GLYCOSYLATION OF APOLIPOPROTEIN C III IN SUBJECTS W/ MYOCARDIAL INFARCTION RISK

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The presence of small dense low-density lipoprotein (LDL) particles (LDL subclass pattern B) as the major plasma LDL particle is a genetically influenced risk factor for coronary heart disease. Individuals with LDL subclass pattern B (approximately 25% of the population) have relatively increased levels of triglyceride (very low density lipoprotein) VLDL and decreased levels of HDL cholesterol, a profile which would predict an increased risk of atherosclerosis. A subsequent study of LDL sublcass patterns versus risk of myocardial infarction found that individuals with LDL subclass pattern B have up to a threefold increase in riskof myocardial infarction. We have previously found that apolipoprotein B (apo B), the major protein constituent of LDL, has decreased glycosylation in pattern B LDL compared to normal (LDLsubclass pattern A) subjects. A metabolism study currently in progress is showing that pattern B subjects show greatly enhanced (up to 10 fold) secretion of VLDL and that both VLDL and LDL in pattern B subjects are metabolized differently than in normal subjects. In addition, we have recently found that both VLDL and LDL from pattern B subjects possess a greater net negative surface charge density than does VLDL and LDL from pattern A subjects. Further, we havevery recently found that apolipoprotein C-III, a minor component of LDL and up to 40% of the protein mass of VLDL is present in pattern B VLDL and LDL at approximately twice the level present in pattern A VLDL and LDL. Apo C-III is involved in triglyceride metabolism (it is a lipase inhibitor) and altered levels may explain the increased triglyceride levels found in pattern B subjects. In addition, apo C-III is an O-linked glycoprotein which exists in the plasma in three forms: a disialated, monosialated and nonglycosylated form. Differences in the ratios of these three forms may explain the increased net negative charge found in pattern B VLDL and LDL and potentially could influence the binding of C-III with VLDL, LDL and/or its interaction with lipases. Based on the known differences in glycosylation of apoB in pattern B LDL, VLDL and LDL metabolism and the charge differences, it seems likely that there will in fact be differences in the glycosylation of C-III in pattern B subjects. If differences in ratios of these isoforms are found, it would indicate that future studies would be necessary to determine potential differences in interactions of these isoforms with VLDL, LDL and various lipases.