Receptor-mediated Catabolism Of Low Density Lipoprotein Research Articles

Lifibrol enhances the low density lipoprotein apolipoprotein B-100 turnover in patients with hypercholesterolemia and mixed hyperlipidemia

Lifibrol (4-(4′-tert-butylphenyl)-1-(4′carboxyphenoxy)-2-butanol), a new hypocholesterolemic drug, effectively reduces total cholesterol (CH), low density lipoprotein (LDL)-CH, and apolipoprotein (apo) B in experimental animals and in humans. The impact of Lifibrol on the metabolism of apoB-100 containing lipoproteins in patients with hyperlipoproteinemia using endogenous labeling with stable isotopes is examined. Kinetic studies were performed in four male hypercholesterolemic individuals (type IIa) before and on treatment with 450 mg of Lifibrol daily for 4 weeks, and in five male individuals suffering from mixed hyperlipidemia (type IIb) before and on therapy for 12 weeks. Kinetic parameters were estimated by multicompartmental modeling. Lifibrol therapy reduced total CH by 16% ( P=0.012) in all patients, increased triglycerides (TG) by 11% (not significant) in type IIa patients and decreased TG by 34% ( P=0.059) in type IIb patients. During Lifibrol therapy, LDL apoB-100 concentrations decreased by 19% ( P=0.011) in all patients. The decrease in LDL apoB concentrations with Lifibrol therapy was due to an overall increase (75%, P=0.006) of the fractional catabolic rates (FCR) of LDL apoB. This increase was partially attenuated by a 33% increase in LDL apoB production rate (PR) ( P=0.041). The overall production of apoB increased only slightly. Our data suggest that the major mechanism by which Lifibrol lowers LDL-CH is an increase in receptor-mediated catabolism of LDL rather than a decrease in hepatic apoB production.

Studies on the mechanism of the ursodeoxycholic acid-induced increase in hepatic low-density lipoprotein binding.

Previously, we have shown, in golden Syrian hamsters, that chronic feeding of ursodeoxycholic acid (UDCA), in contrast to that of its 7 alpha-epimer, chenodeoxycholic acid (CDCA), produced a significant increment in hepatic low-density lipoprotein (LDL) uptake, despite similar suppression of bile acid synthesis by both bile acids. Evidence for a direct effect of this bile acid on hepatic LDL metabolism was shown in vitro, with isolated hamster hepatocytes, suggesting that this effect was unique to UDCA and specific for receptor-mediated LDL catabolism. The aim of the present study was to define the cellular mechanism(s) associated with this phenomenon, using male golden Syrian hamsters. Regardless of chronic exposure of the liver to either UDCA or CDCA, acute incubation with UDCA consistently resulted in an increase of LDL binding to isolated hepatocytes by 15 to 40%. Furthermore, chronic treatment with either UDCA or CDCA did not result in alterations in lipoprotein particle composition. Likewise, incubation of hepatocytes with UDCA was not associated with a change of the membrane lipid composition. In isolated liver membrane fractions, UDCA increased both the maximum number of LDL binding sites and the affinity constant for LDL by around 35%, suggesting an interaction of UDCA with the LDL receptor, at the plasma membrane level, independent of an effect on receptor cycling. The results of the studies support a role for UDCA in the recruitment of cryptic LDL receptors from a cellular membrane pool, possibly due to the unique localization of UDCA in the plasma membrane lipid bilayer.

Differential effects of saturated fatty acids on low density lipoprotein metabolism in the guinea pig.

