Stimulation of cholesteryl ester synthesis in human monocyte-derived macrophages by low-density lipoproteins from Type 1 (insulin-dependent) diabetic patients: the influence of non-enzymatic glycosylation of low-density lipoproteins

Abstract

Diabetes mellitus is an independent risk factor in the development of atherosclerosis. In this study we aimed to demonstrate whether there is an abnormal interaction between low-density lipoproteins from diabetic patients and human macrophages. We measured cholesteryl ester synthesis and cholesteryl ester accumulation in human monocyte-derived macrophages (obtained from non-diabetic donors) incubated with low density lipoproteins from Type 1 (insulin-dependent) diabetic patients in good or fair glycaemic control. Low density lipoproteins from the diabetic patients stimulated more cholesteryl ester synthesis than low density lipoproteins from non-diabetic control subjects (7.19 +/- 1.19 vs 6.11 +/- 0.94 nmol/mg cell protein/20 h, mean +/- SEM, p less than 0.05). The stimulation of cholesteryl ester synthesis by low density lipoproteins isolated from diabetic patients was paralleled by a significant increase in intracellular cholesteryl ester accumulation (p less than 0.02). There were no significant differences in the lipid composition of low density lipoproteins between the diabetic and control groups. Non-enzymatic glycosylation of low density lipoproteins was higher in the diabetic group (p less than 0.01) and correlated significantly with cholesteryl ester synthesis (r = 0.58). Similarly, low-density lipoproteins obtained from non-diabetic subjects and glycosylated in vitro stimulated more cholesteryl ester synthesis in macrophages than control low density lipoproteins. The increase in cholesteryl ester synthesis and accumulation by cells exposed to low density lipoproteins from diabetic patients seems to be mediated by an increased uptake of these lipoproteins by macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells

“…The products of this modification are not fully elucidated. It has been reported that modified LDL isolated from diabetic plasma can stimulate cholesteryl ester synthesis in human monocyte-derived macrophages [53]-consistent with the current results. The extent of modification of lysine residues on LDL isolated from human atherosclerotic lesions has not been reported, so it is not possible to judge the extent, or type, of modification of LDL to which macrophage cells might be exposed in the intima of the artery wall.…”

Glycation Accelerates the Oxidation of Low Density Lipoprotein by Copper Ions.

“…The increased serum glycated LDL level in diabetic patients correlates with their parameters of glycemic control [15]. LDL obtained from diabetic patients is less well metabolized by cultured human skin fibroblasts [2,6] and enhances cholesteryl ester synthesis in human monocyte-derived macrophages [4]. Lopes-Virella et al [16] reported that in vitro glycation enhances LDL metabolism by monocyte-derived macrophages.…”

In vivo oxidizability of LDL in type 2 diabetic patients in good and poor glycemic control

“…Modifications that increase the net negative charge may have important metabolic consequences and enhance LDL atherogenicity [5,6]. Glycated LDL (glyc-LDL) is catabolized more slowly than normal LDL [7,8], and is degraded by the scavenger pathway promoting foam cell formation [9]. The advanced glycation end-products (AGE) process is one of the main pathogenic mechanisms linked to the development of diabetic complications [10].…”