Guinea pig very low density lipoproteins are a good substrate for lipoprotein lipase.

In contrast to plasma from most other animals, guinea pig plasma causes little or no stimulation of lipoprotein lipase activity. Very low density lipoproteins (VLDL) isolated by ultracentrifugation of guinea pig serum caused a definite stimulation of lipase activity, whereas the infranatant inhibited the activity. Gel filtration in 5 M guanidinium hydrochloride of delipidated VLDL demonstrated that the activation was caused by a low molecular weight protein. The VLDL themselves were hydrolized at similar rates as human VLDL both by guinea pig and by bovine lipoprotein lipases. Thus, guinea pig VLDL contain an activator for lipoprotein lipase analogous to that in other animals and there is enough of the activator to support rapid hydrolysis of the VLDL lipids by the lipase.     

Lipoprotein composition as a component in the lipoprotein clearance defect in experimental diabetes

The hypertriglyceridemia associated with streptozotocin-induced diabetes in rats is largely reflected in the plasma lipoproteins of density less than 1.006 g/ml. Analysis of the plasma apolipoproteins of these rats indicated marked alterations in both the total levels and in the lipoprotein distribution of the major apolipoproteins. In whole plasma, diabetes was associated with significant increases in apolipoprotein (apo)-AIV, apo-AI, and apo-B (mainly in the intestinally derived apo-B240) and a marked decrease in apo-E. In the d less than 1.006 g/ml lipoprotein fraction (very-low-density lipoproteins (VLDL], there were significant increases in apo-B240, apo-AI, and apo-AIV and decreased levels of apo-E and the C apolipoproteins. The decrease in apo-C was primarily due to lower levels of apo-CII, and the ratio of the lipoprotein lipase inhibitor, apo-CIII, to the lipoprotein lipase activator, apo CII, was significantly increased over that in controls. The comparative clearance of triglycerides of VLDL particles from control and diabetic rat plasma was tested in recirculating heart perfusion in vitro. During 45-min perfusions of hearts from control donor rats, lipolysis of triglycerides of VLDL from diabetic rats was only 63-64% of that using plasma VLDL from control rats. Perfusion of hearts from diabetic rats with VLDL from control rats gave lipolysis values of only 53% of that obtained with normal hearts. Where both the VLDL and hearts were obtained from diabetic rats, lipolysis was 23% of that observed when both the lipoprotein and the organ were from control rats. The data suggest that in addition to depressed lipoprotein lipase activity in the tissue from diabetic rats, there are also major compositional changes in circulating lipoproteins which may contribute to defective triglyceride clearance from the circulation.     

Studies on the mechanism of hypertriglyceridemia in the genetically obese Zucker rat

The possibility that impaired removal of lipoprotein triglyceride from the circulation may be a participating factor in the hypertriglyceridemia of the obese Zucker rat was examined. We found no significant differences in the heparin-released lipoprotein lipase (LPL) activities of the adipose tissue, skeletal muscle, and heart (expressed per gram of tissue) from the lean and obese Zucker rats. Furthermore, the kinetic properties of adipose tissue and heart LPL from the lean and obese rats were similar, indicating that the catalytic efficiency of the enzyme was unaltered in the obese animals. The postheparin plasma LPL activities of lean and obese rats were also similar. However, the postheparin plasma hepatic triglyceride lipase (H-TGL) activity in the obese rats was elevated. The higher activity of H-TGL could not alleviate the hypertriglyceridemia in these animals. Since hypertriglyceridemia in the obese rats could also be due to the hepatic production of triglyceride-rich lipoproteins which are resistant to lipolysis, we therefore isolated very low density lipoproteins (VLDL) from lean and obese rat liver perfusates and examined their degradation by highly purified human milk LPL. Although certain differences were observed in hepatic VLDL triglyceride fatty acid composition, the kinetic patterns of LPL-catalyzed triglyceride disappearance from lean and obese rat liver perfusate VLDL were similar. The isolated liver perfusate VLDL contained sufficient apolipoprotein C-II for maximum lipolysis. These results indicate that impaired lipolysis is not a contributing factor in the genesis of hypertriglyceridemia in the genetically obese Zucker rat. The hyperlipemic state may be attributed to hypersecretion of hepatic VLDL and consequent saturation of the lipolytic removal of triglyceride-rich lipoproteins from the circulation.     