Studies have shown that dietary fat saturation affects guinea pig plasma low density lipoprotein (LDL) levels by altering both LDL receptor-mediated catabolism and flux rates of LDL (Fernandez et al. 1992. J. Lipid Res. 33: 97-109). The present studies investigated whether saturated fatty acids of varying chain lengths have differential effects on LDL metabolism. Guinea pigs were fed 15% (w/w, 35% calories) fat diets containing either palm kernel oil (PK), 52% lauric acid/18% myristic acid; palm oil (PO), 43% palmitic acid/4% stearic acid; or beef tallow (BT), 23% palmitic acid/14% stearic acid. Plasma LDL cholesterol levels were significantly higher for animals fed the PK diet (P < 0.001) with values of 83 +/- 19 (n = 12), 53 +/- 8 (n = 12) and 44 +/- 16 (n = 10) mg/dl for PK, PO, and BT diets, respectively. The relative percentage composition of LDL was modified by fat type; however, LDL diameters and peak densities were not different between diets, indicating no effect of saturated fatty acid composition on LDL size. ApoB/E receptor-mediated LDL fractional catabolic rates (FCR) were significantly lower in animals fed the PK diet (P < 0.01) and LDL apoB flux rates were reduced (P < 0.01) in animals fed the BT diet. A correlation was found between plasma LDL levels and receptor-mediated LDL catabolism (r = -0.66, P < 0.01). A higher apoB/E receptor number (Bmax), determined by in vitro LDL binding to guinea pig hepatic membranes, was observed for animals fed BT versus PK or PO diets and Bmax values were significantly correlated with plasma LDL levels (r = -0.776, P < 0.001). These results indicate that saturated fatty acids of varying chain length have differential effects on hepatic apoB/E receptor expression and on LDL apoB flux rates which in part account for differences in plasma LDL cholesterol levels of guinea pigs fed these saturated fats.

Effect of simvastatin on plasma lipid and lipoprotein concentrations and low-density lipoprotein metabolism in the nephrotic syndrome.

1. The effect of inhibiting the rate-limiting enzyme (3-hydroxy-3-methylglutaryl-CoA reductase, EC 1.1.1.88) in cholesterol synthesis on plasma lipid and lipoprotein concentrations was investigated in 16 patients with primary glomerular disease, heavy proteinuria, well-preserved renal function and hypercholesterolaemia. 2. Detailed studies of low-density lipoprotein metabolism were performed on eight patients before and after 12 weeks of simvastatin therapy. Radioiodinated tracers were used to quantify the fractional catabolic rate of low-density lipoprotein by apolipoprotein B/E receptors and alternative pathways. 3. Simvastatin produced consistent reductions in total plasma cholesterol concentration (median 36.9%), plasma low-density lipoprotein-cholesterol concentration (43.6%) and apolipoprotein B pool size (29.9%). 4. In contrast, the changes in kinetic parameters of low-density lipoprotein metabolism showed no clear pattern. Although an increase in the receptor-mediated catabolism of low-density lipoprotein was demonstrated in five patients, no change or a slight decrease was seen in three patients. Production rates were not significantly altered, although there was a slight decrease in the median value (from 12.4 to 9.7 mg day-1 kg-1). Plasma lathosterol concentration was reduced in all eight patients (range 34-71%), indirectly confirming significant inhibition of cholesterol synthesis. 5. These results suggest that, as in patients with primary moderate hyperlipidaemia, the significant cholesterol-lowering effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in the nephrotic syndrome is accompanied by variable changes in lipoprotein metabolism. The reasons for this heterogeneous response are unclear. This reflects our limited understanding of the metabolic basis of nephrotic hyperlipidaemia and the relationship between hepatic sterol synthesis and plasma lipoprotein kinetics.

Decreased receptor-mediated LDL catabolism in casein-fed rabbits precedes the increase in plasma cholesterol levels

