Low Density Lipoprotein Catabolism Research Articles

Low density lipoprotein receptor-binding activity in human tissues: quantitative importance of hepatic receptors and evidence for regulation of their expression in vivo.

The heparin-sensitive binding of 125I-labeled low-density lipoprotein (LDL) to homogenates from 18 different normal human tissues and some solid tumors was determined. The binding to adrenal and liver homogenates fulfilled criteria established for the binding of LDL to its receptor--namely, (i) saturability, (ii) sensitivity to proteolytic destruction, (iii) inhibition by EDTA, and (iv) heat sensitivity. When the binding of 125I-labeled LDL was assayed at a constant concentration (50 micrograms/ml), the adrenal gland and the ovary had the highest binding of normal tissues. The highest binding per g of tissue overall was obtained in homogenates of a gastric carcinoma and a parotid adenoma. When the weights of the parenchymatous organs were considered, the major amount of LDL receptors was contained in the liver. To study the possible regulation of hepatic LDL-receptor expression, 11 patients were pretreated with cholestyramine (8 g twice a day for 3 weeks). Increased binding activity (+105%, P less than 0.001) was obtained in homogenates from liver biopsies from the cholestyramine-treated patients as compared with 12 untreated controls. It is concluded that the liver is the most important organ for LDL catabolism in humans and that the receptor activity in this organ can be regulated upon pharmacologic intervention. Further studies are needed to confirm the possibility that certain solid tumors can exhibit high numbers of LDL receptors.

Unexpected failure of bile acid malabsorption to stimulate cholesterol synthesis in sitosterolemia with xanthomatosis. Comparison with lovastatin.

We examined the relationship between cholesterol synthesis and high affinity low density lipoprotein (LDL) catabolism in freshly isolated mononuclear leukocytes and plasma sterols and apolipoprotein concentrations in three homozygous and one heterozygous subject with sitosterolemia with xanthomatosis and in 12 control subjects. Observations in untreated subjects were compared during therapy with lovastatin or interruption of the enterohepatic circulation of bile acids. Plasma cholesterol, plant sterol, and apolipoprotein B concentrations declined more than 50% in the two homozygous sitosterolemic subjects after ileal bypass surgery. In contrast, plasma cholesterol, plant sterol, and apolipoprotein B concentrations remained constant in a homozygous sitosterolemic subject and declined only 7% in a heterozygous sitosterolemic subject during 20 weeks of lovastatin (40 mg/day) treatment compared to a 28% decrease in similarly treated control subjects. Lovastatin treatment decreased cholesterol synthesis more than 60% but did not increase high affinity catabolism of LDL further in the sitosterolemic cells, compared to a more than 20% rise in control mononuclear leukocytes. Conversely, bile acid malabsorption increased cholesterol synthesis 59%, total hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase activity 13%, and receptor-mediated LDL degradation 41% in control cells, but did not stimulate cholesterol synthesis or microsomal HMG-CoA reductase activity in sitosterolemic mononuclear leukocytes although receptor-mediated LDL catabolism rose an additional 26%. These results demonstrate a greater than expected decrease in plasma sterols and apolipoprotein B concentrations in sitosterolemic subjects after stimulation of bile acid synthesis because of the inability to up-regulate cholesterol production. We suggest that bile acid-sequestering drugs or ileal exclusion surgery may be more effective treatments to mobilize accumulated sterol deposits and prevent atherosclerosis in this disease.

