- 作者：Michelle Melone ; MSc鈦?/sup> ; Larissa Wilsie ; PhD&dagger ; ; Oksana Palyha ; BS&dagger ; ; Alison Strack ; PhD&dagger ; ; Shirya Rashid ; PhD鈦?/sup> ; &Dagger ; ; srashid@thrombosis.hhscr.org
- 关键词：dyslipidemia ; hepatic ; LDL receptor ; obesity ; resistin
- 刊名：Journal of the American College of Cardiology
- 出版年：2012
- 期刊代码：201_07351097
- 类别：med
- 出版时间：8 May, 2012
- 卷：59
- 期：19
- 页码：1697-1705
- 文件大小：1535 K
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.