Glycoxidised LDL isolated from subjects with impaired glucose tolerance increases CD36 and peroxisome proliferator-activator receptor gamma gene expression in macrophages.
OBJECTIVE
Glycoxidised LDL has been implicated in the pathogenesis of atherosclerosis, a major complication of diabetes. Since atherogenesis may occur at an early stage of diabetes, we investigated whether circulating LDL isolated from subjects with IGT (n = 20) showed an increased glycoxidation status and explored the proatherogenic effects of LDL samples on macrophages.


METHODS
We investigated LDL modifications using GC-MS. Murine macrophages were incubated with LDL samples for 1 h, and then mRNA expression rates of the scavenger receptors CD36 and scavenger receptor class B type 1 (SCARB1, formerly known as SR-BI) and transcription factor peroxisome proliferator-activator receptor gamma (PPARgamma) were quantified by real-time RT-PCR.


RESULTS
The GC-MS experiments revealed that oxidative modifications of proline, arginine, lysine and tyrosine residues in apolipoprotein B100 were three- to fivefold higher in LDL samples from IGT subjects compared with those from NGT subjects (n = 20). Moreover, LDL glycoxidation estimated by both Nepsilon-(carboxymethyl)lysine (CML) and Nepsilon-(carboxyethyl)lysine (CEL) residues was increased more than ninefold in LDL from IGT subjects compared with samples from NGT subjects. Compared with NGT LDL, IGT LDL elicited a significantly higher CD36 (p < 0.05) and PPARG (p < 0.05) gene expression, whereas SCARB1 mRNA expression was not affected.


CONCLUSIONS
These data suggest that IGT is associated with increased glycoxidation of circulating LDL, which might contribute to the conversion of macrophages into a proatherogenic phenotype.
Graessler
J
J
Department of Internal Medicine, Division of Pathological Biochemistry, Carl Gustav Carus Medical School, University of Technology, Fetscherstrasse 74, D-01307 Dresden, Germany. Juergen.Graessler@uniklinikum-dresden.de
Pietzsch
J
J
Westendorf
T
T
Julius
U
U
Bornstein
S R
SR
Kopprasch
S
S
D000328:Adult; D015703:Antigens, CD / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000097:blood*; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood* / Q000302:isolation & purification; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D047495:PPAR gamma / Q000235:genetics*; D012016:Reference Values
D015703:Antigens, CD; D001786:Blood Glucose; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D047495:PPAR gamma; C099252:oxidized low density lipoprotein