发现人抵抗素在肝细胞低密度脂蛋白受体抑制中的新作用，部分由脯氨酰肽酶枯草溶菌素/柯萨奇蛋白酶 9 介导。
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.
机构信息
Department of Medicine, Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, McMaster University, Hamilton, Ontario, Canada.
出版信息
J Am Coll Cardiol. 2012 May 8;59(19):1697-705. doi: 10.1016/j.jacc.2011.11.064.
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.
目的
本研究旨在探讨人抵抗素是否在调节人肝细胞摄取致动脉粥样硬化性低密度脂蛋白（LDL）中发挥作用。
背景
人肥胖患者血清抵抗素水平升高，且与动脉粥样硬化性心血管疾病呈正相关。然而，抵抗素在人体内的确切功能仍不清楚。
方法
用不同浓度的纯化人抵抗素（有或无洛伐他汀）以及富含抵抗素的肥胖患者血清或用抗体制取沉淀法去除抵抗素的患者血清处理人肝细胞（HepG2 和原代细胞）24 h。采用实时聚合酶链反应和 Western 印迹法分别检测细胞 LDL 受体（LDLR）和前蛋白转化酶枯草溶菌素/kexin 9（PCSK9）信使 RNA 和蛋白水平。
结果
肥胖患者体内生理浓度的抵抗素可显著下调肝细胞 LDLR 表达（下调 40%）。人抵抗素抑制 LDLR 水平的关键机制是通过增加最近鉴定的蛋白酶 PCSK9 的细胞表达，从而增强细胞内 LDLR 溶酶体降解。用抗体制取沉淀法去除人血清中的抵抗素可明显降低血清对肝细胞 LDLR 的刺激（降低 80%），证实了人抵抗素在 LDLR 表达中的重要作用。此外，抵抗素使他汀类药物介导的 LDLR 上调减少了 60%，提示抵抗素可能导致他汀类药物在某些特定人群中的疗效相对较差。
结论
这些结果首次揭示，抵抗素是改善肥胖人群血清 LDL 水平、进而改善动脉粥样硬化性心血管疾病的一个极具吸引力的治疗靶点。
Zotero 插件