Hypertriglyceridemia is exacerbated by slow lipolysis of triacylglycerol-rich lipoproteins in fed but not fasted streptozotocin diabetic rats.

Hydrolysis by endothelial lipases of triacylglycerol-rich lipoproteins of diabetic origin were compared to lipoproteins of non-diabetic origin. The plasma lipoprotein fraction of density < 1.006 g/ml, including chylomicrons and VLDL, were incubated in vitro with post-heparin plasma (PHP) lipases. The lipoproteins of diabetic origin were hydrolysed at a significantly slower rate than lipoproteins from normal rats by the lipoprotein lipase component of PHP. However, if rats were fasted for 16 h prior to lipoprotein recovery, no differences in rates of VLDL hydrolysis were observed. Slower hydrolysis of lipoproteins of diabetic origin reflected a decrease in the apolipoprotein CII/CIII ratio and other changes in the apolipoprotein profile. To assess whether diabetic rats were less able to clear triacylglycerol independent of changes in the nature of the lipoproteins, we monitored the clearance of chylomicron-like lipid emulsions in hepatectomized rats. In vivo, emulsion triacylglycerol hydrolysis was not slowed due to diabetes. However, control and diabetic rats, which had been fasted for 16 h, cleared triacylglycerol at about twice the rate of fed rats. Triacylglycerol secretion rates in diabetic and control rats were similar, whether fed or fasted. We conclude that in streptozocin diabetic rats, hypertriglyceridemia was not due to overproduction of chylomicron- or VLDL-triacylglycerol, nor to decreased endothelial lipase activities. Rather, in fed diabetic rats, the triacylglycerol-rich lipoproteins are poorer substrates for lipoprotein lipase. This may lead to slower formation of remnants which would exacerbate slow remnant removal. VLDL of diabetic origin were hydrolysed as efficiently as VLDL from control donors, suggesting that in the fed state the lipolytic defect may be specific for chylomicrons.     

High-cholesterol diet-induced lipoproteins stimulate lipoprotein lipase secretion in cultured rat alveolar macrophages

We have previously shown that cultured rat alveolar macrophages synthesize and secrete lipoprotein lipase into the medium. The purpose of the present experiments is to examine whether cholesterol-enriched lipoproteins from cholesterol-fed animals have any effects on the lipoprotein lipase secretion and the lipid accumulation in macrophages. Macrophages incubated with the VLDL obtained from rats fed a normal diet secreted 2-fold higher amounts of lipoprotein lipase than those without lipoproteins. Intermediate-, low- and very-low-density lipoproteins from rats fed a high-cholesterol diet also enhanced the lipoprotein lipase secretion. Normal high- and low-density lipoproteins, and high-density lipoproteins from hypercholesterolemic animals did not cause any increase in the lipoprotein lipase secretion. The lipoproteins which stimulated the lipoprotein lipase secretion caused intracellular accumulation of both triacylglycerol and cholesterol. It is speculated that macrophages residing in the environment rich in lipoproteins, especially hypercholesterolemic lipoproteins, take them up and accumulate lipids intracellularly, and that this process links with the lipoprotein lipase secretion. The secreted lipoprotein lipase could facilitate, by degrading lipoproteins, the uptake of lipoprotein lipase-modified lipoproteins. Probably such a series of events is of importance in the foam cell formation of macrophages.     

Studies on the mechanism of hypertriglyceridemia in Tangier disease. Determination of plasma lipolytic activities, k1 values and apolipoprotein composition of the major lipoprotein density classes