Low-density lipoprotein metabolism in the nephrotic syndrome

Hyperlipidemia is a consistent feature of the nephrotic syndrome. In this study, low-density lipoprotein (LDL) metabolism has been investigated in nine patients with nephrotic syndrome and varying degrees of proteinuria. In subjects with moderate proteinuria (less than 10 g/d), total plasma cholesterol values were elevated to approximately 160% of normal due mainly to an increase in circulating LDL cholesterol. Metabolic studies showed that a defect in LDL clearance via the receptor pathway was responsible for its accumulation. The total amount of LDL apolipoprotein catabolized by this mechanism was only 55% of the value seen in controls; 60% more LDL was channelled into alternative, receptor-independent, catabolic pathways. Heavier proteinuria was associated with substantial increases in plasma triglyceride and very-low-density lipoprotein (VLDL) levels. The defect in LDL catabolism was aggravated by oversynthesis of the lipoprotein, which expanded the plasma LDL pool to 250% of normal. These observations indicate that the hyperlipidemia of the nephrotic syndrome is multifactorial in origin. The altered catabolism of LDL may be important in predisposing these subjects to premature atherosclerosis.

Effect of dietary fat saturation and cholesterol on LDL composition and metabolism. In vivo studies of receptor and nonreceptor-mediated catabolism of LDL in cebus monkeys.

The mechanism(s) by which polyunsaturated fats reduce low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B were investigated in 20 cebus monkeys (Cebus albifrons) fed diets containing corn oil or coconut oil as fat (31% of calories) with or without dietary cholesterol (0.1% by weight) for 3 to 10 years. Coconut-oil feeding compared to corn-oil feeding resulted in significant increases in levels of plasma total cholesterol (176%), very low density lipoprotein (VLDL)-LDL cholesterol (236%), high density lipoprotein (HDL) cholesterol (148%), apo B (78%), and apo A-I (112%). The addition of dietary cholesterol to corn oil compared to corn oil alone resulted in smaller, but significant, increases in levels of total cholesterol (44%), HDL cholesterol (40%), and apo A-I (33%). Although the increases in VLDL-LDL cholesterol were of similar magnitude (52%), they barely failed to reach statistical significance (p less than 0.08), while the changes in apo B levels were negligible. The addition of dietary cholesterol to coconut oil, compared to coconut oil alone, resulted in no significant changes in lipoprotein cholesterol or apoproteins, although levels of VLDL-LDL cholesterol and apo B values increased 22% and 16%, respectively. Although hepatic free cholesterol content was not altered by diet, coconut-oil compared to corn-oil feeding resulted in significant increases in hepatic cholesteryl esters (236%) and triglycerides (325%), the latter increasing still further when dietary cholesterol was added to coconut oil (563%). To further assess the effects of these dietary changes on LDL metabolism, radioiodinated normal and glucosylated LDL kinetics were performed. The production rate of LDL apo B was not altered by diet. With corn-oil feeding, 63% of LDL catabolism was via the receptor-mediated pathway. Coconut-oil compared to corn-oil feeding resulted in a 50% decrease in receptor-mediated LDL apo B fractional catabolic rate (FCR) and a 27% reduction in nonreceptor-mediated LDL apo B FCR. The addition of dietary cholesterol to corn oil, compared to corn oil alone, resulted in no significant effect on LDL apo B catabolism. The addition of dietary cholesterol to coconut oil, compared to coconut oil alone, was associated with no significant change in nonreceptor catabolism of LDL apo B but with a 58% decrease in receptor-mediated catabolism of LDL (p less than 0.059). The diet-induced alterations of LDL catabolism were significantly correlated with hepatic lipids, which were enriched in saturated fatty acids.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of feed deprivation on hepatic membrane and lipoprotein fluidity and binding of lipoproteins to hepatic membranes in the chick ( Gallus domesticus)

1. 1. Male chicks were deprived of feed for 48 hr to study the effect of metabolics stress on hepatic membrane and lipoprotein fluidity and binding of radioiodinated lipoproteins to hepatic membranes. 2. 2. Plasma levels of low density lipoprotein (LDL) and high density lipoprotein (HDL) were markedly and slightly elevated, respectively. 3. 3. There was a reduction in lopoprotein and hepatic membrane fluidity. 4. 4. Binding of [ 125I]LDL, but not [ 125I]HDL, to hepatic membranes was decreased. 5. 5. It is suggested that a reduction in the fluidity of LDL and/or hepatic membranes impedes LDL catabolism in vivo

