Factors regulating the metabolism of low-density lipoprotein-proteoglycan complex in macrophages

We studied the factors regulating the metabolism of low-density lipoprotein (LDL)-proteoglycan complex, LDL and acetyl-LDL in mouse peritoneal macrophages. Macrophage conditioned medium stimulated the degradation of LDL-proteoglycan complex and acetyl-LDL in a dose-dependent manner and enhanced cholesteryl ester synthesis mediated by these ligands. The conditioned medium had no such effect in a cell-free system. The conditioned medium enhanced the degradation of both the LDL and proteoglycan components of the complex. The degradation of LDL was not affected by the conditioned medium. The active factor in the conditioned medium was labile to boiling, suggesting that it may be protein in nature. The conditioned medium also lost its stimulatory activity after dialysis through a membrane with an exclusion limit of 25,000 daltons, suggesting the involvement of cytokines and/or other growth factors. Macrophage activation was accompanied by a 2-3-fold increase in the degradation of LDL-proteoglycan complex and acetyl-LDL as compared to the degradation of these ligands in resident macrophages; however, this had no effect on LDL degradation. The degradation of all three ligands increased markedly with decreasing cell density. Preincubation of macrophages for 48 h with increasing concentrations of fetal bovine serum produced a substantial increase in the subsequent degradation of LDL-proteoglycan complex and acetyl-LDL, while it had very little effect on the degradation of LDL. The active factor in serum was destroyed by boiling, suggesting that it may be a protein. These results show that the scavenger receptor, mediating the uptake and degradation of LDL-proteoglycan complex and acetyl-LDL and LDL receptor are regulated differently in mouse peritoneal macrophages.     

Studies on the mechanism of uptake of low density lipoprotein-proteoglycan complex in macrophages

Earlier, we (Vijayagopal, P. et al. (1988) Biochim. Biophys. Acta 960, 210) showed that mouse peritoneal macrophages metabolize low density lipoprotein (LDL)-proteoglycan complex by a receptor pathway distinct from the acetyl-LDL receptor. Further studies were conducted to probe further into the mechanism of LDL-proteoglycan complex uptake by macrophages. Both 125I-methyl-LDL-proteoglycan complex and 125I-LDL-proteoglycan complex were taken up and degraded by the cells to the same extent. Similarly, the ability of these ligands to stimulate cholesteryl ester synthesis was also indistinguishable. These results rule out the possibility of apoB,E receptor involvement in the uptake of LDL-proteoglycan complex in macrophages. Sodium fluoride, cytochalasin D and aggregated LDL inhibited degradation of the complex by 24%, 26% and 28%, respectively, indicating that phagocytosis is only a minor pathway for the uptake. Both binding and degradation of the complex were not inhibited by excess hyaluronic acid suggesting that ligand recognition was not through hyaluronic acid binding sites. As compared to acetyl-LDL, the cellular degradation of LDL-proteoglycan complex was retarded. Macrophages exhibited a rapid stimulation of [3H]inositol trisphosphate (IP3) release and diacylglycerol production when incubated with LDL-proteoglycan complex. Furthermore, pertussis toxin produced a 62% inhibition of LDL-proteoglycan complex mediated IP3 release, suggesting that LDL-proteoglycan complex metabolism in macrophages is dependent upon the G-protein coupled signal transduction mechanism. These results show that receptor mediated endocytosis plays a major role in the metabolism of LDL-proteoglycan complex in macrophages.     

Metabolism of pentacarboxylate porphyrinogens by highly purified human coproporphyrinogen oxidase: further evidence for the existence of an abnormal pathway for heme biosynthesis

