Triglyceride-rich lipoproteins : Postprandial metabolism and composition in relation to atherosclerosis

Sammanfattning: A relationship between postprandial lipaemia and coronary heart disease (CHD) was established as early as the 1950s. Since then, most attention has been paid to postprandial trigleride-rich lipoproteins (TRLs) of intestinal origin, i.e. chylomicrons and chylomicron remnants, whereas TRLs of hepatic origin, i.e. very low density lipoproteins (VLDL) and their remnants have not been examined in detail in relation to CHD. This is surprising since an increase of VLDL particles of Svedberg flotation rate (Sf) 60-400 is the major alteration of lipoprotein particle number occurring in the postprandial state, accounting for 90% of the total cholesterol in crease in the TRL fractions. The present research programme was set up to investigate alterations in metabolism and composition of TRL particles of different origin in relation to atherosclerosis. Healthy human volunteers were challenged with either an oral or an intravenous fat load, and TRLs in plasma samples were separated according to particle size (cumulative flotation in a den sity gradient ) and origin (immunoaffinity purification of VLDL particles from chylomicron-like lipid emulsion particles or chylomicron remnant particles). To separate VLDL from chylomicron and chylomicron remnants, specific monoclonal antibodies directed towards the C-terminus of apo B-100 were used. The apolipoprotein and lipid composition of isolated TRL particles was deter mined by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), urea gel elec trophoresis, and enzymatic lipid measurements. The receptor and non-receptor mediated binding and uptake of VLDL particles was evaluated on fibroblasts in vitro. The metabolic fate of VLDL particles in the postprandial state was further investigated by isotope kinetic studies. The presence of early atherosclerosis as reflected by the carotid intima-media thickness was assessed by B-mode carotid ultrasound in asymptomatic 50-year-old men. During transient triglyceridaemia like that normally seen after a mixed meal, healthy nor molipidaemic men were found to accumulate large VLDL secondary to competition between these particles and chylomicron-like particles for lipoprotein lipase (LPL). This rendered the VLDL particles enriched with apo E, apo C-l and cholesterol, and depleted of apo C-II. These composi tional alterations increased the binding affinity of large VLDL particles to fibroblasts in vitro. Chylomicron remnant particles were relatively enriched with apo C-ll and phospholipids compared with VLDL particles of similar size. Furthermore, whereas VLDL particles exhibited an early increase of apo C-lll in response to an oral fat load, chylomicron remnant particles simultaneously were depleted of apo C-lll. In addition, the cholesterol to triglyceride ratio of large VLDL particles was found to increase transiently, whereas the cholesterol to triglyceride ratio of large chylomicrons and small TRLs increased throughout the entire postprandial period. TRL remnant particles isolated at the end of the postprandial period from asymptomatic healthy 50-year-old men with signs of early atherosclerosis were enriched with apo C-l and cholesterol in particular. Thus, TRL remnant particles undergo specific metabolic and compositional alterations during transient triglyceridaemia which would facilitate their clearance and provide an explanation for differences in metabolism between the two TRL species. In addition, in normolipidaemic men with signs of early atherosclerosis the postprandial composition of TRL particles seems to be perturbed in a way that favours formation of potentially atherogenic TRL remnants, particularly of en dogenous origin. This latter finding supports the contention that lipoprotein remnant particle composition may be a more sensitive predictor of the future risk of CHD than lipoprotein rem nant particle number.