Uptake Of Chylomicron Remnants Research Articles

Deletion of Lymphangiogenic and Angiogenic Growth Factor VEGF-D Leads to Severe Hyperlipidemia and Delayed Clearance of Chylomicron Remnants.

Objective- Dyslipidemia is one of the key factors behind coronary heart disease. Blood and lymphatic vessels play pivotal roles in both lipoprotein metabolism and development of atherosclerotic plaques. Recent studies have linked members of VEGF (vascular endothelial growth factor) family to lipid metabolism, but the function of VEGF-D has remained unexplored. Here, we investigated how the deletion of VEGF-D affects lipid and lipoprotein metabolism in atherogenic LDLR-/- ApoB100/100 mice. Approach and Results- Deletion of VEGF-D (VEGF-D-/-LDLR-/-ApoB100/100) led to markedly elevated plasma cholesterol and triglyceride levels without an increase in atherogenesis. Size distribution and hepatic lipid uptake studies confirmed a delayed clearance of large chylomicron remnant particles that cannot easily penetrate through the vascular endothelium. Mechanistically, the inhibition of VEGF-D signaling significantly decreased the hepatic expression of SDC1 (syndecan 1), which is one of the main receptors for chylomicron remnant uptake when LDLR is absent. Immunohistochemical staining confirmed reduced expression of SDC1 in the sinusoidal surface of hepatocytes in VEGF-D deficient mice. Furthermore, hepatic RNA-sequencing revealed that VEGF-D is also an important regulator of genes related to lipid metabolism and inflammation. The lack of VEGF-D signaling via VEGFR3 (VEGF receptor 3) led to lowered expression of genes regulating triglyceride and cholesterol production, as well as downregulation of peroxisomal β-oxidation pathway. Conclusions- These results demonstrate that VEGF-D, a powerful lymphangiogenic and angiogenic growth factor, is also a major regulator of chylomicron metabolism in mice.

Dietary fat impacts fetal growth and metabolism: uptake of chylomicron remnant core lipids by the placenta

The fetus requires significant energy for growth and development. Although glucose is a major source of energy for the fetus, other maternal nutrients also appear to promote growth. Thus, the goal of these studies was to determine whether triglyceride-rich remnants are taken up by the placenta and whether maternal dietary lipids, independently of adiposity, can impact fetal growth. To accomplish our first goal, chylomicron particles were duallly labeled with cholesteryl ester and triglycerides. The placenta took up remnant particles/core lipids at rates greater than adipose tissue and skeletal muscle but less than the liver. Although the placenta expresses apoE receptors, uptake of chylomicron remnants and/or core lipids can occur independently of apoE. To determine the impact of dietary lipid on fetal growth, independent of maternal adiposity, females were fed high-fat diets (HFD) for 1 mo; there was no change in adiposity or leptin levels prior to or during pregnancy of dams fed HFD. Fetal masses were greater in dams fed HFD, and mRNA levels of proteins involved in fatty acid oxidation (CPT I, PPARα), but not glucose oxidation (pyruvate kinase) or other regulatory processes (HNF-4α, LXR), were increased with maternal dietary fat. There was also no change in mRNA levels of proteins involved in placental glucose and fatty acid transport, and GLUT1 protein levels in microvillous membranes were similar in placentas of dams fed either diet. Thus, the ability of the placenta to take up chylomicron remnant core lipids likely contributes to accelerated fetal growth in females fed high fat diets.

Hepatic Deficiency of Low Density Lipoprotein Receptor-related Protein-1 Reduces High Density Lipoprotein Secretion and Plasma Levels in Mice

The low density lipoprotein receptor-related protein-1 (LRP1) is known to serve as a chylomicron remnant receptor in the liver responsible for the binding and plasma clearance of apolipoprotein E-containing lipoproteins. Previous in vitro studies have provided evidence to suggest that LRP1 expression may also influence high density lipoprotein (HDL) metabolism. The current study showed that liver-specific LRP1 knock-out (hLrp1(-/-)) mice displayed lower fasting plasma HDL cholesterol levels when compared with hLrp1(+/+) mice. Lecithin:cholesterol acyl transferase and hepatic lipase activities in plasma of hLrp1(-/-) mice were comparable with those observed in hLrp1(+/+) mice, indicating that hepatic LRP1 inactivation does not influence plasma HDL remodeling. Plasma clearance of HDL particles and HDL-associated cholesteryl esters was also similar between hLrp1(+/+) and hLrp1(-/-) mice. In contrast, HDL secretion from primary hepatocytes isolated from hLrp1(-/-) mice was significantly reduced when compared with that observed with hLrp1(+/+) hepatocytes. Biotinylation of cell surface proteins revealed decreased surface localization of the ATP-binding cassette, subfamily A, member 1 (ABCA1) protein, but total cellular ABCA1 level was not changed in hLrp1(-/-) hepatocytes. Finally, hLrp1(-/-) hepatocytes displayed reduced binding capacity for extracellular cathepsin D, resulting in lower intracellular cathepsin D content and impairment of prosaposin activation, a process that is required for membrane translocation of ABCA1 to facilitate cholesterol efflux and HDL secretion. Taken together, these results documented that hepatic LRP1 participates in cellular activation of lysosomal enzymes and through this mechanism, indirectly modulates the production and plasma levels of HDL.

