Low Clusterin Levels in High-Density Lipoprotein Associate With Insulin Resistance, Obesity, and Dyslipoproteinemia

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 30; no. 12; pp. 2528 - 2534
• Main Authors: Hoofnagle, Andrew N., Wu, Mingyuan, Gosmanova, Albina K., Becker, Jessica O., Wijsman, Ellen M., Brunzell, John D., Kahn, Steven E., Knopp, Robert H., Lyons, Timothy J., Heinecke, Jay W.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.12.2010; Lippincott Williams & Wilkins
• Subjects: Adult; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Biomarkers - blood; Blood and lymphatic vessels; Blood. Blood coagulation. Reticuloendothelial system; Body Mass Index; Cardiology. Vascular system; Case-Control Studies; Chromatography, Liquid; Clusterin - blood; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - physiopathology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Down-Regulation; Dyslipidemias - blood; Dyslipidemias - physiopathology; Humans; Indicator Dilution Techniques; Insulin Resistance; Lipoproteins, HDL - blood; Male; Medical sciences; Metabolic Syndrome - blood; Metabolic Syndrome - physiopathology; Middle Aged; Obesity - blood; Obesity - physiopathology; Oklahoma; Pharmacology. Drug treatments; Proteomics - methods; Reproducibility of Results; Tandem Mass Spectrometry; Triglycerides - blood; Washington; Oklahoma; Washington; Endocrinopathy; clusterin; apolipoprotein J; high-density lipoprotein; Metabolic diseases; Cardiovascular disease; Apolipoprotein; Lipoprotein; Visceral obesity; Vascular disease; Target tissue resistance; Atherosclerosis; Insulin resistance; intra-abdominal fat; obesity
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.110.212894

OBJECTIVE—To determine whether obesity and insulin resistance associate with changes in the protein content of high-density lipoprotein (HDL) in 2 different groups of men by using targeted proteomics. METHODS AND RESULTS—Insulin resistance and obesity are hallmarks of type 2 diabetes mellitus and the metabolic syndrome, which confer an increased risk of cardiovascular disease. Recent studies suggest that the protein cargo of HDL makes important contributions to the lipoproteinʼs cardioprotective effects. In a discovery study, we used isotope dilution mass spectrometry to quantify the relative concentrations of 5 proteins previously implicated in HDLʼs cardioprotective effects in 3 groups of healthy subjectslean insulin-sensitive, lean insulin-resistant, and obese insulin-resistant individuals. We validated our findings in a different group of subjects. The clusterin concentration in HDL strongly and negatively associated with insulin resistance and body mass index in both populations. HDL clusterin levels were lower in subjects with low HDL and high triglycerides, key components of the metabolic syndrome. There was an inverse correlation between clusterin levels in HDL and very-low-density lipoprotein/low-density lipoprotein. CONCLUSION—Clusterin levels in HDL are lower in men with reduced insulin sensitivity, higher body mass index, and an unfavorable lipid profile. Our observations raise the possibility that clusterin depletion contributes to the loss of HDLʼs cardioprotective properties.