Plasma Low-density Lipoprotein Concentrations Research Articles

Thromboxane A 2 (TXA 2) formation by washed human platelets under the influence of low and high density lipoproteins from healthy donors

Low density lipoprotein (LDL) stimulates TXA 2 formation (measured as malondialdehyde) in washed human platelets with active cyclooxygenase, whereas high density lipoprotein (HOL) does not show any influence on TXA 2 formation in this system. These results support the hypothesis that the proaggregatory action of a high plasma LDL concentration may be mediated by modification in the biosynthesis of eicosanoids. The mode of action of lipoproteins is discussed.

Drug Treatment for Hypercholesterolaemia

In Britain hypercholesterolaemia is common, and roughly a quarter of the adult population have plasma cholesterol levels greater than 6.5 mmol/1. Such levels are widely accepted as being associated with an appreciable risk of coronary heart disease. The risk appears to be directly related to the concentration of low density lipoprotein (LDL) cholesterol which is usually reflected in the total plasma cholesterol measurement [1]. High density lipoprotein (HDL) cholesterol is inversely related to coronary heart disease [1-3] but controversy remains as to whether it is an independent risk factor [4], The majority of people with a raised plasma cholesterol level have polygenic hypercholesterolaemia which is likely to respond to dietary modification (optimised calorie intake, reduction in saturated fat intake, an increase in the ratio of polyunsaturated to saturated fatty acids, and an increase in food containing soluble fibre). However, patients with a number of monogenic inherited disorders such as familial hypercholesterolaemia and familial combined hyperlipidaemia, have a particularly high risk of coronary heart disease and often show an inadequate response to diet changes alone. At least one in 500 people have familial hypercholesterolaemia, which in many adults is characterised by tendon xanthomas, xanthalasma and early corneal arcus, and is inherited in an autosomal dominant manner. The higher plasma concentration of LDL and total cholesterol is due to the fact that the cells of affected individuals have reduced numbers of the receptors responsible for LDL uptake. Untreated, these people have an estimated 50 per cent risk of dying from coronary heart disease before they reach 60 [5], and a significant number die or are disabled in their thirties and forties. Homozygotes, who are fortunately rare, seldom survive beyond the age of 25. Recent studies showing a reduction in the incidence and mortality from coronary heart disease associated with lowering of plasma cholesterol levels in people with primary hypercholesterolaemia [6, 7] have resulted in renewed interest in drug therapy for people who do not respond adequately to dietary modification. Coronary heart disease appears to be reduced irrespective of the type of hypercholeste rolaemia, but the potential benefit is likely to be particularly great in people with familial hypercholesterolaemia because their risk is so high if they are untreated. A number of different forms of lipid-lowerin g medication are available. For most patients with hypercholesterolaemia and normal, or near normal, plasma triglyceride concentration, an anion exchange resin such as cholestyramine or colestipol is the first line of treatment. These resins are not absorbed but act in the intestine by binding bile salts and reducing their enterohepatic circulation. This results in increased hepatic synthesis of bile salts from cholesterol. The dose of cholestyramin e required may vary from 4 to 28 g per day and the plasma cholesterol level can usually be reduced by at least 15 to 25 per cent. LDL cholesterol

Cultured human hepatocytes. Evidence for metabolism of low density lipoproteins by a pathway independent of the classical low density lipoprotein receptor.

