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.
OBJECTIVES: In this study, our goal was to determine if humanresistin 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 humanobesity 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 humanresistin at various concentrations, with and without lovastatin; and 2) obesehuman 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 humanobesity, down-regulated hepatocyte LDLR expression substantially (by 40%). A key mechanism by which humanresistin 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 humanresistin 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 obesehumans.
Authors: Anthony N DeMaria; Jeroen J Bax; Gregory K Feld; Barry H Greenberg; Jennifer L Hall; Mark A Hlatky; Wilbur Y W Lew; João A C Lima; Ehtisham Mahmud; Alan S Maisel; Sanjiv M Narayan; Steven E Nissen; David J Sahn; Sotirios Tsimikas Journal: J Am Coll Cardiol Date: 2013-01-22 Impact factor: 24.094
Authors: Evan D Muse; David I Feldman; Michael J Blaha; Zeina A Dardari; Roger S Blumenthal; Matthew J Budoff; Khurram Nasir; Michael H Criqui; Mary Cushman; Robyn L McClelland; Matthew A Allison Journal: Atherosclerosis Date: 2014-12-23 Impact factor: 5.162
Authors: Sylwia M Figarska; Stefan Gustafsson; Johan Sundström; Johan Ärnlöv; Anders Mälarstig; Sölve Elmståhl; Tove Fall; Lars Lind; Erik Ingelsson Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311