The effect of dietary protein on, in vivo, receptor-dependent and receptor-independent low density lipoprotein (LDL) catabolism was assessed in rabbits fed semipurified cholesterol-free diets containing casein or soy protein for 300 days. Plasma cholesterol (7.37 ± 0.59 versus 1.84 ± 0.28 mmol/L; P < 0.001), LDL cholesterol (2.66 ± 0.41 versus 0.67 ± 0.10 mmol/L; P < 0.001) and LDL apo B concentrations (1.39 ± 0.40 versus 0.54 ± 0.12 g/ L plasma; P < 0.001) were significantly higher in rabbits fed casein. Kinetic parameters calculated following the simultaneous injection of radiolabeled native and methylated LDL showed that in casein-fed rabbits, total LDL apo B fractional catabolic rate (FCR) was significantly lower (0.64 ± 0.11 versus 1.42 ± 0.20 pools/d; P < 0.02), and this was due exclusively to a four-fold reduction in receptor-dependent LDL apo B FCR (0.21 ± 0.07 versus 0.86 ± 0.10 pools/d; P < 0.002), since receptor-independent LDL apo B FCR was similar between groups (0.44 ± 0.05 versus 0.56 ± 0.12 pools/d). In groups of rabbits transferred from a soy protein diet to a casein diet, total LDL apo B FCR was decreased significantly in rabbits fed casein diet, 5 days after being switched from the soy protein diet (1.03 ± 0.08 versus 1.83 ± 0.13 pools/d; P < 0.05). This decrease in total LDL apo B FCR was due to decreases in receptor-mediated catabolism (0.56 ± 0.06 versus 1.03 ± 0.14 pools/d; P < 0.001) and receptor-independent catabolism (0.47 ± 0.09 versus 0.80 ± 0.10 pools/d; P < 0.05). However, the plasma cholesterol in these casein-fed rabbits was not significantly different from that observed in soy protein-fed rabbits (2.33 ± 0.52 versus 2.02 ± 0.39 mmol/L). Compared to soy protein-fed rabbits, the plasma cholesterol was significantly higher when the casein had been fed for 10 to 25 days, and in these rabbits total LDL apo B FCR was also significantly reduced, due exclusively to decreased receptor-mediated catabolism. There was a significant inverse correlation in all rabbits between plasma cholesterol and both total LDL apo B FCR ( R = 0.66; P < 0.001) and receptor-dependent LDL apo B FCR ( R = 0.72; P < 0.001). These studies show that down-regulation of LDL receptors in vivo, precedes the subsequent elevation in plasma cholesterol levels induced by a casein diet.

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.

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)

Role of the liver for the receptor-mediated catabolism of low-density lipoprotein in the 17α-ethinylestradiol-treated rat

Effects of ethinylestradiol on LDL catabolism and plasma cholesterol were studied in the rat. Hormone treatment led to a reduction in plasma cholesterol and to an increased receptor-mediated catabolism of LDL in the liver and the adrenals. The liver was the most important organ accounting for more than 95% of the receptor-mediated tissue accumulation of LDL following estrogen treatment. It is concluded that the reduction in plasma cholesterol during treatment with ethinylestradiol is due to the stimulation of LDL receptors in the liver.

Hereditary hyperlipidemia in the rabbit due to overproduction of lipoproteins. I. Biochemical studies.

An inherited metabolic disorder in a strain of New Zealand White rabbits, characterized by marked hypercholesterolemia (394 +/- 100 mg/dl), with moderately elevated or normal triglyceride levels is described. Low density lipoprotein (LDL), intermediate density lipoprotein (IDL) and very low density lipoprotein (VLDL) cholesterol levels were increased. VLDL and IDL, and to a lesser extent LDL, had increased free cholesterol and esterified cholesterol content, and triglyceride content was reduced. Kinetic studies with 131I and 125I-labelled rabbit lipoproteins showed a marked increase in production rates of VLDL apo B and LDL apo B. LDL cholesterol levels were directly related to LDL apo B production rate (r = 0.938, p less than 0.001). Both in hypercholesterolemic and normal rabbits injected with labelled VLDL, the specific activity-time curves of VLDL apo B and LDL apo B did not intersect, indicating that LDL apo B was in part derived from sources other than VLDL. No defect was demonstrated in receptor-mediated catabolism of LDL by cultured skin fibroblasts from hyperlipidemic animals. The fractional catabolic rate of LDL apo B was subnormal, but increased when the expanded LDL apo B pool size was reduced by exchange transfusion; the low fractional catabolism may therefore be attributable, at least in part, to saturation of LDL receptors consequent upon the increased pool size of LDL. The hyperlipidemia in this strain of rabbits may be unique in that the underlying mechanism appears to be overproduction of VLDL and LDL.

Adrenergic effects on plasma lipoprotein metabolism: Speculation on mechanisms of action

