English abstract
Oxidation of low density lipoproteins (LDL) is a modification believed to be a key event in the development of atherosclerosis. Oxidized LDL (OXLDL) particles are recognized by macrophage scavenger receptors where macrophages become loaded with cholesterol converting into "foam cells" that accumulate into fatty streaks initiating atherosclerosis events. In vitro studies suggest that small LDL particles are more prone to oxidation than larger buoyant LDL. Several studies have shown that formation of smaller LDL particles is associated with increased triglyceride (TG) levels in vivo. However, a direct association between increased triglyceride levels and oxidation of smaller LDL species has not been confirmed. The aim of the study was to examine in vivo levels of oxidized LDL (oxLDL) represented by a known oxidized species, Malondialdehyde-modified (MDA-modified) LDL, in hypertriglyceridemic and control subjects, and the association between oxLDL levels and TG levels in these subjects. A sub-study was also set to examine the effect of transient elevations of TG levels after a fat rich meal on postprandial oxidized LDL levels. Oxidized LDL and lipid parameters were measured in 47 selected (control and hypertriglyceridemic samples) and the correlations of oxLDL with TG, LDL size, apoB, apoA1, Total Chol, HDL-C and LDL-C and glucose were examined. Results showed increased levels of oxLDL in the hypertriglyceridemic group compared to the control group (p = 0.002). In spite of this difference, there was No significant correlation between increased TG levels and oxLDL levels in these subjects (r=0.279, p=0.058). Furthermore, although the hypertriglyceridemic individuals in this study had significantly decreased LDL size, LDL size was also NOT associated with increased oxLDL levels, further supporting that factors independent of increased TG levels and therefore decreased LDL size) are more likely responsible for the formation of oxLDL. Interestingly, the strongest association in this study was found between apoB levels and OXLDL levels (r=0.684, p<0.0001). Regression analysis showed that apoB was the main predictor of oxLDL levels in plasma among all measured parameters that showed a significant correlation with oxLDL levels. As these MDA modified LDL particles (OXLDL) are the result of covalent binding of apoB with oxidatively modified lipid moieties, this study suggests that apoB is the main determinant of LDL oxidation and that it's enhanced availability for such reactions leads to increased generation of oxLDL particles in vivo. The postprandial study on healthy subjects, showed no difference in oxLDL levels (p = 0.553) before and after the fat rich test meal. Area under the curve (AUC), representing rate of clearance of TG after test meal, was not associated with increased oxLDL levels (r = 0.190, p = 0.652). This is in agreement with the first study which shows that increased TG levels is not associated with increased OXLDL levels. In conclusion, it is established that increased TG levels result in decreased LDL size, this is not a significant determinant of increased oxLDL levels in vivo, and that LDL oxidative modification more likely depends on a negative oxidative state mainly associated with an abnormal apoprotein profile.
