functionality in health and disease.
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DOI：
10.1016/j.bbalip.2021.159064
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Gursky O
中科院分区：
文献类型：
--
作者：
Jayaraman S;Pérez A;Miñambres I;Sánchez-Quesada JL;Gursky O
脂蛋白脂酶（LpL）水解VLDL三酰甘油（TG）是能量代谢和VLDL向LDL成熟的重要步骤。大多数功能性LpL锚定在血管内皮上，但少量在富含TG的脂蛋白上循环。由于循环LpL具有低催化活性，其在VLDL重构中的作用尚不清楚。我们使用前肝素血浆和肝素琼脂糖亲和层析分离VLDL组分从血脂正常，高脂血症，或2型糖尿病受试者。仅在肝素结合部分中检测到LpL。与肝素的瞬时结合激活了这种VLDL相关的LpL，其水解TG，导致VLDL逐渐重塑为IDL/LDL和HDL大小的颗粒。这种重塑的产物和时间表与体内VLDL至LDL成熟非常相似。重要的是，不结合肝素的VLDL部分不被重塑。这种相对惰性的无LpL的VLDL富含TG和apoC-III，缺乏apoE和apoC-II，显示出作为外源性LpL或CETP的底物的功能受损，并且可能在血液中具有延长的停留时间，这预期会促进动脉粥样硬化形成。这种未结合的VLDL分数在高脂血症和2型糖尿病中增加，但在恢复血糖控制的糖尿病治疗后降低。与此形成鲜明对比的是，在2型糖尿病中，LDL与肝素的结合增加，触发促动脉粥样硬化LDL修饰。因此，肝素结合的作用与VLDL的动脉粥样硬化形成呈负相关，但与LDL呈正相关。总的来说，结果表明，结合糖胺聚糖启动VLDL重塑循环LpL，并建议肝素结合作为VLDL功能的标志物和治疗代谢紊乱的读数。
Hydrolysis of VLDL triacylglycerol (TG) by lipoprotein lipase (LpL) is a major step in energy metabolism and VLDL-to-LDL maturation. Most functional LpL is anchored to the vascular endothelium, yet a small amount circulates on TG-rich lipoproteins. As circulating LpL has low catalytic activity, its role in VLDL remodeling is unclear. We use pre-heparin plasma and heparin-sepharose affinity chromatography to isolate VLDL fractions from normolipidemic, hypertriglyceridemic, or type-2 diabetic subjects. LpL is detected only in the heparin-bound fraction. Transient binding to heparin activates this VLDL-associated LpL, which hydrolyses TG, leading to gradual VLDL remodeling into IDL/LDL and HDL-size particles. The products and the timeframe of this remodeling closely resemble VLDL-to-LDL maturation in vivo. Importantly, the VLDL fraction that does not bind heparin is not remodeled. This relatively inert LpL-free VLDL is rich in TG and apoC-III, poor in apoE and apoC-II, shows impaired functionality as a substrate for the exogenous LpL or CETP, and likely has prolonged residence time in blood, which is expected to promote atherogenesis. This non-bound VLDL fraction increases in hypertriglyceridemia and in type-2 diabetes but decreases upon diabetes treatment that restores the glycemic control. In stark contrast, heparin binding by LDL increases in type-2 diabetes triggering pro-atherogenic LDL modifications. Therefore, the effects of heparin binding are associated negatively with atherogenesis for VLDL but positively for LDL. Collectively, the results reveal that binding to glycosaminoglycans initiates VLDL remodeling by circulating LpL, and suggest heparin binding as a marker of VLDL functionality and a readout for treatment of metabolic disorders.
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影响因子：
5.8
作者：
Pruneta, V;Autran, D;Moulin, P
通讯作者：
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DOI：
10.1073/pnas.95.23.13841
发表时间：
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影响因子：
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