An abnormal series of porphyrin tetracarboxylic acids known as the isocoproporphyrins, are commonly excreted by patients suffering from the disease porphyria cutanea tarda (PCT). These porphyrins appear to arise by bacterial degradation of dehydroisocoproporphyrinogen that is generated by the premature metabolism of the normal pentacarboxylate intermediate (5dab) by coproporphyrinogen oxidase (copro'gen oxidase). This porphyrinogen can be further metabolized by uroporphyrinogen decarboxylase to give harderoporphyrinogen, one of the usual intermediates in heme biosynthesis. Therefore, it is possible that some of the heme formed under abnormal conditions may originate from the 'isocopro-type' porphyrinogen intermediate. In order to investigate the feasibility of alternative pathways for heme biosynthesis, the four type III pentacarboxylate isomeric porphyrinogens were incubated with purified, cloned human copro'gen oxidase at 37 degrees C with various substrate concentrations under initial velocity conditions. Of the four isomers, only 5dab was a substrate for copro'gen oxidase and this gave dehydroisocoproporphyrin. The structure of the related porphyrin tetramethyl ester was confirmed by proton NMR spectroscopy and mass spectrometry. The K(m) value for proto'gen-IX formation from copro'gen, an indicator of molecular recognition, was similar to the K(m) value for monovinyl product formation with 5dab, although copro'gen-III has an approximately twofold higher K(cat) value. Although 5dab is a slightly poorer substrate than copro'gen-III, these results support the hypothesis that an abnormal route for heme biosynthesis is possible in humans suffering from PCT or related syndromes such as hexachlorobenzene poisoning.     

Metabolism of D-mannose in Aerobacter aerogenes: evidence for a cyclic pathway

Kamel, M. Y. (Michigan State University, East Lansing), and R. L. Anderson. Metabolism of d-mannose in Aerobacter aerogenes: evidence for a cyclic pathway. J. Bacteriol. 92:1689-1697. 1966.-Evidence is presented which suggests a cyclic pathway for the constitutive utilization of d-mannose in extracts of Aerobacter aerogenes PRL-R3. d-Mannose is phosphorylated with d-glucose-6-phosphate to yield d-mannose-6-phosphate and d-glucose. d-Glucose-6-phosphate may be regenerated by isomerization of d-mannose-6-phosphate through d-fructose-6-phosphate, or by phosphorylation of d-glucose with adenosine-5'-triphosphate. The pathway involves the participation of four constitutive enzymes: d-glucose-6-phosphate isomerase, d-mannose-6-phosphate isomerase, a stereospecific d-glucokinase, and a phosphotransferase which phosphorylates d-mannose with d-glucose-6-phosphate, acetyl phosphate, or carbamyl phosphate. The absence of d-mannokinase (adenosine-5'-triphosphate:d-mannose phosphotransferase) activity in extracts of this organism suggests that the pathway may be of functional significance. Also, the pathway accounts for an apparent 2-epimerization of d-mannose to d-glucose that was observed in extracts.     

Metabolism of apoE-free high density lipoproteins in rat hepatoma cells: evidence for a retroendocytic pathway

The cellular metabolism of apoE-free HDL (HDL) was studied in rat hepatoma cells (FU5AH). Cells incubated with HDL showed a dose-dependent decreased incorporation of [14C]acetate into cell sterol, indicating a net cholesterol delivery to the cells. HDL was localized both at the cell surface and inside the cell. This conclusion was drawn from both the association of 125I-labeled HDL with the cells under different experimental conditions and morphological evidence based on the association of colloidal gold-labeled HDL with the cells. Up to 63% of the 125I-labeled HDL protein initially inside the cell was subsequently recovered in the media as trichloroacetic acid precipitable (TCA-ppt) protein after a 30-min, 37 degrees C chase with a 100-fold concentration of unlabeled HDL. About 27% of the TCA-ppt apoprotein originally inside the cell was recovered as TCA-soluble material. Thus, we conclude that of the HDL apoprotein taken up by the cells, the majority is resecreted by a retroendocytosis pathway. The quantity of HDL apoprotein reappearing in the media was stimulated by the presence of unlabeled HDL in the media, while the amount of TCA-soluble material produced was not. Retroendocytosis of HDL was inhibited at 0 degree C and by the presence of 10 mM NaCN, 20 mM 2-deoxy-D-glucose in the media. Thus, the pathway appears to be both temperature- and energy-sensitive. HDL resecreted by the cell were depleted of cholesteryl ester and showed an altered size distribution, indicative of lipoprotein catabolism and remodeling. This study provides evidence for the existence of an endocytosis-retroendocytosis pathway for HDL apoproteins in a rat hepatoma cell and for the possibility that the endocytosis-retroendocytosis pathway may be involved in lipid delivery to the cell.     

