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

Journal of the American College of Cardiology
Michelle MeloneShirya Rashid

Abstract

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. 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. 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. 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 in...Continue Reading

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