Studies of low density lipoprotein (LDL) metabolism in nonhuman model systems have indicated that the mammalian liver has dual mechanisms for the uptake and regulation of the concentration of plasma LDL. Heretofore, direct evaluation of lipoprotein uptake mechanisms in human hepatocytes has not been possible. In order to compare hepatocyte LDL uptake with fibroblast LDL metabolism, human hepatocytes were isolated and cultured from small biopsy specimens obtained from normolipidemic and homozygous familial hypercholesterolemic patients. Cells cultured in serum-free culture medium retained the morphological and biochemical characteristics of hepatocytes for at least 7 days. The uptake and degradation of LDL by hepatocytes was compared to that of the cultured human fibroblasts. Like fibroblasts, hepatocytes bound, internalized, and degraded LDL. In both cell types, uptake approached saturation at a concentration of 50 micrograms of LDL protein/ml. Competition for LDL binding by LDL, high density lipoprotein, and modified LD revealed that the hepatocyte binding was specific for LDL. Cellular cholesterol loading by incubation in LDL-enriched culture medium resulted in diminished LDL uptake in both cell types. Chemical modification of LDL by acetoacetylation, acetylation, and reductive methylation abolished LDL uptake and degradation by fibroblasts. However, hepatocytes bound and degraded the modified LDL at 30-50% the level of native LDL. Homozygous familial hypercholesterolemic hepatocytes were devoid of the LDL receptor pathway but metabolized native LDL to the extent observed with modified LDL uptake by normal hepatocytes. In contrast to the classic LDL receptor pathway, the second or alternate pathway does not lead to regulation of 3-hydroxy-3-methylglutaryl-CoA reductase activity. These findings indicate the presence of two separate pathways of LDL uptake in human hepatocytes which have different effects on hepatocytic cholesterol metabolism.

The influence of exercise training on plasma lipids and lipoproteins in health and disease.

There is a very high probability that lipoprotein metabolism plays a central role in the etiology of coronary heart disease. In sedentary persons one way to favorably alter lipoprotein metabolism and possibly delay the progression of coronary atherosclerosis is by an increase in their habitual physical activity. More physically active persons tend to have lower plasma triglycerides and very low density lipoprotein concentrations, and a greater high-density lipoprotein mass due to higher concentrations of the subfraction HDL2 and apoprotein A-I. Plasma low-density lipoprotein concentrations usually are not significantly reduced by exercise unless accompanied by weight loss, but there may be important changes in the distribution among the low-density subfractions. These exercise effects are most likely mediated by alterations in the activity of enzymes involved in the synthesis, transport and catabolism of the various lipoproteins including lipoprotein lipase, hepatic lipase and lecithin: cholesterol acyltransferase. In healthy persons as well as in patients with ischemic heart disease, diabetes and renal failure, an increase in moderate-intensity, endurance-type activity requiring an expenditure of approximately 4 MJ (1,000 kcal) per week usually produce favorable lipoprotein changes. Above this level a dose-response relationship exists, with greater changes occurring up to energy expenditures of 19 MJ (4,500 kcal) per week.

The effect of portacaval shunt on hepatic lipoprotein metabolism in familial hypercholesterolemia

The hyperlipidemia observed in familial hypercholesterolemia can be reduced by portacaval anastomosis. We report the effects of a portacaval shunt on hepatic morphology and biosynthetic pathways crucial to hepatic cholesterol homeostasis in homozygous receptor-negative familial hypercholesterolemia. Portacaval anastomosis was associated with a dramatic change in hepatocyte morphology, 28% reduction in plasma low-density lipoprotein concentration, and a decrease in hepatic total and free cholesterol content by 27 and 75%, respectively. Furthermore, the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase was decreased by 56%. Finally, the reduced binding of low-density lipoproteins to hepatic membranes preoperatively was increased following the portacaval shunt. These combined results indicate that the changes in circulating lipoprotein concentrations observed after portacaval shunt are due to alterations in the metabolic consequences of the defective recognition of lowdensity lipoproteins by the liver of familial hypercholesterolemic subjects.

Receptor-independent low density lipoprotein transport in the rat in vivo. Quantitation, characterization, and metabolic consequences.