Sequestration of aggregated low-density lipoproteins by macrophages

PURPOSE OF REVIEW: Evidence suggests that much of the LDL in atherosclerotic plaques is aggregated. Aggregation of LDL could be an important factor that determines how this lipoprotein is metabolized by plaque macrophages and the fate of aggregated LDL cholesterol within plaques. This review discusses a novel endocytic pathway by which macrophages process aggregated LDL. RECENT FINDINGS: Recently, it has been shown that aggregated LDL can be sequestered in macrophage surface-connected compartments and plasma membrane invaginations by a process termed patocytosis. In contrast to rapid degradation of LDL and aggregated LDL taken up by macrophages through pinocytosis and phagocytosis, respectively, aggregated LDL sequestered in macrophages undergoes only limited degradation. Macrophages can disaggregate and release sequestered aggregated LDL by activating plasminogen to plasmin. Plasmin degrades LDL apolipoprotein B sufficiently to disaggregate the aggregated LDL, releasing it from the macrophage surface-connected compartments. In contrast, activating macrophages with phorbol-myristate-acetate stimulates degradation of aggregated LDL and inhibits plasminogen-mediated release of the aggregated lipoprotein from macrophage surface-connected compartments. SUMMARY: Macrophage sequestration of aggregated LDL is a unique endocytic pathway relevant not only to the processing of aggregated LDL in atherosclerotic plaques but also for the processing of other materials, such as hydrophobic particles that trigger this endocytic pathway. Macrophage sequestration of aggregated LDL can result in different fates for the aggregated LDL, depending on the state of macrophage activation and the functioning of the plasminogen-based fibrinolytic system. Patocytosis of aggregated LDL should be considered in addition to phagocytosis as a possible uptake pathway in studies of macrophage processing of aggregated LDL.     

Metabolism of 4-chloro-2-methylphenoxyacetate by a soil pseudomonad. Preliminary evidence for the metabolic pathway

1. A pseudomonad capable of utilizing the herbicide 4-chloro-2-methylphenoxyacetate as a sole carbon source was isolated from soil and cultured in liquid medium. 2. Analysis of induction patterns of 4-chloro-2-methylphenoxyacetate-grown cells suggests that 5-chloro-o-cresol and 5-chloro-3-methylcatechol are early intermediates in the oxidation of 4-chloro-2-methylphenoxyacetate. Cells were not adapted to oxidize 4-chloro-6-hydroxy-2-methylphenoxyacetate. 3. In culture, 4-chloro-2-methylphenoxyacetate rapidly disappeared and the chlorine in the molecule was quantitatively released as Cl(-) ion. 4. A lactone (gamma-carboxymethylene-alpha-methyl-Delta(alphabeta)-butenolide) was isolated from cultures and established as an intermediate. 5. The following metabolic pathway is suggested: 4-chloro-2-methylphenoxyacetate --> 5-chloro-o-cresol --> 5-chloro-3-methylcatechol --> cis-cis-gamma-chloro-alpha-methylmuconate --> gamma-carboxymethylene-alpha-methyl-Delta(alphabeta)-butenolide --> gamma-hydroxy-alpha-methylmuconate. 6. The tentative identification of 5-chloro-o-cresol, a gamma-chloro-alpha-methylmuconate and gamma-hydroxy-alpha-methylmuconate in culture extracts supports this scheme. However, the catechol was never observed to accumulate in cultures. 7. The detection of 4-chloro-6-hydroxy-2-methylphenoxyacetate, 2-methyl-phenoxyacetate, a dehalogenated cresol and oxalate in culture extracts is discussed in relation to the proposed metabolic pathway.     

Further evidence for an opioid receptor complex

We recently presented evidence that distinct morphine and enkephalin receptors coexist in an opioid receptor complex. These studies used membranes prepared from whole rat brain. In this paper the receptor complex is demonstrated to occur in membranes prepared from rat striatum, cortex, and pooled nonstriatal-noncortical regions of the brain. The observation that morphine masks enkephalin receptors is confirmed using 3H-methionine enkephalin to label the enkephalin receptor. These data further support the hypothesis that populations of morphine and enkephalin receptors coexist in an opioid receptor complex.     