Pyridoxine reduces cholesterol and low-density lipoprotein and increases antithrombin III activity in 80-year-old men with low plasma pyridoxal 5-phosphate

We have previously observed that pyridoxine treatment reduced plasma total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol concentrations and increased antithrombin III (AT III) activity in atherosclerotic patients with subnormal plasma pyridoxal 5-phosphate (PLP) levels. In order to confirm these results, we selected 17 males with low plasma PLP levels from a group of 122 80-year-old males in whom PLP has been determined. After supplementation with 120 mg of pyridoxine per day for 8 weeks their mean plasma TC and LDL cholesterol concentrations were decreased by 10% (p less than 0.01) and 17% (p less than 0.001), respectively. There was no effect on high-density lipoprotein cholesterol and triglycerides but plasma AT III activity was increased by 6% (p less than 0.05). The mechanism by which pyridoxine acts is unclear but it is hypothesized that pyridoxine-derived PLP may enhance the catabolism of LDL and the activity of AT III by inhibiting their glycosylation.

Effect of simvastatin on receptor-dependent low density lipoprotein catabolism in normocholesterolemic human volunteers

Simvastatin, an inhibitor of HMG-CoA reductase was given to 7 normolipidemic healthy volunteers for 1 month at a dose of 20 mg/day. Measurements of turnover of low density lipoprotein apolipoprotein B (LDL-apo B) were determined before and after drug treatment using intravenous injection of 125I-labeled LDL and 131I-labeled cyclohexanedione-treated LDL to quantify the receptor pathway. In addition to a 13% increase in HDL cholesterol and apolipoprotein A-I concentrations, plasma cholesterol was reduced by 20%, LDL-cholesterol by 32%, and apolipoprotein B by 23%. Assuming a heterogeneous pool of LDL, the new model presented in the companion paper was built to calculate the contribution of the receptor-dependent and the receptor-independent pathways and the corresponding fractional catabolic rates. Simvastatin did not modify constantly the synthetic rate of LDL-apo B but increased the fractional catabolic rate of the receptor-dependent pathway and the contribution of this pathway in the catabolism. The fall in LDL plasma levels observed in normocholesterolemic subjects can be then entirely explained by an enhanced fractional removal of LDL from the circulation by the receptor route.

HYPOCHOLESTEROLAEMIA AND INCREASED ELIMINATION OF LOW-DENSITY LIPOPROTEINS IN METASTATIC CANCER OF THE PROSTATE

To study the influence of tumour mass on lipid metabolism, the lipoprotein pattern in untreated patients with newly diagnosed cancer of the prostate was examined. Total cholesterol levels were reduced in patients with evidence of metastasis (n=30) compared with those without metastasis (n = 73). Since the major fraction of serum cholesterol is contained in low-density lipoproteins (LDL), turnover of LDL was studied in detail in 8 patients compared with 12 age-matched healthy men. LDL were cleared faster in the 3 patients with metastatic disease than in the patients without metastasis and in controls, indicating faster catabolism of LDL. Thus in prostatic cancer an increased tumour burden is associated with increased elimination of LDL, which contributes to reduced serum cholesterol levels.

Effect of Dietary Restriction on Receptor-Mediated and Independent Catabolism of β-Very Low Density Lipoproteins in Cholesterol-Fed Rabbits

