Braschi S, Couture N, Gambarotta A, Gauthier B R, Coffill C R, Sparks D L, Maeda N, Schultz J R
Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, University of Ottawa, H445A, 1053 Carling Avenue, Ottawa, Ont. K1Y 4E9, Canada.
Biochim Biophys Acta. 1998 Jun 15;1392(2-3):276-90. doi: 10.1016/s0005-2760(98)00046-0.
Transgenic mice were created overproducing a range of human HL (hHL) activities (4-23-fold increase) to further examine the role of hepatic lipase (HL) in lipoprotein metabolism. A 5-fold increase in heparin releasable HL activity was accompanied by moderate (approx. 20%) decreases in plasma total and high density lipoprotein (HDL) cholesterol and phospholipid (PL) but no significant change in triglyceride (TG). A 23-fold increase in HL activity caused a more significant decrease in plasma total and HDL cholesterol, PL and TG (77%, 64%, 60%, and 24% respectively), and a substantial decrease in lipoprotein lipids amongst IDL, LDL and HDL fractions. High levels of HL activity diminished the plasma concentration of apoA-I, A-II and apoE (76%, 48% and 75%, respectively). In contrast, the levels of apoA-IV-containing lipoproteins appear relatively resistant to increased titers of hHL activity. Increased hHL activity was associated with a progressive decrease in the levels and an increase in the density of LpAI and LpB48 particles. The increased rate of disappearance of 125I-labeled human HDL from the plasma of hHL transgenic mice suggests increased clearance of HDL apoproteins in the transgenic mice. The effect of increased HL activity on apoB100-containing lipoproteins was more complex. HL-deficient mice have substantially decreased apoB100-containing low density lipoproteins (LDL) compared to controls. Increased HL activity is associated with a transformation of the lipoprotein density profile from predominantly buoyant (VLDL/IDL) lipoproteins to more dense (LDL) fractions. Increased HL activity from moderate (4-fold) to higher (5-fold) levels decreased the levels of apoB100-containing particles. Thus, at normal to moderately high levels in the mouse, HL promotes the metabolism of both HDL and apoB-containing lipoproteins and thereby acts as a key determinant of plasma levels of both HDL and LDL.
通过构建一系列人类肝脂酶（hHL）活性超量表达（增加4 - 23倍）的转基因小鼠，进一步研究肝脂酶（HL）在脂蛋白代谢中的作用。肝素可释放的HL活性增加5倍时，血浆总胆固醇、高密度脂蛋白（HDL）胆固醇和磷脂（PL）中度降低（约20%），但甘油三酯（TG）无显著变化。HL活性增加23倍导致血浆总胆固醇、HDL胆固醇、PL和TG更显著降低（分别为77%、64%、60%和24%），以及IDL、LDL和HDL组分中脂蛋白脂质大量减少。高水平的HL活性使载脂蛋白A-I、A-II和载脂蛋白E的血浆浓度降低（分别为76%、48%和75%）。相反，含载脂蛋白A-IV的脂蛋白水平似乎对hHL活性升高相对不敏感。hHL活性增加与LpAI和LpB48颗粒水平逐渐降低及密度增加有关。125I标记的人HDL从hHL转基因小鼠血浆中消失的速率加快，表明转基因小鼠中HDL载脂蛋白的清除增加。HL活性增加对含载脂蛋白B100的脂蛋白的影响更为复杂。与对照组相比，HL缺陷小鼠含载脂蛋白B100的低密度脂蛋白（LDL）显著减少。HL活性增加与脂蛋白密度谱从主要为漂浮性（VLDL/IDL）脂蛋白向更致密（LDL）组分的转变有关。HL活性从适度（4倍）增加到更高（5倍）水平会降低含载脂蛋白B100颗粒的水平。因此，在小鼠体内处于正常至中度高水平时，HL促进HDL和含载脂蛋白B的脂蛋白的代谢，从而成为HDL和LDL血浆水平的关键决定因素。