Transferrin receptor 2: evidence for ligand-induced stabilization and redirection to a recycling pathway

Transferrin receptor 2 (TfR2) is a homologue of transferrin receptor 1 (TfR1), the protein that delivers iron to cells through receptor-mediated endocytosis of diferric transferrin (Fe(2)Tf). TfR2 also binds Fe(2)Tf, but it seems to function primarily in the regulation of systemic iron homeostasis. In contrast to TfR1, the trafficking of TfR2 within the cell has not been extensively characterized. Previously, we showed that Fe(2)Tf increases TfR2 stability, suggesting that trafficking of TfR2 may be regulated by interaction with its ligand. In the present study, therefore, we sought to identify the mode of TfR2 degradation, to characterize TfR2 trafficking, and to determine how Fe(2)Tf stabilizes TfR2. Stabilization of TfR2 by bafilomycin implies that TfR2 traffics to the lysosome for degradation. Confocal microscopy reveals that treatment of cells with Fe(2)Tf increases the fraction of TfR2 localizing to recycling endosomes and decreases the fraction of TfR2 localizing to late endosomes. Mutational analysis of TfR2 shows that the mutation G679A, which blocks TfR2 binding to Fe(2)Tf, increases the rate of receptor turnover and prevents stabilization by Fe(2)Tf, indicating a direct role of Fe(2)Tf in TfR2 stabilization. The mutation Y23A in the cytoplasmic domain of TfR2 inhibits its internalization and degradation, implicating YQRV as an endocytic motif.     

Antigen handling by guinea pig macrophages: further evidence for the sequestration of antigen relevant for activation of primed T lymphocytes.

Guinea pig macrophages can take up sufficient 2,4 dinitrophenyl guinea pig albumin during a brief in vitro exposure at 37 degrees C to trigger proliferation and lymphokine production with primed T lymphocytes on subsequent co-culture. Treatment of such antigen-bearing macrophages with trypsin, a procedure which removes surface antigen, does not alter the ability of such macrophage to initiate the release of migration inhibition factor from sensitized T lymphocytes. In addition, formation of antigen-specific rosettes between primed T cells and antigen-bearing macrophages is not blocked by high concentrations of antibody directed against the antigen mediating this interaction. Similarly, primed T lymphocyte DNA synthesis induced by antigen-bearing macrophages is not inhibited by specific antibody to that antigen. These data support the conclusion that the fraction of macrophage-associated antigen which is relevant to T lymphocyte activation does not reside on the macrophage surface but rather remains in a restricted compartment from which it is accessible to the T cell but unavailable to either blockade by specific antibody or removal by proteolytic enzymes.     

Evidence for a further enterotoxin complex produced by Bacillus cereus

Abstract Out of 321 strains of Bacillus cereus from several sources and isolated in four different countries, 239 (74%) produced cytotoxins. Only 127 (53%) of the cytotoxic strains were positive for the B-component gene of the haemolysin BL (enterotoxin) by polymerase chain reaction (PCR). Western blots using antiserum produced against enterotoxin(s) gave positive results for 199 (83%) of the cytotoxic B. cereus strains. On closer examination of seven of the strains, involved in food poisoning, we found that two strains completely lacked the L₂- and B-components (of the haemolysin BL), and two strains were negative for the B-component gene by PCR, but were positive for the L₂-component. From our experiments we concluded that there is at least one enterotoxin complex in addition to the haemolysin BL enterotoxin and enterotoxin T.     

TOR and ageing: a complex pathway for a complex process

Studies in invertebrate model organisms have led to a wealth of knowledge concerning the ageing process. But which of these discoveries will apply to ageing in humans? Recently, an assessment of the degree of conservation of ageing pathways between two of the leading invertebrate model organisms, Saccharomyces cerevisiae and Caenorhabditis elegans, was completed. The results (i) quantitatively indicated that pathways were conserved between evolutionarily disparate invertebrate species and (ii) emphasized the importance of the TOR kinase pathway in ageing. With recent findings that deletion of the mTOR substrate S6K1 or exposure of mice to the mTOR inhibitor rapamycin result in lifespan extension, mTOR signalling has become a major focus of ageing research. Here, we address downstream targets of mTOR signalling and their possible links to ageing. We also briefly cover other ageing genes identified by comparing worms and yeast, addressing the likelihood that their mammalian counterparts will affect longevity.     

Metabolism of oxidized LDL by macrophages

Oxidation products of lipids and proteins are found in atherosclerotic plaque and in macrophage foam cells. Macrophages avidly endocytose in-vitro oxidized LDL and accumulate sterols. What is the evidence that such a process is involved in in-vivo foam cell formation? The present review surveys current knowledge on the metabolism of oxidized LDL by macrophages, and the types, amounts and location of oxidation products that accumulate in these cells. Comparable studies of lesion lipoproteins and foam cells indicate that limited extracellular lipoprotein oxidation, perhaps followed by more extensive intracellular oxidation subsequent to uptake by macrophages, is a more likely scenario in vivo.     