Recently, the effects of alpha-adrenergic and beta-adrenergic antagonists on plasma lipoprotein concentrations have been reported. Evidence from diverse lines of research has been brought together that suggests three potential mechanisms by which these antihypertensive agents affect lipoprotein metabolism. First, the known alterations in plasma triglyceride levels caused by adrenergic antagonists may be mediated through the activity of lipoprotein lipase. This enzyme, located on the capillary endothelium of adipose tissue and skeletal muscle, catabolizes chylomicrons and very-low-density lipoproteins. Catecholamine-induced changes in precapillary sphincter tone could affect the delivery of triglyceride-rich lipoproteins to endothelial lipase, cause changes in capillary endothelial surface area for lipase-binding sites, and/or modulate the synthesis of lipoprotein lipase by adipocytes and myocytes. Since high-density lipoprotein levels increase by taking up components of chylomicrons released by lipoprotein lipase, these pathways might explain the adrenergic-induced changes in high-density lipoprotein that are reciprocal to those in plasma triglycerides. Second, hepatic production of very-low-density lipoproteins might be affected by adrenergic-induced changes in insulin release. Decreased insulin release may direct glucose metabolites from adipocytes to hepatocytes for lipogenesis. Catecholamines and other glucoregulatory hormones are known to alter hepatic cholesterol synthesis and secretion of very-low-density lipoproteins. These observations also suggest that dietary carbohydrate and fat might modulate adrenergic influences on lipoprotein metabolism by other than classic means. Third, as suggested by studies of cultured fibroblasts, alpha-adrenergic antagonists may increase receptor-mediated catabolism of low-density lipoprotein.

Effects of high density lipoprotein subfractions on cholesterol homeostasis in human fibroblasts and arterial smooth muscle cells.

Ultracentrifugally isolated high density lipoprotein (HDL) particles of d greater than 1.125 g/ml promote net transport of cholesterol from cultured cells. Consequently, when cultured human fibroblasts and arterial smooth muscle cells were incubated with HDL3 (d = 1.125-1.21 g/ml) and "very high" density lipoprotein (VHDL, d = 1.21-1.25 g/ml), low density lipoprotein (LDL) receptor activity was induced and the rate of LDL degradation by the cells was increased. Enhancement of LDL degradation by HDL3 and VHDL was sustained over incubation periods of 5 days at medium LDL concentrations greater than needed to saturate the LDL receptors. Even during these long-term incubations with LDL, HDL3 and VHDL caused marked reductions in cellular cholesterol content. Thus, an increase in the rate of cholesterol transport from cells may lead to a steady-state decrease in cellular cholesterol content and a sustained increase in the rate of clearance of LDL from the extracellular fluid. In contrast to the effects of HDL3 and VHDL, the major subclasses of HDL2 (HDL2b, d = 1.063-1.100 g/ml; HDL2a, d = 1.100-1.125 g/ml) did not promote net cholesterol transport from cells. Moreover, by apparent direct blockage of the effects that HDL3 and VHDL had on cholesterol transport, HDL2 reversed the increased rate of LDL degradation induced by HDL3 and VHDL. These results suggest that the relative proportion of HDL subfractions in the extracellular fluid may be an important determinant of both the rate of cholesterol transport from cells and the rate of receptor-mediated catabolism of LDL.

The effect of partial ileal bypass on receptor-mediated uptake and catabolism of low density lipoprotein in the rhesus monkey.

The fractional rates of catabolism (FCR) of 125I-labelled low-density lipoprotein (LDL) and 131I-labelled LDL coupled with 1,2-cyclohexanedione (LDL-CHD) were determined before and 6 weeks after partial ileal bypass in three Rhesus monkeys. Receptor-mediated catabolism, determined as the difference between the FCRs of 125I-LDL and 131I-LDL-CHD, increased significantly after partial ileal bypass. Analysis of tissue distribution of radioactivity in one monkey, killed at the conclusion of a third turnover study 6 months after partial ileal bypass, suggested that the liver was the main tissue site of accumulation of LDL, and that uptake had occurred mainly via a receptor-mediated mechanism. It is concluded that partial ileal bypass stimulates receptor-mediated LDL catabolism in the Rhesus monkey as in man, and that this increase is probably mediated via hepatic LDL receptors.

