We have previously shown that both recombinant apo(a) and native Lp(a) inhibit the binding of Glu-plasminogen to fibrin surfaces [Fleury & Anglés-Cano (1991) Biochemistry 30, 7630-7638; Rouy et al. (1992) Biochemistry 31, 6332-6339]. The aim of the present study was to characterize the mechanism of this inhibition and to define the parameters governing binding when two different Lp(a) species compete with plasminogen for fibrin, a situation that may be found in vivo in subjects heterozygous for the apo(a) trait. The Kd for the binding of plasminogen to fibrin was 660 nM whereas the affinity of Lp(a) was inversely related to apo(a) size (Kd range: 50 to > 500 nM). To determine the effect of plasminogen on Lp(a) binding and reciprocally, competition experiments were performed. The Kd of either Lp(a) or plasminogen for fibrin remained unchanged in the presence of the other competitor whereas Bmax, the maximal amount bound, was importantly decreased. In a similar fashion, competition for fibrin binding among Lp(a) isoforms was shown with the use of Lp(a) density fractions containing varying proportions of isoforms B (approximately 460 kDa) and S3 (approximately 640 kDa); variations in Kd values (from 141 nM to 460 nM) as a function of the relative content in isoform S3 were observed. Altogether, these results are indicative of multiple binding by ligands that bind with different affinities to equivalent but independent sites. Thus, in plasma from heterozygous subjects, the influence of each Lp(a) isoform on fibrinolysis will depend on their affinity for fibrin and on their concentration relative to each other and to plasminogen.
In the rat, pancreatic amylase and, to a lesser extent, lipase adapt quantitatively to the amount of their respective substrates in the diet by an increase in specific activity and total contents (range of variation, fivefold for amylase and twofold for lipase). Colipase responded to protein intake (r = 0.85, P less than 0.01) and not to lipids provided protein intake was below 3.5 g or above 6.0 g. With this latter amount of protein, a maximal level was obtained, even with 2% lipid in the diet. Between 3.5 and 6.0 g, lipid intake was found to modulate colipase in parallel with lipase. When different types of fat were compared, the degree of saturation was found to have no impact on lipase, colipase, and amylase. Diets containing medium-chain triglycerides (C8-C10) did not maximally increase specific activity and total content of lipase and colipase, whereas they did not repress amylase as much longer chain triglycerides did. With coconut oil (45% C12), lipase was maximally stimulated but amylase was not maximally repressed, showing that the regulation of the hydrolases may be partly reciprocal and partly independent.
HDL-phospholipids are determinants in reverse cholesterol transport. They are mostly derived from triacylglycerol (TG)-rich lipoproteins. Chylomicron size is important, therefore, because it is related to the ratio surface phospholipids: core TG and, thus, determines the availability of postprandial phospholipids for transfer to HDL. Eleven healthy young women each ingested four different fat loads supplemented with retinyl palmitate and containing 60 g sunflower oil (SO), oleicsunflower oil (OSO), mixed oil (MO; (g/kg) linoleic acid 480, oleic acid 380, linolenic acid 13) or beef tallow (BT). At the peak of TG absorption for all loads (4 h) chylomicron diameters, determined by agarose-gel filtration, were larger after SO compared with OSO (i><0-05) and BT (i>=006) and after MO compared with BT (P < 0-05). At 6 h chylomicron size was larger after the vegetable oils compared with BT (P < 0 05 in each case). After each fat load chylomicron size decreased at 6 and 8h compared with that at 4h (P<005) except for OSO. Retinyl ester and TG concentrations were lower in chylomicrons after BT than after the other fats but not in the chylomicron-free serum (containing chylomicron remnants), suggesting absorption in the form of very small particles. Compared with the fasting value, the concentration of the Svedberg unit of flotation 20-400 fraction, which contains VLDL and chylomicron remnants, was lower 8 h after MO, the only fat to contain significant amounts of linolenic acid. We conclude that chylomicron size is dependent on the fatty acid composition of ingested fats and the time-course of digestion, being larger for polyunsaturated fatty acid-rich fats and in the early phase of digestion. On the basis of retinyl ester concentration there were no differences between fats in chylomicron-remnant clearance.
Cholesterol ester transfer protein (CETP) is a key regulating factor of lipid metabolism, and the polymorphism of its gene may be a candidate for modulating the lipid parameters in type 2 diabetic subjects. In a group of 406 type 2 diabetic patients aged 59.5 +/- 10.8 y, with a body mass index of 28.9 +/- 5.3 kg/m2 and HbA1c = 8.2 +/- 1.9%, we studied the B polymorphism at the CETP locus detectable with the restriction enzyme TaqI. Patients were separated into groups, 231 males (78 B1B1, 108 B1B2, 45 B2B2) and 175 females (48 B1B1, 94 B1B2, 33 B2B2), and compared on the basis of their lipid parameters (total cholesterol, triglycerides, high-density lipoprotein-cholesterol (HDL-C), ApoA1 ApoB, and low-density lipoprotein-cholesterol), their micro and macrovascular complications. HDL-C was significantly higher in man with the B2B2 genotype (respectively, 1.31 +/- 0.44 mmol/L vs. 1.13 +/- 0.32 mmol/L, P < 0.05), together with a lower incidence of coronary heart disease (9 vs. 25% for B1B1 and B1B2 together). Women displayed a higher HDL-C than men and a equally high incidence of coronary heart disease in B2 homozygotes as in other genotypes (26 vs. 27%). Thus, in type 2 diabetic patients, Taq1b polymorphism seems to exert a modulating role in males only. This may contribute to the loss of macrovascular protection in type 2 diabetic females.
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