Lp (a) is an important contributing factor to the development of atherosclerosis, and in structure is similar to LDL. Given the central role of the LDL receptor (LDL-R) in the metabolism of LDL, we felt that a study of the binding and degradation of Lp (a) facilitated by the LDL-R of human monocyte derived macrophages (HMDM) would be of value in understanding its pathological nature. In this study we compared equimolar amounts of Lp (a) and LDL and found that nearly equal amounts of Lp (a) and LDL bound to the LDL-R of HMDM at 4°C, however the affinity of both lipoproteins was much lower than has been observed for the LDL-R of fibroblasts, being 0.80 μM for Lp (a) and 0.23 μM for LDL. The binding of Lp (a) to HMDM could be competed by 63% with a 50-fold excess of LDL. Degradation of Lp (a) at 37°C, unlike 4°C binding, was mainly nonspecific (75% of total Lp (a) degradation) and when compared on an equimolar basis, nearly 6 times more LDL than Lp (a) was processed by the LDL-R pathway in 5 hr. Lower degradation of Lp (a) appears to be the result of lower binding at 37°C and a lower degradation rate when compared to LDL. It was not caused by increased intracellular accumulation or retroendocytosis. Degradation of both lipoproteins was only modestly affected by up and down regulation of the LDL-R. Because the binding of LDL at 4°C and degradation at 37°C is mainly LDL-R specific, whereas only the 4°C binding of Lp (a) is so, suggests that the poor LDL-R dependent degradation of Lp (a) at 37°C is caused by a conformational change that is jnduced in Lp (a) upon lowering the temperature to 4°C which allows better recognition of Lp (a) by the HMDM LDL-R.

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Elevated plasma levels of lipoprotein (a) [LP (a)] are associated with increased an risk of developing atherosclerosis. This increased risk may be due to an Lp (a) -mediated depression of fibrinolytic activity. Lp (a) regulates fibrinolysis by controlling the activity of plasminogen activators. Lp (a) is a low density lipoprotein with an apoprotein (a) subunit which has a high degree of homology with the fibrinolytic zymogen plasminogen. The apoprotein (a) subunit contains up to thirty seven copies of a domain homologous to the plasminogen kringle 4 domain, which enables Lp (a) to bind to fibrin. The subunit also has a zymogen domain, but it is not activated by plasminogen activators. Lp (a) inhibits plasminogen activation by competing with plasminogen for access to plasminogen activators bound to vascular surfaces. Lp (a) also competes with the irreversible inhibitor of plasminogen activators, plasminogen activator inhibitor-1. Therefore increases in Lp (a) concentration may decrease fibrinolytic activity by preventing activation of plasminogen, but Lp (a) may also prolong plasminogen activation by preventing the irreversible inhibition of the activators. At elevated levels of Lp (a) the decreased rate of plasmin generation may not be offset by the prolongation in plasminogen activation, and fibrinolysis will be inhibited.

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Several apo (a) isoforms, controlled by a series of alleles Lp (a) ^F, Lp (a) ^B, Lp (a) ^S1, Lp (a) ^S2, Lp (a) ^s3, Lp (a) ^s4 and null, were found in 470 healthy Japanese by 4% SDS-PAGE and immunoblotting techniques. There was a strong inverse relationship between the apparent molecular weight of apo (a) isoforms and plasma concentrations of Lp (a). Lp (a) in d <1.006 fraction increased 2-4 h after oral fat load. Lp (a) exhibited a marked avidity for triglyceride-rich lipoprotein (TRL), and we suggest that the TRL-bound Lp (a) is the intact Lp (a) derived from serum. We demonstrated that the lipid-free apo (a) does not contain apo B-100 in serum, and has a molecular mass of ca 200 kDa. The free apo (a) level in normal subjects was 1.75 mg/dl (as Lp (a)) and was no different from the level in CAD patients.