Receptor-independent low density lipoprotein (LDL) transport plays a critical role in the regulation of plasma cholesterol levels; hence, these studies were done to characterize this process in the tissues of the rat. High rates of receptor-independent clearance were found in the spleen, but other organs, like liver, gastrointestinal tract, and endocrine glands manifested lower clearance rates that varied from 3 to 9 microliter/h per g, while the rates in nervous tissue, muscle, and adipose tissue were less than 1 microliter/h per g. Receptor-dependent uptake was much higher in liver (85 microliter/h per g) and adrenal gland (219 microliter/h per g), but was also low in most other tissues. At normal plasma LDL concentrations, 67% of the receptor-dependent transport in the whole animal was accounted for by LDL uptake in the liver. In contrast, the receptor-independent uptake found in the whole animal took place in many organs, including skeletal muscle (20%), liver (16%), small bowel (15%), skin (10%), and spleen (7%). Furthermore, in liver, the rate of cholesterol synthesis could be varied 11-fold, yet the rate of receptor-independent LDL clearance remained constant at approximately 8 microliter/h per g. When the circulating levels of LDL were systematically increased, receptor-independent LDL clearance also remained constant, so that hepatic LDL-cholesterol uptake by this mechanism increased linearly, from 1 to 20 micrograms/h per g, as the plasma LDL-cholesterol level was increased from 10 to 250 mg/dl. Finally, when equal amounts of LDL-cholesterol were delivered into the liver by either the receptor-dependent or receptor-independent mechanism, there was significant suppression of cholesterol synthesis and an increase in cholesteryl esters. Thus, in any situation in which receptor-dependent LDL degradation is lost, cholesterol balance in the whole animal and across individual organs is maintained by receptor-independent mechanisms, although when the new steady state is achieved, circulating levels of LDL must necessarily be very much increased.

Abnormalities in metabolism of low density lipoproteins associated with coronary heart disease.

Low density lipoprotein (LDL) is probably the most atherogenic of all the lipoproteins. Several abnormalities in LDL metabolism seem to be associated with coronary heart disease (CHD) one of them being an elevation of plasma LDL concentration. Recent findings suggest that disorders in the metabolism of LDL could be associated with accelerated atherosclerosis even without elevated LDL levels such as increased flux of LDL and changes in the LDL composition. Elevation of plasma LDL levels can be caused by two factors, first, a decrease in the clearance of LDL and second, an overproduction of this lipoprotein. Catabolism of LDL is largely determined by the LDL receptors as clearly shown in patients with familial hypercholesterolemia (FH). In this inherited disease the patients do not have normal LDL receptors and their LDL levels are remarkably elevated. LDL production is also increased in these subjects. In the rest of the population LDL levels are regulated by both the LDL clearance and production rate. The latter also seems to be related to the LDL receptor activity. The conversion of the LDL precursor, very low density lipoprotein (VLDL) to LDL is the most important factor regulating LDL synthesis. When the LDL receptor activity is low a large fraction of VLDL apolipoprotein B (apoB), the major structural protein in VLDL, is converted to LDL, and LDL production is high. On the other hand, only a small part of VLDL apoB is converted to LDL resulting in low LDL synthesis rate in conditions with high LDL receptor activity. The relationships between production and clearance of LDL are, however, more complex. There are individuals who produce a large number of VLDL and LDL particles but maintain LDL concentrations at a normal level by clearing their LDL very effectively. These subjects obviously have another abnormality in lipoprotein metabolism namely an overproduction of apoB. This disorder has been observed in several conditions like obesity, adult-onset diabetes mellitus, several patients with familial combined hyperlipidemia and some normolipidemic subjects with premature coronary heart disease. In all these conditions increased transport of LDL can be associated with coronary artery disease even in the absence of hypercholesterolemia. This raises the possibility that increased flux of LDL could itself be atherogenic possibly by overloading reverse cholesterol transport. Finally, there is some evidence that LDL particle composition may be important in the process of atherogenesis. High LDL apoB but normal LDL cholesterol levels, hyperapobetalipoproteinemia, has been associated with premature coronary heart disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of the liver in low-density-lipoprotein catabolism in the rat.

Plasma low-density-lipoprotein (LDL) kinetics and hepatic LDL uptake were studied in the rat after an intravenous pulse injection of [14C]sucrose-labelled LDL. Some 96% of injected radioactivity was associated with apoprotein B of LDL (d 1.020-1.050). The disappearance of labelled LDL from plasma was accompanied by a linear increase in the hepatic uptake of LDL, up to 12 h after injection. Oestradiol treatment lowered plasma cholesterol concentration by 58% and the intravascular pool of LDL by 78%. This was associated with a 4-fold increase in the fractional catabolic rate of LDL and a 2-fold increase in the hepatic uptake of LDL. Oestradiol treatment did not significantly change the synthesis rate of LDL; it decreased the skin and lung uptake of LDL, but increased adrenal uptake. These results suggest that the liver plays an important role in the regulation of plasma LDL concentration.