Mechanisms responsible for hypertriglyceridemia in Tangier disease were elucidated by an analysis of the plasma post-heparin lipolytic activities and the structural and metabolic properties of very low (VLDL) and low (LDL) density lipoproteins. The levels of lipoprotein lipase activity in six Tangier patients were significantly lower (P less than 0.001) than in 40 control subjects (8.1 +/- 3.3 (+/- S.D.) vs. 14.1 +/- 3.7 units/ml). In contrast, the levels of hepatic triacylglycerol lipase were higher (P less than 0.01) than in normal controls (14.4 +/- 3.9 vs. 9.3 +/- 4.0 units/ml). Because kinetic parameters such as Km or Vmax cannot be obtained with naturally occurring triacylglycerol-rich lipoproteins, the pseudo-first-order rate constant (k1) of triacylglycerol hydrolysis was used to assess the effectiveness of triacylglycerol-rich lipoproteins as substrates for lipoprotein lipase. The k1 values for Tangier VLDL (k1 = 0.017 +/- 0.002 min-1) were significantly lower (P less than 0.001) than the k1 values (0.036 +/- 0.008 min-1) for control VLDL. Both the Tangier and control LDL2 are similar in their resistance to the action of lipoprotein lipase, as shown by their low k1 values (0.002 +/- 0.001 and 0.001 +/- 0.001 min-1, respectively). The major compositional difference between the lipoproteins of Tangier disease and normal subjects was a significant increase in the percent content of apolipoprotein A-II in all lipoprotein particles with d less than 1.063 g/ml, with the greatest increase occurring in VLDL and the lowest in LDL2. These results were interpreted as indicating that, in Tangier disease, there is a lower reactivity of VLDL with lipoprotein lipase which may in part be attributed to the abnormal apolipoprotein composition. This finding, in conjunction with the reduced levels of lipoprotein lipase activity, may explain the hypertriglyceridemia in Tangier disease.     

Suppression of 3-hydroxy-3-methylglutaryl-CoA reductase by low density lipoproteins produced in vitro by lipoprotein lipase action on nonsuppressive very low density lipoproteins.

Very low density lipoproteins (VLDL), Sf60 to 400, from normolipemic individuals do not suppress 3-hydroxy-3-methylglutaryl-CoA reductase activity in cultured normal human fibroblasts at concentrations 20-fold higher than those of low density lipoproteins (LDL) that give total suppression. To determine if these VLDL contain all of the structural elements necessary for receptor-mediated suppression, they were converted in vitro with bovine milk lipoprotein lipase to low density lipoproteins. These LDL-like lipoproteins were as effective in suppression as LDL isolated directly from plasma, with half-maximal and complete suppression at 1 and 4 microgram of cholesterol ml-1. Neither native LDL nor LDL produced in vitro suppressed receptor-negative fibroblasts. We conclude that action of lipoprotein lipase on VLDL leads to a rearrangement of lipoprotein components that permits interaction of LDL produced in vitro with the LDL-specific cell surface receptor of fibroblasts and subsequent suppression of 3-hydroxy-3-methylglutaryl-CoA reductase.     

Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV

Lipoprotein lipase (LPL)-mediated hydrolysis of triglycerides (TG) contained in chylomicrons requires the presence of a cofactor, apolipoprotein (apo) C-II. The physiological mechanism by which chylomicrons gain apoC-II necessary for LPL activation in whole plasma is not known. Using a gum arabic stabilized TG emulsion, activation of LPL by lipoprotein apoC-II was studied. Hydrolysis of TG by LPL was greater in the presence of serum than with addition of either high density lipoproteins (HDL) or very low density lipoproteins (VLDL). LPL activation by either VLDL or HDL increased with addition of the lipoprotein-free fraction of plasma. A similar increase in LPL activity by addition of the lipoprotein-free fraction together with HDL or VLDL was observed when another TG emulsion (Intralipid) or TG-rich lipoproteins from an apoC-II deficient subject were used as a substrate. Human apoA-IV, apoA-I, apoE, and cholesteryl ester transfer protein were assessed for their ability to increase LPL activity in the presence of VLDL. At and below physiological concentrations, only apoA-IV increased LPL activity. One hundred percent of LPL activity measured in the presence of serum was achieved using VLDL plus apoA-IV. In the absence of an apoC-II source, apoA-IV had no effect on LPL activity. Removal of greater than 80% of the apoA-IV from the nonlipoprotein-containing fraction of plasma by incubation with Intralipid markedly reduced its ability to activate LPL in the presence of VLDL or HDL. Gel filtration chromatography demonstrated that incubation of the nonlipoprotein-containing fraction of plasma with HDL and the TG emulsion caused increased transfer of apoC-II to the emulsion and association of apoA-IV with HDL. Our studies demonstrate that apoA-IV increases LPL activation in the presence of lipoproteins. We hypothesize that apoA-IV is required for efficient release of apoC-II from either HDL or VLDL, which then allows for LPL-mediated hydrolysis of TG in nascent chylomicrons.     