P32 EVALUATION OF SYSTEMIC INFLAMMATION IN FAMILIAL HYPERCHOLESTEROLEMIA BY BIOMARKER PROFILING ON BIOCHIP ARRAYS: IMPACT OF LDL-APHERESIS

The extent and kinetics of postprandial changes are highly variable and are modulated by numerous factors including diet, lifestyle conditions, genetic background and pathological conditions. This review focuses on dietary factors affecting postprandial chylomicron and lipoprotein metabolism in humans. The first key step in the process is fat digestion within the stomach and small intestine which can be modulated by fat and dietary fiber amounts and types.The second key step is intestinal absorption per se. The uptake and secretion of absorbed nutrients in chylomicrons is affected by numerous factors, including nutrients themselves. The amount of dietary triglycerides as well as the nature of fatty acids ingested from habitual diet or present in a test meal modulates the extent of chylomicron and plasma triglyceride levels postprandially. The amount of dietary cholesterol also modulates the extent of postprandial chylomicron and plasma triglycerides. Other nutrients can alter the postprandial occurrence of chylomicrons such as proteins, alcohol, carbohydrates or fibers. Addition of glucose and more markedly fructose, to a fat test meal increases the accumulation of chylomicrons, as does a high-glycemic index meal. In contrast, some sources of dietary fibers such as oat bran noticeably decrease the occurrence of chylomicron postprandially. Overall, changing the habitual dietary pattern, for instance from a Western-type diet to Mediterranean-type one, can in turn alter the postprandial response of the subjects. The last step in postprandial lipid metabolism is clearance from plasma through combined lipolysis processes and tissue uptake of chylomicron remnants. Both the processes can also be modulated by the nutrients.Because most day-time is usually spent in a postprandial state, the link between dietary patterns and cardiovascular health or risk is clearly mediated by the secretion and clearance rates of chylomicrons in the circulation.

Hepatic SR-BI, not endothelial lipase, expression determines biliary cholesterol secretion in mice

High density lipoprotein cholesterol is thought to represent a preferred source of sterols secreted into bile following hepatic uptake by scavenger receptor class B type I (SR-BI). The present study aimed to determine the metabolic effects of an endothelial lipase (EL)-mediated stimulation of HDL cholesterol uptake on liver lipid metabolism and biliary cholesterol secretion in wild-type, SR-BI knockout, and SR-BI overexpressing mice. In each model, injection of an EL expressing adenovirus decreased plasma HDL cholesterol (P < 0.001) whereas hepatic cholesterol content increased (P < 0.05), translating into decreased expression of sterol-regulatory element binding protein 2 (SREBP2) and its target genes HMG-CoA reductase and LDL receptor (each P < 0.01). Biliary cholesterol secretion was dependent on hepatic SR-BI expression, being decreased in SR-BI knockouts (P < 0.001) and increased following hepatic SR-BI overexpression (P < 0.001). However, in each model, biliary secretion of cholesterol, bile acids, and phospholipids as well as fecal bile acid and neutral sterol content, remained unchanged in response to EL overexpression. Importantly, hepatic ABCG5/G8 expression did not correlate with biliary cholesterol secretion rates under these conditions. These results demonstrate that an acute decrease of plasma HDL cholesterol levels by overexpressing EL increases hepatic cholesterol content but leaves biliary sterol secretion unaltered. Instead, biliary cholesterol secretion rates are related to the hepatic expression level of SR-BI. These data stress the importance of SR-BI for biliary cholesterol secretion and might have relevance for concepts of reverse cholesterol transport.