WHY DOES PLASMA LOW DENSITY LIPOPROTEIN CONCENTRATION IN ADULTS INCREASE WITH AGE?

WHY DOES PLASMA LOW DENSITY LIPOPROTEIN CONCENTRATION IN ADULTS INCREASE WITH AGE?

Lipoprotein metabolism in the ovariectomized rat.

The hyperlipoproteinemia observed after ovariectomy in rats was previously shown to be associated with increased concentrations of cholesterol, triglycerides, and apolipoproteins B, E, and C. In the present study, it was shown that increases in low density lipoproteins and high density lipoproteins were almost entirely responsible for the changes in plasma lipids and apolipoproteins after ovariectomy. The size of the low density lipoproteins and high density lipoproteins isolated from the plasma of ovariectomized rats as determined by agarose chromatography appeared to be somewhat different from that of control rats. Specifically, the apolipoprotein B appeared to be associated with somewhat smaller particles, whereas the apolipoprotein E from those rats appeared to be associated with larger particles than that of control rats. To determine the mechanism for the increased plasma low density lipoproteins, apolipoprotein B pool sizes and turnover rates were calculated and compared. In addition to an increased mass of low density lipoproteins in ovariectomized rats, the turnover rate of low density lipoproteins was increased almost twofold, indicating an increased low density lipoprotein synthesis and catabolism in those animals. We postulate that the increased low density lipoprotein levels of ovariectomized rats are due to an initial increased production of low density lipoproteins, followed by an enhanced catabolism of low density lipoproteins to establish a steady state at higher plasma low density lipoprotein concentrations.

Lack of Correlation between the Maximum Low-Density Lipoprotein (Ldl) Receptor Activity of Blood Lymphocytes and Plasma LDL Concentration in Normal Men

1. Measurements were made of the maximal low-density lipoprotein (LDL) receptor activities of blood lymphocytes from 81 healthy men with a wide range of plasma LDL cholesterol concentrations (1.45-7.55 mmol/l). 2. Receptor activity was quantified by measuring the degradation of 125I-labelled LDL (10 micrograms of protein/ml) to trichloroacetic acid-soluble material during a 6 h incubation, after derepression of the lymphocytes for 72 h in lipoprotein-deficient medium. 3. No significant correlation existed between LDL receptor activity in vitro and plasma LDL cholesterol concentration in vivo (r = -0.08).

The metabolic basis of familial hypercholesterolemia.

Familial hypercholesterolaemia (FH) is a dominantly inherited error of metabolism characterised by a raised plasma low-density lipoprotein (LDL) concentration, xanthomas of skin and tendons, and a tendency to premature heart disease due to atherosclerosis of the coronary arteries. The clinical and biochemical abnormalities are more marked in homozygotes than in heterozygotes. Other biochemical changes include an increased concentration of very-low-density lipoprotein (VLDL) remnants and of a minor subfraction of high-density lipoproteins. Measurement of plasma lipoprotein turnover shows reduced fractional rates of catabolism of LDL and VLDL remnants, and increased production of LDL. Similar abnormalities are found in Watanabe rabbits, an inbred strain carrying a mutation similar to that responsible for FH. Cultured cells from human and animal tissues express surface receptors with high binding affinity for LDL. Binding of LDL to LDL receptors is followed by endocytosis and lysosomal digestion of the lipoprotein. Cultured cells from FH heterozygotes express only half the normal number of LDL receptors; those from homozygotes have little or no receptor activity and are therefore unable to degrade significant amounts of LDL by the LDL-receptor pathway. The LDL receptor has been isolated from cell membranes; it has a molecular weight of about 160 kd. Several different mutant forms of the receptor have been identified in the cells of FH homozygotes. The LDL-receptor pathway for the catabolism of LDL accounts for at least 1/3 of the total LDL catabolised by normal human subjects in vivo and almost none of that catabolised by FH homozygotes. Deficiency of LDL receptors accounts for the increased plasma concentrations of LDL and VLDL remnants in FH. The increased plasma concentration in these lipoproteins is the cause of deposition of lipid in xanthomas and arterial wall, but the mechanism by which lipoprotein enters the cells in which lipid accumulates is not yet understood.

