Glycation impairs high-density lipoprotein function.
OBJECTIVE
To examine the effects of incubation of high-density lipoprotein (HDL) under hyperglycaemic conditions on several functions of HDL in vitro.


METHODS
Human HDL (5 mg protein) was incubated for 1 week at 37 degrees C in the presence or absence of 25 mmol/l glucose. Additional samples of human HDL were incubated in butylated hydroxytoluene to control for oxidation.


RESULTS
High-density lipoprotein incubated for 1 week in 25 mmol/l glucose had significant increases in the glycation product, fructoselysine and in the advanced glycation end product, N epsilon-(carboxymethyl)-lysine. High-density lipoprotein apolipoprotein AI and AII concentrations were not altered but glycated HDL had a 65% reduction in paraoxonase enzymatic activity. Glycated HDL did not inhibit monocyte adhesion to human aortic endothelial cells in response to oxidised low-density lipoprotein in vitro (43 +/- 4 monocytes bound vs 21 +/- 2 monocytes for control HDL, p < 0.0001). Hepatic lipase-mediated non-esterified fatty acid release from HDL lipids was enhanced in glycated HDL compared with control HDL (25 +/- 1 vs 16 +/- 1 nmol non-esterified fatty acid hydrolysed/min, respectively, p < 0.0001). Direct glycation of purified paraoxonase protein by incubation in 25 mmol/l glucose caused a 40% reduction in enzymatic activity. This glycated paraoxonase did not inhibit monocyte adhesion to human aortic endothelial cells in vitro (68 +/- 3 monocytes vs 49 +/- 2 monocytes bound for control paraoxonase, respectively, p < 0.001). We also measured a 40% reduction in paraoxonase activity in patients with Type II (non-insulin-dependent) diabetes mellitus and documented coronary artery disease compared with non-diabetic subjects, p < 0.0001.


CONCLUSIONS
Alterations in function of HDL caused by exposure to hyperglycaemic conditions could contribute to the accelerated atherosclerosis observed in Type II diabetes.
Hedrick
C C
CC
Division of Cardiology, University of California School of Medicine, Los Angeles 90095-1679, USA.
Thorpe
S R
SR
Fu
M X
MX
Harper
C M
CM
Yoo
J
J
Kim
S M
SM
Wong
H
H
Peters
A L
AL
D001011:Aorta / Q000166:cytology / Q000502:physiology; D043303:Aryldialkylphosphatase; D002448:Cell Adhesion / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D004950:Esterases / Q000378:metabolism / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D009000:Monocytes / Q000502:physiology; D010084:Oxidation-Reduction; D013379:Substrate Specificity
D017127:Glycation End Products, Advanced; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D004950:Esterases; D008049:Lipase; D043303:Aryldialkylphosphatase; D005947:Glucose