164 Discovery of a new role of human resistin in hepatocyte low-density lipoprotein (LDL) receptor suppression mediated by PCSK9

Abstract

Serum levels of the adipose tissue adipokine, resistin, are increased in human obesity and are positively correlated with atherosclerotic cardiovascular disease (ASCVD). However, the function of resistin in humans has been enigmatic. In this study, we wished to determine if human resistin plays a role in regulating the uptake of atherogenic low-density lipoproteins (LDL) in human hepatocytes. Human hepatocytes (HepG2 and primary) were treated for 24 hours with: (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 LDL receptor (LDLR) and PCSK9 mRNA and protein levels were determined via real-time PCR and Western blotting, respectively. Resistin, at physiological levels observed in human obesity, downregulated hepatocyte LDLR expression substantially by 40%. A key mechanism by which human resistin inhibited hepatocyte LDLR was via increased 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 obese human serum, which decreased serum stimulation of LDLR markedly by 80%. Furthermore, resistin diminished statin-mediated upregulation of LDLR by 70%, implicating resistin in the relative ineffectiveness of statins in selective target populations. These results reveal for the first time that resistin is a highly attractive therapeutic target in ameliorating elevated serum LDL, and, thereby, ASCVD, in obese humans.