Plasma low density lipoprotein transport kinetics in noninsulin-dependent diabetes mellitus.

Plasma low density lipoprotein (LDL) transport kinetics were determined from the disappearance of 125I-LDL injected into age- and weight-matched groups of 13 normal subjects, 20 mild diabetics, and 8 moderately severe diabetic patients (fasting plasma glucose less than 150 and greater than 150 mg/100 ml, respectively). In mild diabetics, LDL apo-lipoprotein-B (apo-B) synthetic rate (SR) was significantly greater than normal. The fractional catabolic rate (FCR), however, was also increased so that plasma LDL concentration remained normal. In moderately severe diabetics, LDL SR was normal but FCR was reduced resulting in increased plasma LDL cholesterol and apo-B concentrations. In normal subjects, moderate obesity was associated with increased LDL secretion. In diabetic subjects, however, changes in LDL turnover were of equal magnitude in obese and nonobese patients. In normolipemic and hyperlipemic mild diabetic subjects with equal degrees of glucose intolerance, both LDL apo-B SR and FCR were greater than normal. The magnitude of these increases, however, was lower in the hyperlipemic individuals. Stepwise regression analysis revealed that both LDL SR and FCR correlated positively and linearly with insulin response to glucose loading, but negatively and curvilinearly with fasting plasma glucose and glucose response. We propose that in noninsulin-dependent diabetes, mild hyperglycemia is accompanied by increased LDL turnover, despite normal plasma LDL levels, whereas moderately severe hyperglycemia is associated with decreased LDL catabolism, resulting in increased plasma LDL levels. These changes cannot be attributed to the presence of obesity or hypertriglyceridemia, and may relate to varying degrees of insulin resistance and decreased insulin secretion affecting plasma very low density lipoprotein (VLDL) secretion, VLDL conversion to LDL, and LDL catabolism. Both increased LDL turnover in mild diabetes and delayed removal of LDL in moderately severe diabetes could increase cholesterol ester availability to peripheral tissues, and may result in an increased risk of atherosclerosis.

Low density lipoprotein metabolism by cultured skin fibroblasts from atherosclerotic patients

The aim of this study was to determine whether an abnormality in low density lipoprotein (LDL) metabolism could be demonstrated in fibroblasts cultured from normolipidaemic subjects with atherosclerosis. Seventeen male subjects aged 30–55 years with normal plasma lipid concentrations were divided into 2 groups on the basis of the presence or absence of proven coronary artery and/or peripheral vascular disease. LDL metabolism was assessed in cultured fibroblasts obtained from each of these subjects. After 6 h incubation with 125I-labelled LDL, it was found that binding, uptake and degradation of the lipoprotein were all significantly higher in cells from the atherosclerotic group of subjects than the controls. Variations in cellular LDL metabolism were also correlated with 4 risk factors for cardiovascular disease. Plasma LDL concentration in the atherosclerotic subjects was found to be inversely related to LDL binding and degradation. Subject age was inversely related to LDL degradation in both groups of subjects. No association was demonstrated in either group of subjects between LDL metabolism and glucose intolerance, or between LDL metabolism and cigarette smoking. It is concluded from these results that cellular LDL binding may constitute a factor in determining the rate of atheroma formation, which is independent of other cardiovascular risk factors.

Quantitative studies of very low density lipoprotein: conversion to low density lipoprotein in normal controls and primary hyperlipidaemic states and the role of direct secretion of low density lipoprotein in heterozygous familial hypercholesterolaemia.