Lipoprotein metabolism in hepatic lipase deficiency: studies on the turnover of apolipoprotein B and on the effect of hepatic lipase on high density lipoprotein

Hepatic lipase deficiency produces significant distortion in the plasma lipoprotein profile. Particles with reduced electrophoretic mobility appear in very low density lipoprotein (VLDL). Intermediate density lipoprotein (IDL) increases markedly in the circulation and plasma low density lipoprotein (LDL) levels fall. At the same time there is a mass redistribution within the high density lipoprotein (HDL) spectrum leading to dominance in the less dense HDL2 subfraction. The present study examines apolipoprotein B turnover in a patient with hepatic lipase deficiency. The metabolism of large and small very low density lipoproteins was determined in four control subjects and compared to the pattern seen in the patient. Absence of the enzyme did not affect the rate at which large very low density lipoproteins were converted to smaller particles within this density interval (i.e., of VLDL). However, subsequent transfer of small very low density lipoproteins to intermediate density particles was retarded by 50%, explaining the abnormal accumulation of VLDL in the patient's plasma. Despite this, intermediate density particles accumulated to a level 2.4-times normal because their subsequent conversion to low density lipoprotein has been almost totally inhibited. Consequently, the plasma concentration of low density lipoprotein was only 10% of normal. On the basis of these observations, hepatic lipase appears to be essential for the conversion of small very low density and intermediate density particles to low density lipoproteins. The pathways of direct plasma catabolism of these species were not affected by the enzyme defect. In vitro studies were performed by adding purified hepatic lipase to the patient's plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipid metabolism in endotoxic rats: decrease in hepatic triglyceride lipase activity

Studies were conducted to investigate the effect of E. coli endotoxin administration on hepatic triglyceride lipase (H-TGL) activity in rats, since H-TGL activity is known to behave differently from lipoprotein lipase (LPL) activity in various situations. Plasma triglyceride and free fatty acid concentrations were markedly elevated in animals after injection of endotoxin. Cholesterol and phospholipids were also increased significantly. Lipoprotein analysis by ultracentrifugation showed that the most pronounced increase of lipoproteins was in the VLDL and IDL fractions. Triglyceride lipase activities in post-heparin plasma were markedly decreased. A selective assay for H-TGL activity using a specific antibody revealed that this enzyme as well as LPL is significantly decreased (26% of control) in endotoxic animals. Thus, the increase of VLDL and IDL appears to result from the decrease of both of LPL and H-TGL.     

Characterization of the plasma lipoproteins of the genetically obese hyperlipoproteinemic Zucker fatty rat

The plasma lipoproteins of the Zucker fatty rat were characterized with respect to lipid and apoprotein composition, and results were compared with those obtained from lean controls. Information on apoproteins was obtained from gel filtration experiments and electrophoresis on polyacrylamide gels. Very low density lipoproteins (VLDL) were increased several-fold in fatties, and 78% of their mass was triglycerides compared with 60% in the controls. Low density (LDL) and high density (HDL) lipoproteins were increased by a factor of 2, although their compositions were similar to those of the controls. Levels of apoVLDL, apoLDL, and apoHDL were five, two and two times higher, respectively, in the fatties, and the two most rapidly moving subunit peptides on polyacrylamide gels were disproportionately elevated in the apoproteins. The slower of these two bands was present in relatively greater amounts than the faster one in fatties. If the slower peptide is an activator of lipoprotein lipase, analogous to the comparable subunit peptides of human apolipoproteins, plasmas of fatties could contain up to 10 times more lipase activator activity than control plasma. This finding, and the fact that adipose tissue lipoprotein lipase activity of fatties was about 150% of controls, suggests that fatties have increased capacities for VLDL catabolism. We have previously shown that hepatic VLDL secretory rates are higher than normal in these animals. The increased capacity for catabolism may be a response to the altered secretory rates.     

Acute inhibition of hepatic lipase and increase in plasma lipoproteins after alcohol intake

Chronic alcohol intake is associated with an increase in fasting plasma high density lipoproteins (HDL). To study alcohol's acute effects on plasma lipoproteins, we measured plasma lipoprotein concentrations and activities of postheparin plasma lipases in nine normolipemic males after ingestion of 40 g of ethanol (as whiskey). After alcohol there was no change in lipoprotein lipase activity but hepatic lipase was decreased to 67% of baseline at 6 hr. There were associated increases in HDL phospholipids (12 mg/dl) and cholesterol (10 mg/dl) resulting in prominence of larger, lipid-enriched HDL particles. Changes were most pronounced in the HDL3 and HDL2a subclasses. Very low density lipoprotein (VLDL) phospholipids and cholesterol were also increased by 13 and 9 mg/dl, respectively, with no significant change in triglycerides. Changes in lipoproteins and lipase were largely reversed 10 hr after alcohol intake. The transient increases in VLDL and HDL lipids after alcohol may result in part from acute inhibition of hepatic lipase activity. The results suggest a role of hepatic lipase in the catabolism of phospholipids of VLDL and possibly HDL.     

