Low clusterin levels in high-density lipoprotein associate with insulin resistance, obesity, and dyslipoproteinemia.
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.


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 lipoprotein's cardioprotective effects. In a discovery study, we used isotope dilution mass spectrometry to quantify the relative concentrations of 5 proteins previously implicated in HDL's cardioprotective effects in 3 groups of healthy subjects: lean 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.


CONCLUSIONS
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 HDL's cardioprotective properties.
Hoofnagle
Andrew N
AN
Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. ahoof@u.washington.edu
Wu
Mingyuan
M
Gosmanova
Albina K
AK
Becker
Jessica O
JO
Wijsman
Ellen M
EM
Brunzell
John D
JD
Kahn
Steven E
SE
Knopp
Robert H
RH
Lyons
Timothy J
TJ
Heinecke
Jay W
JW
D000328:Adult; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D051152:Clusterin / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000503:physiopathology; D015536:Down-Regulation; D050171:Dyslipidemias / Q000097:blood* / Q000503:physiopathology; D006801:Humans; D007201:Indicator Dilution Techniques; D007333:Insulin Resistance; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000503:physiopathology; D008875:Middle Aged; D009765:Obesity / Q000097:blood* / Q000503:physiopathology; D009825:Oklahoma; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry; D014280:Triglycerides / Q000097:blood; D014861:Washington
D015415:Biomarkers; C495242:CLU protein, human; D051152:Clusterin; D008075:Lipoproteins, HDL; D014280:Triglycerides