Autologous 131I-labelled very low density lipoprotein (VLDL) and 125I-labelled low density lipoprotein (LDL) were injected into seven normal subjects and twenty-eight genetically classified hyperlipidaemic patients to quantitate lipoprotein interconversion. The apoprotein B specific activity--time curves for VLDl and intermediate density lipoprotein (IDL, density = 1 . 006--1 . 019 g/ml) intersected at or before the IDL-B maximum in thirty-one studies (five normal controls and twenty-six hyperlipidaemic subjects) implying that all IDL-B may be derived from VLDL-B. The fractional conversion of VLDL-B to LDL-B (density 1 . 019--1 . 063 g/ml) following a simultaneous spike injection of 131I-VLDL and 125-LDL was obtained by deconvolution of the 125I and 131I-LDL-B activity curves. 21--65% (mean = 44%) of VLDL-B was converted to LDL-B in twenty-three subjects studied. The mean conversion time ranged from 10 to 24 h in ten normotriglyceridaemic subjects and from 19 to 42 h (mean = 33 h) in twelve hypertriglyceridaemic subjects. In one patient with broad-beta disease the mean conversion time was 55 h. LDL-B production from VLDL-B and total LDL-B synthetic rate were essentially equal in normal controls and normocholesterolaemic subjects and in the patient with broad-beta disease. But in all six patients with familial hypercholesterolaemia LDL-B synthetic rate significantly exceeded LDL-B production from VLDL-B, indicating direct secretion of 20--72% of LDL-B at a rate which correlates positively with plasma LDL concentration. Three of five patients with familial combined hyperlipidaemia showed a lesser but nevertheless significant direct secretion of LDL-B.

ROLE OF ENDOTHELIUM IN SEQUESTRATION OF LIPOPROTEIN AND FIBRINOGEN IN AORTIC LESIONS, THROMBI, AND GRAFT PSEUDO-INTIMAS

In the soft, gelatinous thickenings that appear to be the precursors of fibrous plaques, concentrations of plasma low-density lipoproteins (LP) and fibrinogen were three to four times higher than that in normal intima, but their concentration of fibrin was not significantly higher. By contrast, in 60% of cholesterol-rich areas from more advanced plaques, fibrin (mean concentration 22·7 mg/100 mg lipidextracted dry weight) was ten times higher than normal, and this was associated with a twelve-fold increase in a bound LP fraction that was released by incubation with fibrinolytic enzymes. The origin of this fibrin is uncertain, and to test similarity of fibrin in the lesion with that of mural thrombus free and bound LP, fibrinogen, and cholesterol were measured in thrombi and pseudo-intimas from prosthesis grafts. In the pseudo-intimas and the thrombi that were not covered with endothelium the concentrations of all these substances were very low, but in thrombi covered with endothelium the concentrations of free and bound LP were similar to those in intimal lesions. Thus, endothelialisation appears to promote accumulation of LP in mural thrombi.

Metabolism of apolipoprotein B-containing lipoproteins in familial hypercholesterolaemia effects of plasma exchange

The turnover of apolipoprotein B (apo B) in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) was investigated in 2 homozygous and 3 heterozygous patients with familial hypercholesterolaemia. The effects of a marked reduction in plasma LDL concentration, brought about by plasma exchange, upon apo B turnover were studied in 4 patients. Specific activity-time curves for the plasma apo B after intravenous radioactive VLDL before plasma exchange indicated that in the heterozygotes all IDL-apo B was derived from VLDL and all LDL-apo B was derived from IDL, but the curves from the homozygotes showed that a significant fraction of the LDL in the plasma was not derived from IDL. Plasma exchange did not increase the rates of synthesis of LDL-apo B or VLDL-apo B and had no significant effect on the precursor—product relationship between IDL-apo B and LDL-apo B in heterozygous or homozygous patients. These findings provide no support for the hypothesis that apo B synthesis is controlled by the plasma LDL.

Isolation and characterization of a human serum cholesteryl ester transfer protein.