Molybdate-stabilized glucocorticoid receptor: evidence for a receptor heteromer

The composition of the molybdate-stabilized glucocorticoid receptor (GR) complex has been investigated with a monoclonal antibody against the steroid-binding Mr 94 000 (94K) GR protein. It was concluded that one antibody molecule binds one 94K GR molecule. This finding constituted the basis for calculating the number of antibodies bound to the molybdate-stabilized nonactivated GR complex, which has an Mr of 302 000 (302K). Gel filtration on Sephacryl S-400 and density gradient centrifugation showed that only one antibody molecule bound to the molybdate-stabilized GR complex (calculated relative molecular mass for the antibody--molybdate-stabilized GR complex, 456 000; relative molecular mass for one antibody molecule, 157 000). Furthermore, experiments performed with a second antibody immunoprecipitation assay in the presence of an excess of both antibody and GR confirmed the above results. The possibility of steric hindrance not allowing more than one antibody molecule to bind to the molybdate-stabilized GR complex could be excluded. These results suggest that the molybdate-stabilized GR complex with an Mr of 302K only contains one steroid-binding 94K GR molecule and therefore represents a heteromeric complex.     

C-terminus of heat shock protein 60 can activate macrophages by lectin-like oxidized low-density lipoprotein receptor 1

Immune responses against antigens generally require an efficient activation of antigen-presenting cells (APCs). Currently, the targeting of vaccine antigens to APCs has emerged as a promising strategy for boosting vaccine immunogenicity. Here, we reported that the C-terminus of heat shock protein 60 (HSP60C) can activate mouse peritoneal macrophages to secret a series of cytokines, and phosphorylation of p38 mitogen-activated protein kinase (MAPK) and NF-κB p65 was involved in the pathway. We showed that the activation effect of HSP60C on macrophages was independent of toll-like receptor (TLR) 4 and the TLR-associated myeloide differentiation factor 88 (MyD88). Knockdown of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) reduced the activation of HSP60C-induced macrophage p38 MAPK, NF-κB p65 and cytokine secretion to some extent. Finally, we found that HSP60C up-regulated the expression of LOX-1 on macrophages and ovalbumin (OVA) model antigen fused with HSP60C markedly enhanced OVA-specific IgG responses. Thus, our results unravel a novel LOX-1-dependent pathway by which HSP60C can effectively activate macrophages and APCs targeting based on LOX-1 interaction is a promising approach to improve vaccines.     

Rectal sensitivity assessed by a reflexologic technique: further evidence for two types of mechanoreceptors

We previously showed that slow-ramp rectal distensions induce graded inhibitions of the somatic nociceptive RIII reflex recorded from the lower limb, which correlated with both distension volume and visceral sensation. In contrast, rapid phasic rectal distensions induced facilitatory or biphasic effects (i.e., facilitations followed by inhibitions) depending on the level of distension. To examine the role of mucosal and serosal rectal mechanoreceptors in these viscerosomatic interactions, we analyzed, in six healthy volunteers, the effects of both types of rectal distension on the RIII reflex after topical application of lidocaine or placebo administered in a double-blind and crossover fashion. Inhibitions of the RIII reflex induced by both slow-ramp and rapid distensions were strongly reduced after administration of lidocaine but not after placebo. In contrast, facilitations of the RIII reflex observed during the initial phase of rapid distensions were not modified after lidocaine or placebo applications. These results suggest that inhibitions, but not facilitations, of the nociceptive RIII reflex triggered by rectal distensions depend preferentially on the activation of superficial mucosal receptors. This reflexologic technique might thus represent an interesting tool for studying the role of the different rectal mechanoreceptors involved in visceral sensations.     