Metabolism of VLDL is increased in streptozotocin-induced diabetic rat hearts

In streptozotocin (STZ)-induced diabetic rats, we previously showed an increased heparin-releasable (luminal) lipoprotein lipase (LPL) activity from perfused hearts. To study the effect of this enlarged LPL pool on triglyceride (TG)-rich lipoproteins, we examined the metabolism of very-low-density lipoprotein (VLDL) perfused through control and diabetic hearts. Diabetic rats had elevated TG levels compared with control. However, fasting for 16 h abolished this difference. When the plasma lipoprotein fraction of density <1.006 g/ml from fasted control and diabetic rats was incubated in vitro with purified bovine or rat LPL, VLDL from diabetic animals was hydrolyzed as proficiently as VLDL from control animals. Post-heparin plasma lipolytic activity was comparable in control and diabetic animals. However, perfusion of control and diabetic rats with heparinase indicated that diabetic hearts had larger amounts of LPL bound to heparan sulfate proteoglycan-binding sites. [(3)H]VLDL obtained from control rats, when recirculated through the isolated heart, disappeared at a significantly faster rate from diabetic than from control rat hearts. This increased VLDL-TG hydrolysis was essentially abolished by prior perfusion of the diabetic heart with heparin, implicating LPL in this process. These findings suggest that the enlarged LPL pool in the diabetic heart is present at a functionally relevant location (at the capillary lumen) and is capable of hydrolyzing VLDL. This could increase the delivery of free fatty acid to the heart, and the resultant metabolic changes could induce the subsequent cardiomyopathy that is observed in the chronic diabetic rat.     

Loss of the lipoprotein lipase activating ability of rat serum after administration of some fatty liver inducing drugs.

The effects of the administration of different fatty liver inducing drugs on the serum lipoprotein lipase activating ability was investigated in rats. Addition of serum from 2-mercaptoethanol-, 2-mercaptoacetate-, ethionine- or D-galactosamine- treated rats failed to activate heart and adipose tissue lipoprotein lipase from control rats. The activating effect of serum was only slightly reduced in isopropanol-treated rats, whereas it was found unaffected in ethanol-treated ones. Electrophoresis of the lipoproteins and of the very low density lipoproteins (VLDL) fraction of sera from 2-mercaptoethanol-, 2-mercaptoacetate-, isopropanol-, ethionine- and D-galactosamine-treated rats suggest that the lack of lipoprotein lipase activation ability of these sera is most probably related to the impairing effects of these drugs upon VLDL metabolism, i.e. reduction of VLDL secretion in the case of 2-mercaptoethanol, 2-mercaptoacetate and isopropanol, production of abnormal VLDL in the case of D-galactosamine and both decreased VLDL secretion and production of abnormal VLDL in the case of ethionine.     

Plasma lipoproteins,postheparin plasma lipoprotein lipase activity intralipid half-life,triglyceride secretion rate and liver lipids in the mouse fed different cholesterol diets

Mice (SC), fed a semipurified diet containing cholesterol, cholic acid and sucrose, exhibited, in comparison to control animals (S), an increase in cholesterol, phospholipid and protein of VLDL, LDL₁ and LDL₂, but triglyceride of the same lipoproteins decreased, as did total plasma triglycerides. Postheparin plasma lipoprotein lipase activity of SC animals was 1.72 times that of S mice. At the same time Intralipid half-life in SC mice was decreased by 52%. Triglyceride secretion rate, after Triton WR 1339 treatment, and liver triglyceride content were reduced in SC animals. HDL mass was decreased in SC mice. Mice (AC) fed a standard diet containing cholesterol showed, in comparison to normal fed animals (A), an increase in cholesterol of VLDL, LDL₁ and LDL₂ but triglyceride of the same lipoproteins decreased as did total plasma triglycerides. Postheparin plasma lipoprotein lipase activity of AC animals was unmodified as was Intralipid half-life. In AC animals triglyceride secretion rate, after Triton WR 1339 treatment, was reduced but in a less extent than in SC mice. Liver triglyceride was unmodified. HDL mass was decreased in AC mice.     