This study was designed to define the effect of dietary restriction and cholesterol feeding on disturbances of very low density lipoprotein (VLDL) catabolism. Three groups of 15 New Zealand rabbits were fed standard or cholesterol-rich diets either ad libitum or in restricted amounts and in vitro binding assays on hepatocyte membranes were carried out after 4, 8, 12 and 20 d. Cholesterol feeding reduced the specific binding of labeled beta-VLDL to liver membranes. Dietary restriction, which enhances the hypercholesterolemia induced by cholesterol feeding, had no additional effect on the down-regulation of beta-VLDL specific binding. In another set of experiments the uptake of labeled beta-VLDL by various tissues was measured after 15 d of feeding the diets. Cholesterol feeding decreased uptake of these lipoproteins by the liver and various extrahepatic tissues, such as skin, intestine, muscle, adipose tissue, kidneys, spleen and aorta. Additional changes occurred in liver and intestine with dietary restriction. In liver beta-VLDL uptake in the group fed a restricted amount of the cholesterol-containing diet was 70% of that in the group fed the same diet ad libitum. Taken together, the results suggest that dietary restriction acts mainly on the receptor-independent catabolism of beta-VLDL.

Unesterified Fatty Acids Inhibit the Binding of Low Density Lipoproteins to the Human Fibroblast Low Density Lipoprotein Receptor

Micromolar concentrations of oleate were found to inhibit reversibly the binding of low density lipoprotein (LDL) to the human fibroblast LDL receptor. The decrease in LDL binding caused a parallel reduction of both 125I-LDL uptake and degradation at 37 degrees C. At 4 degrees C, oleate was also found to displace 125I-LDL already bound to the LDL receptor. The effect of oleate was rapid, reaching 70-80% of maximum displacement with 5-10 min of incubation, and was closely correlated to oleate-albumin molar ratios. Partition analysis of unesterified fatty acids between cells and LDL showed that the inhibitory effect of oleate resulted mainly from an interaction of unesterified fatty acids with the cell surface rather than with the LDL particles. Using different unesterified fatty acids and fatty acid analogs, we found that the inhibitory effect was modulated by both the length and the conformation of the monomeric carbon chain and was directly dependent on the presence of a negative charge on the carboxylic group. At 4 degrees C, the inhibitory effect of oleate never exceeded half of maximum binding capacity. This limitation was associated with the ability of oleate to interact only with part of the population of LDL receptors which spontaneously recycles in the absence of ligand, as demonstrated by the fact that oleate did not induce any reduction of LDL binding after cell treatment with monensin in the absence of LDL. Our results indicate that unesterified fatty acids could participate in the control of LDL catabolism in vivo by direct modulation of the ability of LDL receptor to bind LDL.

Trapidil derivatives and low density lipoprotein metabolism by human skin fibroblasts and by human hepatoma cell line Hep G2

The effect of trapidil (Rocornal R) and some of its newly developed derivatives (AR 12456, AR 12463, AR 12465, AR 12464) on the receptor-mediated low density lipoprotein (LDL) binding, uptake and degradation was studied in human skin fibroblasts (HSF) and in human hepatoma cell line Hep G2. Compound AR 12456 influenced this pathway in a selective way: it enhanced the uptake and degradation of 125I-LDL by Hep G2 cells in a dose-dependent manner, but inhibited it in HSF. Scatchard analysis of the saturable LDL binding in Hep G2 indicates that the effect of compound AR 12456 is the result of an increased number of LDL binding sites. Compound AR 12465 was less effective on LDL catabolism. Trapidil and the other derivatives were inactive under the same experimental conditions. When Ar 12456 was preincubated with Hep G2 cells and then the incubation medium was transferred to HSF, a stimulation of specific LDL pathway occurred also in this cell line. These findings suggest that a metabolite(s) of AR 12456 might be responsible for the enhanced expression of LDL receptors in cultured human cells.

Carbon disulfide modification and impaired catabolism of low density lipoprotein

Carbon disulfide interacts in vitro with low density lipoprotein (LDL), resulting in an increased electrophoretic mobility of the particle, due to a decrease in free amino groups of apolipoprotein B-100. The processing of carbon disulfide-modified LDL through the apo B E receptor pathway of cultured human fibroblasts is decreased as compared to that of native LDL, depending on the level of modification. Carbon disulfide-modified LDL is recognized and degraded by the scavenger pathway of macrophages, but to a lesser extent than acetylated LDL. Carbon disulfide modification decreases the ability of the LDL to down-regulate sterol synthesis and to stimulate cholesterol esterification in fibroblasts. Carbon disulfide-modified LDL markedly stimulates cholesteryl ester formation in macrophages, albeit to a lesser extent than acetylated LDL. These results indicate that after carbon disulfide modification the LDL catabolism is shifted to the scavenger pathway, and are consistent with the fact that carbon disulfide intoxication accelerates the appearance of atherosclerotic lesions.

