Johan Björkegren
Triglyceride-rick lipoproteins Postprandial metabolism and composition in relation to athersoclerosisABSTRACT
Academic DissertationKarolinska Sjukhusets aula May 15 1998 kl 09.00 The King Gustaf V Research Institute and the Dpt of Medicine, Karolinska Hospital, Karolinska Institute, 171 76 Stockholm
A relationship between postprandial lipaemia and coronary heart disease (CHD) was established as early as the 1950s. Since then most attention has been apid to postprandial triglyceride-rich lipoproteins (TRLs) of intestinal origin, i.ex. 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 particule number occurring in the postprandial state, accounting for 90% of the total cholesterol increase 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 challanged with either an oral or intravenous fat load, and TRLs in plasma samples were separated according to particle size (cumulative flotation in a density gradient) and origin (immunoaffinity purification of VLDL particles from chylomicron-like lipid emulsion particles of 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 determined by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), urea gel electrophoresis, and enzymatic lipid measurements. The receptor and non-receptormediated 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 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 normolipidaemic 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-I and cholesterol, and depleted of apo C-II. These compositional alterations increased the binding affinity of large VLDL particles to fibroblasts in vitro. Chylomircron remnant particles were relatively enriched with apo C-II and phospholipids compared with VLDL particles of similar size. Furthermore, whereas VLDL particles exhibited an early increase of apo-C-III in response to an oral fat load, chylomicron remnant particles simultaneously were depleted of apo C-III. 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-I 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 endogenous origin. This latter finding supports the contention that lipoprotein remnant particle composition may be a more sensitive predictor fo the future risk of CHD than lipoprotein remnant particular number.
Key words triglyceride-rich lipoproteins, very low density lipoproteins, chylomicrons, lipoprotein remnants, apolipoprotein E and C, cholesterol, atherosclerosis
Handledare Bitr prof Anders Hamsten, Docent Fredrik Karpe
Fakultetsopponent Prof John Betteridge University College London, London, UK
