Apolipoprotein E content of VLDL limits LPL-mediated triglyceride hydrolysis.
Apolipoprotein E content of VLDL limits LPL-mediated triglyceride hydrolysis.
复制标题
DOI：
10.1016/j.jlr.2021.100157
复制
发表时间：
2022-01
影响因子：
6.5
通讯作者：
Davidson WS
中科院分区：
文献类型：
--
作者：
Whitacre BE;Howles P;Street S;Morris J;Swertfeger D;Davidson WS
高水平的循环甘油三酯（TG）或高甘油三酯血症是代谢性疾病（如2型糖尿病、代谢综合征和CVD）的关键组成部分。由于TG由血浆中的脂蛋白携带，因此高甘油三酯血症可由富含TG的脂蛋白（TRL）（如VLDL）的过度产生或缺乏清除引起。TRL清除的主要驱动力是LPL介导的TG水解。LPL受许多TRL蛋白组分（包括辅因子载脂蛋白C-II）的调节，但尚不清楚它们的作用如何联合收割机影响个体间的TRL水解。使用一种新的检测设计，以模拟人体血浆条件下，在体外，我们测试的能力，极低密度脂蛋白从15个血脂正常的捐助者作为底物的人LPL。我们发现，当在蛋白质或TG的基础上比较颗粒时，个体之间的水解速率存在惊人的10倍差异。虽然极低密度脂蛋白TG含量适度与水解速率相关，我们注意到这些颗粒内的非载脂蛋白B蛋白的MS的实质性变化。LPL水解极低密度脂蛋白TG的能力与载脂蛋白C-II含量不相关，但它与载脂蛋白E（APOE），并在较小程度上，载脂蛋白A-II呈强烈的负相关。添加外源性APOE以剂量依赖性方式抑制LPL脂解。APOE 3和（特别是）APOE 4亚型在限制LPL水解方面是有效的，而APOE 2则不是。我们的结论是VLDL上的APOE调节LPL活性，并且可能是代谢疾病发病机制的相关因素。
High levels of circulating triglycerides (TGs), or hypertriglyceridemia, are key components of metabolic diseases, such as type 2 diabetes, metabolic syndrome, and CVD. As TGs are carried by lipoproteins in plasma, hypertriglyceridemia can result from overproduction or lack of clearance of TG-rich lipoproteins (TRLs) such as VLDLs. The primary driver of TRL clearance is TG hydrolysis mediated by LPL. LPL is regulated by numerous TRL protein components, including the cofactor apolipoprotein C-II, but it is not clear how their effects combine to impact TRL hydrolysis across individuals. Using a novel assay designed to mimic human plasma conditions in vitro, we tested the ability of VLDL from 15 normolipidemic donors to act as substrates for human LPL. We found a striking 10-fold difference in hydrolysis rates across individuals when the particles were compared on a protein or a TG basis. While VLDL TG contents moderately correlated with hydrolysis rate, we noticed substantial variations in non-apoB proteins within these particles by MS. The ability of LPL to hydrolyze VLDL TGs did not correlate with apolipoprotein C-II content, but it was strongly inversely correlated with apolipoprotein E (APOE) and, to a lesser extent, apolipoprotein A-II. Addition of exogenous APOE inhibited LPL lipolysis in a dose-dependent manner. The APOE3 and (particularly) APOE4 isoforms were effective at limiting LPL hydrolysis, whereas APOE2 was not. We conclude that APOE on VLDL modulates LPL activity and could be a relevant factor in the pathogenesis of metabolic disease.
登录
查看更多内容
DOI：
10.1161/01.atv.0000146267.71816.30
发表时间：
2004-12-01
影响因子：
8.7
作者：
Annuzzi, G;De Natale, C;Rivellese, AA
通讯作者：
Rivellese, AA
影响因子：
6.5
作者：
Larsson, Mikael;Allan, Christopher M.;Fong, Loren G.
通讯作者：
Fong, Loren G.
影响因子：
4.8
作者：
Huang, YD;Liu, XQ;Mahley, RW
通讯作者：
Mahley, RW
影响因子：
2.9
作者：
MARKWELL, MAK;HAAS, SM;TOLBERT, NE
通讯作者：
TOLBERT, NE
影响因子：
15.9
作者：
KARPE, F;STEINER, G;HAMSTEN, A
通讯作者：
HAMSTEN, A