Low-density lipoprotein catabolism in WHHL rabbits after partial ileal bypass surgery

The effect of partial ileal bypass surgery (PIB) on lipoprotein concentrations and compositions and on the catabolism of low-density lipoproteins (LDL) was studied in Watanabe heritable hyperlipidemic (WHHL) rabbits. After PIB, total serum cholesterol was 65% lower (6.22 +/- 1.58 vs. 17.24 +/- 3.22 mmol/l) and LDL cholesterol 81% lower (2.02 +/- 0.95 vs. 10.90 +/- 3.60 mmol/l) than in control WHHL rabbits; cholesteryl esters, expressed as percentage of mass, were 55% lower in the very-low and intermediate-density lipoprotein (VLDL + IDL) fractions, and 45% lower in LDL, whereas triacylglycerols were 89% higher in VLDL + IDL and 121% higher in LDL. The fractional catabolic rate (FCR) of LDL protein (apoLDL) from operated animals was 10% higher than that from controls in all animals (0.55 +/- 0.10 vs. 0.50 +/- 0.10 pools/day; P less than 0.01). The FCR of autologous apoLDL in PIB rabbits was 50% higher than that of autologous apoLDL in control rabbits (0.63 +/- 0.05 vs. 0.42 +/- 0.06 pools/day); this was not caused by induction of receptor-mediated clearance of LDL. The production rate of apoLDL after PIB in PIB rabbits was 50% lower compared to control apoLDL in controls (26.0 +/- 6.7 vs. 51.7 +/- 16.4 mg/kg per day). We conclude that PIB lowers LDL cholesterol in WHHL rabbits by a decreased production of LDL, by an increased non-specific clearance of LDL and by compositional changes, which lead to LDL particles containing less cholesterol.

Colestipol-induced changes in LDL composition and metabolism. II. Studies in humans.

We investigated the effect of the bile acid sequestrant, colestipol hydrochloride, on the composition and metabolism of human low density lipoprotein (LDL). Colestipol treatment produced a disproportionate decrease in LDL cholesterol compared to LDL apoB, resulting in a significant decrease in the LDL cholesterol/apoB ratio. Electron microscopy revealed that LDL particles were smaller in size and analytical ultracentrifugation demonstrated that colestipol therapy selectively depleted larger, more buoyant LDL particles of Sf degrees 6-7. Thus, colestipol therapy produced LDL that were smaller in size, more dense, and characterized by a decreased cholesterol to protein ratio. To determine whether the altered LDL had different metabolic properties, autologous LDL was isolated from subjects before and during colestipol therapy and their fractional catabolic rates (FCR) were then simultaneously determined in the same patient while on therapy. Eight LDL turnover studies comparing the catabolism of LDL isolated during therapy (Rx-LDL) and LDL isolated off therapy (Con-LDL) were performed in six subjects. All subjects responded to colestipol treatment, with an average 29% fall in LDL cholesterol. In four of six subjects, and in six of eight studies, the FCR of Rx-LDL was substantially slower than that of Con-LDL. These studies demonstrate that a drug intervention may alter subpopulations of LDL particles in such a way that overall LDL composition is changed. This alteration may independently affect the intrinsic metabolic behavior of the LDL. We suggest that such drug- (or dietary-) induced changes in LDL composition need to be considered in kinetic studies designed to assess the overall impact of the perturbation being studied.

