Discovery of a New Role of Human Resistin in Hepatocyte Low-Density Lipoprotein Receptor Suppression Mediated in Part by Proprotein Convertase Subtilisin/Kexin Type 9
Discovery of a New Role of Human Resistin in Hepatocyte Low-Density Lipoprotein Receptor Suppression Mediated in Part by Proprotein Convertase Subtilisin/Kexin Type 9
复制标题
DOI：
10.1016/j.jacc.2011.11.064
复制
发表时间：
2012-05-08
影响因子：
24
通讯作者：
Rashid, Shirya
中科院分区：
文献类型：
--
作者：
Melone, Michelle;Wilsie, Larissa;Rashid, Shirya
在这项研究中，我们的目标是确定是否人β-淀粉样蛋白在调节动脉粥样硬化的低密度脂蛋白在人类hepatocytes.Background摄取的作用，β-淀粉样蛋白，脂肪组织来源的脂肪因子，血清水平增加，在人类肥胖和动脉粥样硬化性心血管疾病呈正相关。然而，在humans.Methods人肝细胞（HepG 2和原代）的功能是谜（24小时）与以下内容：1）纯化的人ALGORN在各种浓度，有和没有洛伐他汀;和2）肥胖的人血清ALGORN水平升高或血清从ALGORN被删除，通过抗体免疫沉淀。细胞低密度脂蛋白受体（LDLR）和前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）信使核糖核酸和蛋白质水平的治疗效果分别通过使用实时聚合酶链反应和Western blotting，Resistin，在人体肥胖的生理水平观察，下调肝细胞LDLR的表达大幅（40%）。人Ignorn抑制LDLR水平的一个关键机制是通过增加最近鉴定的蛋白酶PCSK 9的细胞表达，其增强细胞内LDLR溶酶体降解。通过抗体免疫沉淀法去除人血清中的人Ignorn，证明了人Ignorn在LDLR表达中的定量重要作用，这显著降低了肝细胞LDLR的血清刺激（80%）。此外，GREEN减少他汀类药物介导的LDLR的上调60%，这意味着GREEN在他汀类药物在选择性目标population. Conclusions相对无效，这些结果首次揭示，GREEN是一个非常有吸引力的治疗目标，在改善血清低密度脂蛋白升高，从而，动脉粥样硬化性心血管疾病肥胖的人。（J Am科尔心脏病学杂志2012;59：1697-705）（C）美国心脏病学会基金会2012年
Objectives In this study, our goal was to determine if human resistin plays a role in regulating the uptake of atherogenic low-density lipoproteins in human hepatocytes.Background Serum levels of resistin, an adipose tissue-derived adipokine, are increased in human obesity and are positively correlated with atherosclerotic cardiovascular diseases. However, the function of resistin in humans is enigmatic.Methods Human hepatocytes (HepG2 and primary) were treated (24 h) with the following: 1) purified human resistin at various concentrations, with and without lovastatin; and 2) obese human serum with elevated resistin levels or serum from which resistin was removed via antibody-immunoprecipitation. The effect of the treatments on cellular low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) messenger ribonucleic acid and protein levels were determined by using real-time polymerase chain reaction and Western blotting, respectively.Results Resistin, at physiological levels observed in human obesity, down-regulated hepatocyte LDLR expression substantially (by 40%). A key mechanism by which human resistin inhibited LDLR levels was by increased cellular expression of the recently identified protease, PCSK9, which enhances intracellular LDLR lysosomal degradation. The quantitatively important role of human resistin in LDLR expression was demonstrated by antibody-immunoprecipitation removal of resistin in human serum, which decreased serum stimulation of hepatocyte LDLRs markedly (by 80%). Furthermore, resistin diminished statin-mediated up-regulation of the LDLR by 60%, implicating resistin in the relative ineffectiveness of statins in selective target populations.Conclusions These results reveal for the first time that resistin is a highly attractive therapeutic target in ameliorating elevated serum low-density lipoprotein and, thereby, atherosclerotic cardiovascular diseases in obese humans. (J Am Coll Cardiol 2012;59:1697-705) (C) 2012 by the American College of Cardiology Foundation