Chang Po-Yuan, Lu Shao-Chun, Su Ta-Chen, Chou San-Fang, Huang Wen-Huei, Morrisett Joel D, Chen Chu-Huang, Liau Chiau-Suong, Lee Yuan-Teh
Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
J Lipid Res. 2004 Nov;45(11):2116-22. doi: 10.1194/jlr.M400229-JLR200. Epub 2004 Aug 16.
Hypercholesterolemic human LDL contains oxidized subfractions that have atherogenic properties. Paradoxically, atherosclerosis incidence is low in patients with primary biliary cirrhosis (PBC), a disease characterized by marked increases in plasma LDL, including the LDL subfraction lipoprotein-X (Lp-X). To investigate the mechanisms underlying this paradox, we first examined the propensity to oxidation of unfractionated LDL isolated from PBC patients. After prolonged incubation with copper, PBC-LDL failed to increase the oxidation index or electrophoretic mobility noted in control LDL. An admixture of PBC-LDL or Lp-X with control LDL prevented oxidation of the latter in a dose-dependent manner. PBC-LDL was also noncompetitive against copper-oxidized LDL (oxLDL) for binding with a murine monoclonal anti-oxLDL antibody in a competitive ELISA. OxLDL exerts its proapoptotic and antiangiogenic effects in part by inhibiting fibroblast growth factor 2 (FGF2) expression. Preincubation of oxLDL with PBC-LDL, but not control LDL, attenuated the inhibitory effects of oxLDL on FGF2 expression in cultured bovine aortic endothelial cells (ECs). The antioxidant and prosurvival properties of PBC-LDL diminished after the patients underwent orthotopic liver transplantation. These results suggest that Lp-X reduces LDL atherogenicity by preventing LDL oxidation to protect EC integrity in the presence of hypercholesterolemia. They also suggest that altering LDL composition may be as important as reducing LDL concentration in preventing or treating atherosclerosis.
高胆固醇血症患者的低密度脂蛋白（LDL）含有具有致动脉粥样硬化特性的氧化亚组分。矛盾的是，在原发性胆汁性肝硬化（PBC）患者中动脉粥样硬化的发生率较低，PBC是一种以血浆LDL显著升高为特征的疾病，包括LDL亚组分脂蛋白-X（Lp-X）。为了研究这一矛盾现象背后的机制，我们首先检测了从PBC患者中分离出的未分级LDL的氧化倾向。与铜长时间孵育后，PBC-LDL未能增加对照LDL中观察到的氧化指数或电泳迁移率。PBC-LDL或Lp-X与对照LDL的混合物以剂量依赖的方式阻止了后者的氧化。在竞争性酶联免疫吸附测定中，PBC-LDL与铜氧化的LDL（oxLDL）竞争结合鼠单克隆抗oxLDL抗体时也无竞争性。oxLDL部分通过抑制成纤维细胞生长因子2（FGF2）的表达发挥其促凋亡和抗血管生成作用。用PBC-LDL而非对照LDL预孵育oxLDL可减弱oxLDL对培养的牛主动脉内皮细胞（ECs）中FGF2表达的抑制作用。患者接受原位肝移植后，PBC-LDL的抗氧化和促生存特性减弱。这些结果表明，在高胆固醇血症情况下，Lp-X通过防止LDL氧化来保护EC完整性，从而降低LDL的致动脉粥样硬化性。它们还表明，改变LDL的组成在预防或治疗动脉粥样硬化方面可能与降低LDL浓度同样重要。