Thymus fraction (FIII) Effect on cholesterol metabolism: Modulation of the low density lipoprotein receptor pathway

1. 1. A heat stable protein fraction from calf thymus is able to determine a marked drop of total serum cholesterol and B apoproteins in rats fed a cholesterol enriched diet. 2. 2. It is known that the catabolism of low density lipoprotein (LDL) cholesterol is mediated by the existence of high affinity surface receptor on membrane cells. 3. 3. The purpose of the present paper is to verify if the heat stable thymus protein fraction is able to affect the LDL receptor pathway in vitro. 4. 4. The results obtained show that the protein calf thymus is able to increase human and rat LDL catabolism.

Mechanism of action of bile acid sequestrants and other lipid-lowering drugs.

Although the primary and direct action of the bile acid sequestrants is to bind bile acids in the gut, their interruption of the enterohepatic recirculation of bile acids has important effects on hepatic lipoprotein metabolism. Three key enzyme systems are affected: phosphatidic acid phosphatase, cholesterol 7 alpha-hydroxylase, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Activation of phosphatidic acid phosphatase promotes hepatic triglyceride (TG) synthesis, induces secretion of TG-rich, very low density lipoprotein particles, and consequently, increases plasma TG levels. The activation of hepatic cholesterol 7 alpha-hydroxylase promotes the conversion of intracellular cholesterol to bile acids. The decrease in intracellular cholesterol stores, in turn, increases low-density lipoprotein (LDL) receptor expression on hepatocyte surface membranes and, consequently, receptor-mediated fractional catabolism of LDL. Reduction of intracellular cholesterol may also increase the synthesis of cholesterol through activation of HMG CoA reductase. The potential loss of the sequestrant's cholesterol-lowering efficacy can be overcome by adding a drug to the regimen that inhibits HMG CoA reductase. Finally, bile acid sequestrants promote apoprotein AI synthesis by an unknown mechanism and tend to raise high-density lipoprotein (HDL) cholesterol levels, primarily by increasing plasma HDL-2 concentrations.

Down-regulation of hepatic LDL receptor protein and messenger RNA in fasted rabbits.

Rabbits fasted for 9 and 14 d exhibited 6- and 8-fold increase in plasma cholesterol level, respectively. As one of the mechanisms causing hypercholesterolemia in fasted rabbits, the decreased activity of hepatic low-density lipoproteins (LDL) receptor has been reported (Stoudemire, J.B., Renaud, G., Shames, D.M., & Havel, R.J. (1984) J. Lipid Res. 25, 33-39). In order to demonstrate the down-regulation of hepatic LDL receptor on a molecular basis, we carried out immunoblotting of the liver membranes with a specific antibody against LDL receptors and blot hybridization of hepatic RNAs with cDNA of LDL receptor. Immunoblotting showed that LDL receptors in fasted rabbits were markedly decreased, and blot hybridization of RNAs showed a significant decrease in mRNA level of hepatic LDL receptor in fasted rabbits. Further, significant decreases both in LDL binding to liver membrane and in hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in fasted rabbits were demonstrated. From these results, we concluded that hypercholesterolemia in fasted rabbits is caused by the impaired catabolism of LDL due to down-regulated biosynthesis of hepatic LDL receptor.

Defective receptor binding of low density lipoprotein from pigs possessing mutant apolipoprotein B alleles.

We previously identified a defect in the in vivo catabolism of low density lipoprotein (LDL) from hypercholesterolemic pigs carrying a mutant apolipoprotein B allele. In the present studies, we examined the in vitro metabolism of mutant LDL in cultured pig fibroblasts. A 3-fold higher concentration of mutant LDL (compared to control) was needed to displace 50% of control 125I-LDL binding. Mutant LDL had a 6-fold higher dissociation constant than control LDL. Scatchard plots of the binding data were concave upward, suggesting multiple classes of binding sites or negative cooperativity. The mutant LDL degradation rate was reduced by 40%; this decrease could be attributed to a dense LDL subspecies. Mutant and control buoyant LDL subspecies were degraded more slowly than the corresponding dense LDL subspecies. Together, these studies show that diminished LDL receptor binding can result from mutations in apolipoprotein B and from changes in the lipid composition of LDL particles.