Human plasma has been shown to contain an apolipoprotein that mediates the transport of cholesteryl ester from high density lipoprotein (HDL) to very low density lipoprotein (VLDL) or low density lipoprotein (LDL). This activity, confined to the density greater than 1.063 g/ml interval, has been isolated from HDL and appears as a single migrating species by anionic or sodium dodecyl sulfate/polyacrylamide gel electrophoresis. It is unreactive to antibodies to the major HDL apolipoproteins. Antibodies prepared against this factor and immobilized on Sepharose remove the capacity of HDL and density greater than 1.21 g/ml fractions as well as whole plasma to transport cholesteryl ester from HDL. The system shows saturation kinetics with respect to plasma LDL and VLDL concentrations, and transport of cholesteryl ester was associated with reciprocal and equimolar back-transport of triglyceride from VLDL and LDL to the HDL fraction. The possible relationship of this apoprotein to apoprotein D is discussed.

Atherosclerosis: The low-density lipoprotein receptor hypothesis

Recent biochemical, genetic, and ultrastructural studies have disclosed that non-hepatic human cells, such as fibroblasts, lymphocytes, and aortic smooth muscle cells, utilize a specific metabolic pathway, the low-density lipoprotein (LDL) pathway, to supply themselves with cholesterol. The critical component of this pathway is a specific high-affinity receptor on the cell surface that binds LDL, the major cholesterol-carrying lipoprotein of human plasma. Cellular uptake of the receptor-bound LDL is followed by intralysosomal degradation of the lipoprotein with release of its cholesterol for use in cellular membrane synthesis. When the LDL receptor is genetically absent, as in the homozygous form of familial hypercholesterolemia, the degradation of LDL is impaired, the lipoprotein accumulates to very high levels in the plasma, and a severe form of atherosclerosis ensues. In this paper we present the hypothesis that the normal function of the high-affinity cell-surface LDL receptor is to allow non-hepatic cells to supply themselves with cholesterol at a time when the LDL concentration in plasma is maintained at low levels. We then discuss a mechanism by which this hypothesis might explain the widespread occurrence of atherosclerosis in humans with “normal” plasma LDL-cholesterol levels. The data on the LDL pathway lend biochemical support to the conclusion previously derived from epidemiologic studies—namely, that the “normal” plasma level of LDL-cholesterol in Western man is unphysiologically high.

Uptake and degradation of low density lipoprotein by swine arterial smooth muscle cells with inhibition of cholesterol biosynthesis

We have previously proposed on the basis of studies in hepatectomized animals that low density lipoproteins are degraded at a significant rate by peripheral tissues. To test the capacity of one peripheral cell type to catabolize low density lipoprotein, cultures of swine aortic smooth muscle cells were incubated with homologous 125I-labeled low density lipoprotein and uptake and degradation measured. Degradation of 125I-labeled low density lipoprotein to products soluble in trichloroacetic acid showed an initial lag period of 1–2 h after which the rate increased and remained linear for the following 15 h. Rates of degradation increased sharply with low density lipoprotein concentration over the lower range (from 0–25μg protein/ml) and then more slowly up to the highest concentration tested, 300 μg protein/ml. Even at very low concentrations, 1 μg low density lipoprotein protein/ml (less than 10% of the plasma low density lipoprotein concentration), the in vitro degradation rate (per kg of smooth muscle cells) exceeded the in vivo degradation rate (per kg of total body weight). To the extent that smooth muscle cells are representative of other peripheral cells, the results support the proposal that peripheral degradation of low density lipoprotein apoprotein may be quantitatively important. The rate of incorporation of labeled acetate into sterols was suppressed in cells incubated with whole serum, low density and very low density lipoproteins, or suspensions of free cholesterol. In this respect, the results were similar to those observed in human skin fibroblasts studied concurrently. However, high density lipoprotein inhibited sterol synthesis by about 25% in swine smooth muscle cells while it had no effect in human skin fibroblasts. Cells incubated overnight in lipoprotein-deficient medium showed a net decrease in cholesterol content which could be restored by incubating with low density lipoprotein but not with high density lipoprotein. At high concentrations of low density lipoprotein, when uptake and degradation proceed at very high rates, the amount of cholesterol delivered to the cell is in excess of observed net changes in cell cholesterol content. These findings suggest that there may be a very active “reverse cholesterol transport” in vivo carrying cholesterol from peripheral cells (in which low density lipoprotein is being degraded) back to the liver for ultimate metabolism and excretion.