Lipoprotein lipase of cultured mesenchymal rat heart cells. IV. Modulation of enzyme activity by VLDL added to the culture medium.

Lipoprotein lipase activity was studied in rat heart cell cultures grown in the presence of 20% fetal calf and horse serum and a medium concentration of triacylglycerol of 0.03 mg/ml. After 6--8 days, when the enzyme activity had reached high levels, the cells were incubated for 24 h in a medium containing 20% serum derived from fasted or fed rats. No change in enzyme activity occurred in the presence of fasted rat serum, but a 50% fall was observed with fed rat serium. When the complete culture medium was supplemented with rat plasma VLDL (0.075--0.75 mg triacylglycerol) a pronounced decrease in lipoprotein lipase activity occurred after 3--5 h of incubation. Similar extent of enzyme fall was observed also in the presence of triacylglycerol-rich lipoproteins isolated from rat plasma after feeding of safflower oil or lard, even though the fatty acid composition of the triacylgylcerol varied markedly. As the addition of VLDL to the culture medium resulted in a lesser fall of heparin releasable than residual activity it seems that there was no direct inhibition of surface bound enzyme activity and that the transport of the enzyme to the cell surface was not affected. These data indicate that addition of VLDL to the culture medium resulted in a fall in enzyme synthesis, while total protein synthesis as determined by incorporation of [3H]leucine, remained unchanged. This inhibition could be reproduced by increasing free fatty acid concentration of the medium, however addition of excess albumin to VLDL-containing medium did not prevent the fall in enzyme activity. The present results obtained with cultured rat hearts cells suggest that in vivo plasma levels of triacylglycerol-rich lipoproteins could modulate the lipoproteins could modulate the lipoprotein lipase activity of the heart.     

Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin: cholesterol acyltransferase and lipase deficiency

Density gradient ultracentrifugation was used to isolate and characterize the plasma lipoproteins from African green monkeys before and 24 and 48 h after subcutaneous injection of 300 micrograms/kg lipopolysaccharide (LPS) to induce an acute phase response. Compared with 0 h values, reductions occurred in plasma cholesterol (39%), high density lipoprotein (HDL) cholesterol (54%), lecithin:cholesterol acyltransferase (LCAT) activity (55%), and post-heparin plasma lipase activity (68%) 48 h after LPS injection while plasma triglyceride concentrations increased 700%. Cholesterol distribution among lipoproteins shifted from 7 to 41% in very low density lipoproteins (VLDL), 65 to 38% in low density lipoproteins (LDL), and 28 to 21% in HDL after LPS injection. At 48 h after LPS injection, all lipoprotein classes were relatively enriched in phospholipid and triglyceride and depleted of cholesteryl ester. The plasma concentration of all chemical constituents in VLDL was increased 3-9-fold within 48 h after LPS injection. By negative stain electron microscopy, HDL were discoidal in shape while VLDL and LDL appeared to have excess surface material present. Even though total HDL protein concentration in plasma was unaffected, the plasma mass of the smallest HDL subfractions (HDL3b,c) doubled while the mass of intermediate-sized subfractions (HDL3a) was dramatically decreased within 24 h after treatment. HDL became enriched in apoE, acquired apoSAA, and became depleted of apoA-I, A-II, and Cs by 48 h after LPS injection while apoB-100 remained the major apoprotein of VLDL and LDL. We conclude that administration of LPS to monkeys prevents normal intravascular metabolism of lipoproteins and results in the accumulation of relatively nascent forms of lipoproteins in plasma. These immature lipoproteins resemble those isolated from the recirculating perfusion of African green monkey livers, which are relatively deficient of LCAT activity and those isolated from the plasma of patients with familial LCAT deficiency.     

Lipoprotein lipase activation by red ginseng saponins in hyperlipidemia model animals.