Low density lipoprotein kinetics in African Green monkeys showing variable cholesterolaemic responses to diets realistic for westernised people

African Green (vervet) monkeys were fed either an atherogenic Western diet (WD), a prudent diet (PD), or a high carbohydrate diet (HCD) for various lengths of time. Monkeys differed greatly in their response to the WD, and a strong negative correlation was observed between the fractional catabolic rates (FCR) of low density lipoprotein (LDL) and the total plasma cholesterol concentrations ( r = −0.83 P = 0.0029). Similarly the individual synthetic rates (SR) of LDL plotted against the total plasma cholesterol concentrations showed a correlation coefficient of r = 0.94 P = 0.01 for WD animals. There was no correlation for PD or HCD animals for either SR or FCR and the total plasma cholesterol concentrations. The aortic lesion scores correlated with the SRs ( r = 0.66 P = 0.040) but not with the FCRs. LDL turnover was also studied using 125I-labelled native LDL and methylated 131I-labelled LDL in African Green monkeys showing high or low cholesterolaemic response to an atherogenic Western diet. Measurements after 4 weeks and again after 6 months on the diet showed a decrease in both total and non-receptor mediated clearance of LDL. Receptor-mediated catabolism was significantly lowered in the hyperresponding group ( P = 0.0011) and not in the hyporesponding group with a resultant significant difference between the two groups being P = 0.0355 after 6 months. Non-receptor mediated catabolism of LDL was similarly affected in that there was no significant difference between the two groups at 4 weeks but the clearance of methylated LDL was markedly lowered at 6 months, for the hyporesponding group P = 0.0003 and for the hyperresponding group P = 0.0184. Furthermore the hyperresponding group was depressed to a significantly greater extent when compared to the hyporesponding group ( P = 0.0241).

Low density lipoproteins in atherosclerosis.

Low density lipoproteins (LDL) have long been implicated in the development of atherosclerosis. Perhaps the most convincing evidence that these lipoproteins are causative factors in this disease is the genetic disorder, familial hypercholesterolemia, in which homozygous patients develop massive LDL concentrations and frequently die within the second decade of life from complications of coronary artery atherosclerosis (1). The reasons for the atherogenicity of LDL are incompletely understood. In epidemiologic studies, the concentration of LDL cholesterol in plasma has been shown to be highly correlated to the incidence of coronary heart disease (CHD) (2). Hence, factors that regulate LDL concentration through formation and catabolism are undoubtedly important in determining atherogenicity associated with LDL. Indeed, the massive LDL concentration that results from the absence of the LDL receptor in familial hypercholesterolemia is a graphic illustration of how a lack of control of LDL catabolism can lead to increased LDL concentrations and, subsequently, to premature complications of atherosclerosis (3). In addition, much new information has been developed about the heterogeneity in composition and character of plasma LDL particles. It now is apparent that many forms of LDL exist within and among individuals and it seems possible that some forms are more atherogenic than others. The purpose of this review will be to examine several aspects of low density lipoproteins that may be contributory to the development of CHD. We will review the information about LDL heterogeneity and how this may relate to the development of atherosclerosis. Since LDL concentration is also important in atherosclerosis, we will also review information about LDL formation and catabolism. Nonhuman primate models of experimental atherosclerosis have been extensively studied in this laboratory, so we will include, where appropriate, the lessons learned from these experimental models. Diet-induced elevations of the average size and concentration of LDL have been shown to be highly correlated to the extent of atherosclerosis in the coronary arteries of nonhuman primates (4). It seems clear that the low density lipoproteins are important in initiation andlor exacerbation of coronary artery atherosclerosis in the experimental primate model as well as in man. For prevention and treatment of CHD, it will be important to learn what factors cause elevated LDL concentrations and which properties of LDL lead directly to the atherogenicity of these lipoproteins.