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To clarify the association between apo (a) and TG-rich lipoproteins, we studied changes in plasma Lp (a) concentration and apo (a) distribution in lipoprotein fractions after fat intake. The subjects were 15 hyperlipidemic patients and 3 healthy volunteers with fasting Lp (a) concentrations ranging from 2.5-52 mg/dl. They were given a fatty meal (50 g fat/m² and 60 mg retinyl palmitate) after a 12-hour overnight fast and venous blood samples were taken at 0, 3, 4.5, 6, 7.5, 9, 12 and 24 hours. Fractions of sf > 400, sf 20-400 and d >1.006 g/ml were isolated from plasma samples by ultracentrifugation. Plasma Lp (a) levels increased transiently at 4.5 hours, decreased between 4.5 and 12 hours, and recovered almost to initial levels by the next morning. Plasma Lp (a) peaked before the plasma RP peak appeared. Apo (a) associated with TG-rich lipoprotein fractions increased and apo (a) in the d >1.006 fraction decreased after fat intake in most of the subjects, suggesting the transfer of apo (a) from the d >1.006 fraction to the TG-rich lipoproteins. The increase in TG-rich lipoprotein apo (a) correlated with the RP area under the curve (r = 0.79, p < 0.05) and the decrease in d > 1.006 apo (a) (r = 0.80, p < 0.05). This distributional change of apo (a) after fat intake was confirmed by gel filtration and density gradient ultracentrifugation. Transfer of apo (a) from the main Lp (a) fraction of the plasma obtained from a subject with a high Lp (a) level to the TG-rich lipoprotein fraction of the plasma obtained 4.5 hours after fat intake from a subject with a low plasma Lp (a) level was also shown in vitro by density gradient ultracentrifugation. Our studies revealed a significant association between apo (a) and TG-rich lipoproteins in the postprandial. Further studies are necessary to clarify the pathophysiological role of Lp (a) in TG-rich lipoproteins.

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We demonstrated that Lp (a) levels in patients with arteriosclerosis obliterans (21.4 ± 2.5 mg/ dl) and in patients with ischemic heart disease (17.2 ±0.8 mg/dl) are higher than those in controls (15.4±0.7 mg/di) or healthy controls (11.3 ±1.1 mg/dl). Lp (a) levels in patients with these vascular diseases were especially higher when there were known atherosclerotic risk factors such as diabetes mellitus, hypercholesterolemia or hypertension, although Lp (a) levels in patients with these risk-positive group was not different from that of control. These results suggest that Lp (a) contributes to the development of atherosclerotic vascular diseases especially when known atherosclerotic risk factrs are not present. We also investigated the case of thromboangiitis obliterans, which is believed to develop from nonatherosclerotic mechanisms, and found that Lp (a) levels were higher (26.5 ±9.6 mg/dl) in such patients.

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Apolipoprotein E (apoE) plays an important role in plasma lipoprotein metabolism through its high affinity binding to cell surface low density lipoprotein (LDL) receptor. To determine the role of apoE in plasma lipoprotein metabolism, transgenic mouse lines with integrated rat apoE gene under control of metallothionein promotor were established. The plasma level of rat apoE in homozygotes for the transgene was 17.4 mg/dl after zinc induction. In this group, plasma cholesterol and triglycerides levels were 43%, 68% reduced as compared with controls, respectively. Gel filtration chromatography showed that lipid reduction was mainly due to decreased both very low desity lipoproteins (VLDL) and LDL. Furthermore, we studied the effects of apoE on the atherogenic process in Watanabe heritable hyperlipidemic (WHHL) rabbits. We administered 10 mg of purified apoE intravenously into five WHHL rabbits three times a week from their age of 2.5 months to 11 months for 8.5 months. After sustained administration of apoE, we found a significant reduction in the accumulation of cholesterol ester in aortae (1.55±0.07 mg/g tissue) as compared to control rabbits (4.32±0.61 mg/g tissue). Thus, apoE plays an important role not only in plasma lipoprotein metabolism but also in atherosclerotic process.