Receptor-mediated low-density lipoprotein catabolism

Low-density lipoprotein (LDL) receptors are demonstrable in cultured fibroblasts from normal subjects but are decreased or absent in cells from patients with heterozygous or homozygous familial hypercholesterolaemia. In vivo receptor-mediated LDL catabolism, determined as the difference between the turnover rates of 125I-LDL and 131I-LDL coupled with cyclohexanedione, is responsible for approximately one-third of the total catabolism of LDL in normal subjects, but less than one-fifth in heterozygotes and is totally absent in homozygotes. Receptor-mediated catabolism can be stimulated in normal subjects and in heterozygotes by measures that promote bile acid synthesis, namely, administration of anion-exchange resins or creating a partial ileal bypass. Studies in dogs have shown that such measures stimulate the high-affinity binding of LDL by liver cell membranes. Taken together, these observations suggest the existence of LDL receptors in human liver, the function of which is to maintain cholesterol homeostasis within the hepatocyte during periods of increased demand. Partial or complete absence of such hepatic receptors may play a major role in the pathogenesis of familial hypercholesterolaemia.

SUPERIORITY OF PARTIAL ILEAL BYPASS OVER CHOLESTYRAMINE IN REDUCING CHOLESTEROL IN FAMILIAL HYPERCHOLESTEROLAEMIA

Low density lipoprotein (LDL) turnover studies were conducted on three occasions in each of six patients with heterozygous familial hypercholesterolaemia (FH)-on diet, after 1 month on cholestyramine 16 g/day, and 2 months after partial ileal bypass. Partial ileal bypass lowered total and LDL cholesterol levels and increased the fractional catabolic rate of LDL to a greater extent than did cholestyramine; this difference presumably reflects the greater increase in bile acid excretion induced by the surgical procedure. Studies in two other heterozygotes showed that partial ileal bypass specifically enhanced receptor-mediated catabolism of LDL. The findings support the concept that therapeutic stimulation of bile acid synthesis increases the rate of receptor-mediated uptake and degradation of LDL by the liver.

Acceleration of low-density lipoprotein catabolism in man by total parenteral nutrition.

Since insulin enhances the catabolism of low-density lipoprotein (LDL) by cultured human cells, a potential role of insulin in the regulation of plasma LDL levels in man is suggested. To evaluate the possible effect of insulin on LDL catabolism in vivo, the disappearance rates of injected 125I-labeled autologous LDL were determined before and after endogenous hyperinsulinemia was evoked by total parenteral nutrition. Multicompartmental analysis of plasma decay curves showed a 26% increase in the fractional catabolic rate of LDL after total parenteral nutrition was started. An associated reduction of plasma cholesterol levels resulted from changes in both LDl and high-density lipoprotein. These results suggest that the reduction of LDL levels during total parenteral nutrition is at least partly accounted for by enhanced LDL catabolism. It is postulated that the enhanced LDL catabolism may result from the hyperinsulinemia that accompanies total parenteral nutrition, via insulin stimulation of receptor-mediated LDL catabolism.

Effects of Partial Ileal Bypass on Receptor-Mediated Low Density Lipoprotein Catabolism

Effects of Partial Ileal Bypass on Receptor-Mediated Low Density Lipoprotein Catabolism

Evidence for Defect of Receptor-Mediated Low-Density Lipoprotein Catabolism in Familial Hypercholesterolaemia In Vivo

Evidence for Defect of Receptor-Mediated Low-Density Lipoprotein Catabolism in Familial Hypercholesterolaemia <i>In Vivo</i>

Receptor-mediated low density lipoprotein catabolism in man.

Binding of human low density lipoproteins (LDL) to their specific receptor on cultured cells can be inhibited by treatment with 1,2-cyclohexanedione which blocks a number of functionally significant arginyl residues on the apolipoprotein. We have used this observation to examine the role of the receptor pathway in LDL catabolism in man. The plasma clearance rates of 125I-LDL and 131I-cyclohexanedione-treated LDL were measured in four normal and four heterozygous familial hypercholesterolemic subjects. Chemical modification of the lipoprotein significantly reduced its fractional clearance rate and permitted calculation of receptor-mediated and receptor independent catabolism in both groups. The normal subjects cleared 11% of their plasma LDL pool (corresponding to 3.0 mg/kg per day) by a receptor-independent path. In tared daily by these pathways, respectively. Because the mean apoLDL pool size in the group was increased 3-fold over normal, this gave absolute clearance rates for the apoprotein of 2.5 mg/kg per day via the receptors and 12.8 mg/kg per day by the nonreceptor pathway. We conclude that the specific LDL receptor mechanism operates in vivo and probably accounts for 33% and 16% of overall LDL catabolism in normal and heterozygous familial hypercholesterolemic subjects, respectively.