Activated human monocytes oxidize low-density lipoprotein by a lipoxygenase-dependent pathway

Monocyte-mediated oxidation of low-density lipoprotein (LDL) converts the lipoprotein to a potent cytotoxin. The oxidation process requires monocyte activation and requires superoxide anion since it can be blocked by superoxide dismutase. In this study, the requirement for lipoxygenase activity is shown, in that 1) inhibitors of lipoxygenase prevent the alteration of LDL, 2) copper (II) (3,5-diisopropylsalicylic acid), an agent shown to enhance lipoxygenase activity in a cell-free system, similarly enhances monocyte-mediated LDL alteration, and 3) the (3,5-diisopropylsalicylic acid)-enhanced monocyte-mediated modification of LDL can be completely blocked by inhibitors of lipoxygenase or by superoxide dismutase. These data suggest an integral role for monocyte lipoxygenase in the generation by activated monocytes of the extracellular superoxide anion that participates in the oxidation of LDL and the conversion of LDL to a cytotoxin. Monocyte-modified LDL may be a mediator in tissue damage that accompanies atherosclerosis or occurs at sites of inflammation.     

The oxidative modification of low-density lipoproteins by macrophages.

1. Mouse resident peritoneal macrophages in culture modified human 125I-labelled low-density lipoprotein (LDL) to a form that other macrophages took up about 10 times as fast as unmodified LDL. The modified LDL was toxic to macrophages in the absence of serum. 2. There was a lag phase of about 4-6 h before the LDL was modified so that macrophages took it up faster. A similar time lag was observed when LDL was oxidized by 5 microM-CuSO4 in the absence of cells. 3. LDL modification was maximal when about 1.5 x 10(6) peritoneal cells were plated per 22.6 mm-diam. well. 4. Re-isolated macrophage-modified LDL was also taken up much faster by macrophages, indicating that the increased uptake was due to a change in the LDL particle itself. 5. Micromolar concentrations of iron were required for the modification of LDL by macrophages to take place. The nature of the other components in the culture medium was also important. Macrophages would modify LDL in Ham's F-10 medium but not in Dulbecco's modified Eagle's medium, even when iron was added to it. 6. The macrophage-modified LDL appeared to be taken up almost entirely via the acetyl-LDL receptor. 7. LDL modification by macrophages was inhibited partially by EDTA and desferrioxamine and completely by the general free radical scavengers butylated hydroxytoluene, vitamin E and nordihydroguaiaretic acid. It was also inhibited completely by low concentrations of foetal calf serum and by the anti-atherosclerotic drug probucol. It was not inhibited by the cyclo-oxygenase inhibitors acetylsalicylic acid and indomethacin. 8. Macrophages are a major cellular component of atherosclerotic lesions and the local oxidation of LDL by these cells may contribute to their conversion into cholesterol-laden foam cells in the arterial wall.     

Metabolism of human plasma triacylglycerol-rich lipoproteins in rodent macrophages: capacity for interaction at beta-VLDL receptor

The capacity of human plasma triacylglycerol-rich lipoproteins to be metabolized by rat macrophages was studied with plasma triacylglycerol-rich lipoproteins obtained from subjects with fasting chylomicronemia or from normal subjects after a fat meal. Triacylglycerol-rich lipoproteins were separated by chromatography into two fractions designated TRL1 and TRL2; from their composition and changing concentration during alimentary lipemia, TRL1 contained a higher proportion of chylomicron remnants than TRL2. Degradation of 125I-labeled TRL1 was greater than that of 125I-labeled TRL2. In competition studies with 125I-labeled beta-VLDL from cholesterol-fed rabbits, unlabeled TRL1 displaced beta-VLDL as completely as did unlabeled beta-VLDL, being slightly more potent than TRL2, which contained less apolipoprotein E than TRL1. This reflected common interaction at receptors that probably included both beta-VLDL and B/E receptors, since: (1) in fresh macrophages, VLDL from hypertriglyceridemic subjects partially displaced beta-VLDL; (2) in B/E receptor-repressed macrophages, TRL1 maintained capacity to totally displace beta-VLDL. This was confirmed in experiments with J774 murine macrophages in which triacylglycerol-rich lipoproteins and beta-VLDL displaced each other equally, whereas LDL was ineffective in displacing beta-VLDL. Furthermore, monoclonal antibodies raised against apolipoprotein B48 and reacting strongly with LDL, failed to inhibit the binding of triacylglycerol-rich lipoprotein to the macrophages. This indicates an interaction through apolipoprotein E which is present in high concentration in triacylglycerol-rich lipoprotein as well as in beta-VLDL. It applies to triacylglycerol-rich particles derived from either the intestine (chylomicron remnants) or the liver (VLDL remnants from hypertriglyceridemic subjects).