Glycoxidised LDL isolated from subjects with impaired glucose tolerance increases CD36 and peroxisome proliferator–activator receptor γ gene expression in macrophages

Abstract

Aims/hypothesis 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. Subjects and 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 γ (PPARγ) 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 N " -(carboxymethyl)lysine (CML) and N " -(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/interpretation 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.

Insights into binding of S100 proteins to scavenger receptors: class B scavenger receptor CD36 binds S100A12 with high affinity

“…Oxidized LDL, on the other hand, has another binding site at the CD36 protein (Silverstein and Febbraio 2009). This is likely to support the hypothesis that the observed interaction of S100A12 and CD36, the subsequent recruitment of CD36 to the membrane, and the up-regulation in CD36 synthesis, could be involved in translocation of fatty acids and regulation of PPARγ (Kopprasch et al 2004; Graessler et al 2007; Silverstein and Febbraio 2009). But to prove this hypothesis, further investigations have to be carried out.…”

“…CD36 is a membrane receptor that is present on platelets, macrophages, monocytes, adipocytes, hepatocytes, myocytes, and some epithelial cells (Silverstein and Febbraio 2009). In monocytes and macrophages, CD36 acts as receptor and transporter for bioactive lipids leading to the activation of the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, which subsequently regulates glucose metabolism and free fatty acid uptake (Tontonoz et al 1998; Koonen et al 2005; Graessler et al 2007). It has to be considered that RAGE and certain scavenger receptors share a common ligand recognition principle based on electrostatic interactions between the positively charged receptor surface domains and negatively charged ligands (Adachi and Tsujimoto 2006; Jimenez-Dalmaroni et al 2009; Gao et al 2010; Fritz 2011).…”