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The plasma levels of blood coagulation and fibrinolytic factors and the serum levels of lipids were measured in 62 subjects (22 normolipidemia and 40 hyperlipidemia) to investigate whether hyperlipidemia may affect the hemostatic system. Prothrombin, factors VII, IX and X were elevated in hyperlipidemic patients. The positive correlations were found between factors VII, IX and X, and triglyceride. The significant correlations were also found between VII and IX, and total cholesterol. Plasma levels of thrombin-antithrombin III complex (TAT), which reflects activation of coagulation system, were slightly but significantly higher in type llb hyperlipidemia, although they were within normal range. Plasma levels of active plasminogen activator inhibitor (PAI) in type lib and IV were significantly higher than in normals. A significant correlation was found between active PAI and triglyceride (r=0.76, p<0.0001). After the administration of fat emulsion to 18 patients with various diseases, which induced artificial hypertriglyceridemia, PAI levels as well as triglyceride levels significantly increased. These results suggest that hypertriglyceridemia may increase the synthesis and/or release of PAI, inducing a hypofibrinolytic condition, which could lead to thrombosis. It has been established that lipoprotein (a) [Lp (a)], which has a molecular structure homology to plasminogen, impairs fibrinolysis by its competitive inhibition of adsorption of plasminogen to vascular endothelial surface and/or fibrin. We assayed plasma levels of Lp (a) and parameters of blood coagulation and fibrinolysis in 168 patients with type II diabetes mellitus and 48 normal controls. In the diabetics, the levels of Lp (a) as well as levels of tissue-type plasminogen activator (t-PA) antigen and PAI activity were significantly higher than normal controls. Furthermore, it was shown that Lp (a) had a weakly negative correlation with t-PA antigen in the diabetics. These results suggest that an elevated level of Lp (a) may decrease release of t-PA, although the underlying mechanism remains unsolved.

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It has been suggested that impaired fibrinolytic-coagulation system, such as increased concentration of inhibitors to fibrinolysis or activators to coagulations, occasionally may play a role in the development of atheroscrelotic vascular disese. In this study, we aimed to elucidate the relationship of serum lipids to fibrinolytic-coagulation system. The subjects studied were 190 outpatients at Kyorin University Hospital, 108 of whom were mostly hypertension, diabetes mellitus and hyperuricemia (Control), 59 of whom were coronary heart disease (CHD), 25 of whom were cerebrovascular disease (CVD). Blood samples were measured the levels of blood coagulation factors VII (F-VII) and X (F-X), and plasminogen activator inhibitor-1 (PAI-1) in these subjects, together with the concentrations of serum lipids. The serum levels of F-X was significantly higher in CHD subjects than in controls (111±19% vs 101±22%, p<0.05). However, there was a no significant difference of F-VII among three groups. And we found that the levels of serum lipids, especially serum triglycerides showed a significant positive correlation between the concentrations of F-Vll (r=0.343, p<0.01) and F-X (r=0.513, p<0.01), and PAI-1 (r=0.528, p<0.001) in CHD and CVD subjects. For this reason, 156 bank employee subjects were also admitted to this study (Bank employees). In bank employee subjects, the serum levels of triglycerides also showed a significant positive correlation with the levels of F-Vll (r=0.321, p<0.001), F-X (r=0.254, p<0.001) and PAI-1 (r=0.420, p<0.001). These data suggest that serum lipids, particularly triglycerides have a close relationship with thrombogenesis as evidenced by activated F-Vll and F-X in the extrinsic coagulation system and also by elevated PAI-1 activities in fibrinolysis. Therefore, when we try to prevent the patients from CHD or treat them, we ought pay attentions not only to serum cholesterol or LDL-cholesterol for their atherogenic actions, but also to triglycerides because of their close correlation with extrinsic coagulation system and anti-fibrinolytic activities. The reduction of fibrinolytic capacity due to increased plasma levels of F-VII, X and PAI-1 may have importance in atherosclerotic vascular disease, particulary in patients with hypertriglyceridemia.

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Fatty liver has prevailed by 14% in the healthy population of this country. The factors contributing genesis of fatty liver were gender (male), obesity, high alcohol consumption, glucose intolerance and hypertriglyceridemia. And hypertriglyceridemia seems to be the common underlying factor to all other causes. The mechanism for accumulation of triglycerides in the liver can be explained at least by increased HTGL activities and elevated apo A-II levels, a postulated co-factor of HTGL. And hypertriglyceridemic patients with fatty liver had the insulin resistance.

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