The effect of ginseng saponins isolated from red ginseng (a steamed and dried root of Panax ginseng) has been studied in a cyclophosphamide (CPM)-induced hyperlipidemia model in fasted rabbits. In this model, chylomicrons and very low density lipoprotein (VLDL) accumulation was known to occur as a result of reduction in lipoprotein lipase (LPL) activity in the heart and heparin-releasable heart LPL. Oral administration of ginseng saponins at a dose of 0.01 g/kg for 4 weeks was found to reverse the increase in serum triglycerides (TG) and concomitant increase in cholesterol produced by CPM treatment, especially in chylomicrons and VLDL. In addition, ginseng saponins treatment led to a recovery in postheparin plasma LPL activity and heparin-releasable heart LPL activity, which were markedly reduced by CPM treatment. In rats given 15% glycerol/15% fructose solution, postheparin plasma LPL activity declined to two third of normal rats, whereas ginseng saponins reversed it to normal levels. In the present study we first demonstrated that ginseng saponins sustained LPL activity at a normal level or protected LPL activity from being decreased by several factors, resulting in the decrease of serum TG and cholesterol.     

Metabolic disorders of serum lipoproteins in endotoxin-poisoned mice: the role of high density lipoprotein (HDL) and triglyceride-rich lipoproteins

A study was performed to clarify the role of serum lipoproteins, especially high density lipoprotein (HDL) and triglyceride-rich lipoproteins in endotoxemic or endotoxin-poisoned animals. The level of HDL-cholesterol decreased markedly in mouse serum 18-24 hr postintoxication, while the amount of low density lipoprotein (LDL)-cholesterol in the sera of poisoned mice was about 175% of that of the controls. Serum lecithin-cholesterol acyltransferase activity in the poisoned mice decreased slightly for 3-6 hr after endotoxin injection, but became markedly increased at 18-24 hr as compared with that in the controls. The amount of serum very low density lipoprotein (VLDL) showed a marked increase in the poisoned mice 8-24 hr postintoxication. The HDL fraction in the electrophoretic patterns of serum was reduced according to the dose of endotoxin 18 hr postintoxication. The HDL fraction in mice injected with lead acetate plus endotoxin was markedly lower than that in the poisoned mice. When streptozotocin-diabetic mice were injected with endotoxin, the HDL fraction was higher than that in the endotoxin-poisoned mice. In endotoxin-poisoned mice a correlation was observed between the lipid peroxide and LDL levels in the serum. In disk electrophoretic patterns, the HDL fraction in mice given vitamin E-supplemented diet showed a higher level than that in mice given a normal diet. Lipoprotein lipase (LPL) activity in poisoned mice significantly decreased to 59% of the control value 18 hr postintoxication, but hepatic triglyceride lipase activity was only slightly increased in endotoxin-poisoned mice. In analysis of HDL apoprotein peptide in serum lipoprotein, the apo C-II peptide level was clearly lower in mouse serum 18 hr postintoxication than that in the controls. These results suggest that the decrease in LPL activity in endotoxin-poisoned mice may be closely related to a decrease in the apo C-II peptide level, and also that it plays an important part in HDL and triglyceride-rich lipoprotein metabolism in the poisoned mice.     

Triacylglycerol increase in plasma very low density lipoproteins in cyclophosphamide-treated rabbit: relationship with cholesteryl ester transfer activity

We have studied the cholesteryl ester transfer between HDL and VLDL in cyclophosphamide-treated rabbits, in order to explain the abnormal cholesteryl ester partition between these two lipoprotein classes. The hypertriglyceridemia caused by treatment with the drug was associated with cholesteryl ester- and triacylglycerol-rich VLDL and with HDL poor in esterified cholesterol but relatively enriched in triacylglycerol. These two lipoprotein classes were characterized by their chemical composition and by gel filtration chromatography. VLDL particles were slightly larger in size, compared with controls. Different transfer combinations were envisaged between these abnormal lipoproteins and control ones. The transfer study involved the plasma fraction of d greater than 1.21 g/ml containing the cholesteryl ester transfer protein (CETP). It appeared that the chemical composition of lipoproteins was responsible for the level of cholesteryl ester transfer between lipoproteins. Actually, when the cholesteryl ester acceptor lipoproteins (VLDL) were enriched in triacylglycerol, the transfer was enhanced. Therefore, the effect of lipolysis on the transfer has also been explored. Lipoprotein lipase seemed to enhance the transfer of cholesteryl ester from HDL to VLDL when these lipoproteins were normal, but an important decline was obtained when triacylglycerol-rich VLDL were lipolyzed. This study defines the relationship between lipoprotein chemical composition and transfer activity of cholesteryl ester from HDL to VLDL.