Macronutrient intake and modulation on chylomicron production and clearance

The extent and kinetics of postprandial changes are highly variable and are modulated by numerous factors including diet, lifestyle conditions, genetic background and pathological conditions. This review focuses on dietary factors affecting postprandial chylomicron and lipoprotein metabolism in humans. The first key step in the process is fat digestion within the stomach and small intestine which can be modulated by fat and dietary fiber amounts and types. The second key step is intestinal absorption per se. The uptake and secretion of absorbed nutrients in chylomicrons is affected by numerous factors, including nutrients themselves. The amount of dietary triglycerides as well as the nature of fatty acids ingested from habitual diet or present in a test meal modulates the extent of chylomicron and plasma triglyceride levels postprandially. The amount of dietary cholesterol also modulates the extent of postprandial chylomicron and plasma triglycerides. Other nutrients can alter the postprandial occurrence of chylomicrons such as proteins, alcohol, carbohydrates or fibers. Addition of glucose and more markedly fructose, to a fat test meal increases the accumulation of chylomicrons, as does a high-glycemic index meal. In contrast, some sources of dietary fibers such as oat bran noticeably decrease the occurrence of chylomicron postprandially. Overall, changing the habitual dietary pattern, for instance from a Western-type diet to Mediterranean-type one, can in turn alter the postprandial response of the subjects. The last step in postprandial lipid metabolism is clearance from plasma through combined lipolysis processes and tissue uptake of chylomicron remnants. Both the processes can also be modulated by the nutrients. Because most day-time is usually spent in a postprandial state, the link between dietary patterns and cardiovascular health or risk is clearly mediated by the secretion and clearance rates of chylomicrons in the circulation.

Lipoprotein lipase-facilitated uptake of LDL is mediated by the LDL receptor

LPL mediates the uptake of lipoproteins into different cell types independent of its catalytic activity. The mechanism of this process and its physiological relevance are not clear. Taking into account the importance of the endothelial barrier for lipoprotein uptake, in vitro studies with primary aortic endothelial cells from wild-type and low density lipoprotein receptor (LDLR)-deficient (LDLR(-/-)) mice were performed. Addition of LPL almost doubled the uptake of LDL into wild-type cells. However, there was virtually no LPL-mediated change of LDL uptake into LDLR(-/-) cells. Upregulation of LDLR by lipoprotein-deficient serum/lovastatin in wild-type cells resulted in a 7-fold increase of LPL-mediated LDL uptake. Uptake of chylomicron remnants was not affected by LDLR expression. In proteoglycan-deficient cells, LPL did not increase the uptake of lipoproteins. The physiological relevance of this pathway was studied in mice that were both LDLR(-/-) and transgenic for catalytically inactive LPL in muscle. In the presence of LDLR, inactive LPL reduced LDL cholesterol significantly (13-24%). In the absence of LDLR, LDL cholesterol was not affected by transgenic LPL. Metabolic studies showed that in the presence of LDLR, LPL increased the muscular uptake of LDL by 77%. In the absence of LDLR, transgenic LPL did not augment LDL uptake. Chylomicron uptake was not affected by the LDLR genotype. We conclude that LPL-mediated cellular uptake of LDL, but not of chylomicrons, is dependent on the presence of both LDLR and proteoglycans.

LDL composition in E2/2 subjects and LDL distribution by Apo E genotype in type 1 diabetes

Apo E plays an important role in chylomicron and VLDL remnant processing, uptake or conversion to LDL. The type of lipoprotein that isolates in the LDL density of E2/2 subjects was investigated and the effect of the apo E isoforms on LDL mass was determined in all genotypes in a large group of Type 1 diabetics. Analysis of the LDL composition of E2/2 homozygotes ( n = 6) compared to subjects with the common E3/3 isoform ( n = 6) demonstrated an enrichment in apo E, unesterified cholesterol, phospholipid and triglyceride relative to apo B in E2/2 subjects, more typical of a dense IDL remnant than of LDL. Although diabetics were studied, these findings are considered to reflect those of the general population. Comparison of the lipoprotein distribution of homozygous and heterozygous subjects revealed that, as genotype changed from E4/4 ( n = 22) to E3/4 ( n = 262), E3/3 ( n = 710) = E2/4 ( n = 30), E2/3 ( n = 151), E2/2 ( n = 6), LDL cholesterol decreased significantly in a stepwise manner. The decrease was not in a specific subgroup of LDL. In conclusion, for E2/2 subjects, lipoproteins isolated in the LDL density range appear to be composed mainly of dense IDL remnants and some Lp(a). The apo E isoform also has a significant effect on LDL concentration in both homozygotes and heterozygotes.

An investigation by electron microscopy of chylomicron remnant uptake by human monocyte-derived macrophages

Human monocyte-derived macrophages (HMM) internalise proatherogenic chylomicron remnants via several high affinity receptor pathways. However, the endocytic ultrastructures responsible for the uptake of chylomicron remnants by macrophages have not previously been described. In this study, we have utilised transmission electron microscopy together with colloidal gold-labelling of chylomicron remnants to investigate the pathways involved in macrophage uptake of chylomicron remnants. We found that macrophages internalise chylomicron remnants via surface-connected compartments of up to 600 nm as well as non-clathrin coated pits. Chylomicron remnants were found to be distributed internally in a number of endocytic vesicles including early cysternal endosomes, spherical late endosomes and tubular vesicular compartments. Uptake of chylomicron remnants by HMM via phagocytosis or macropinocytosis was excluded based on the observations that lipoproteins were not found in phagolysosomes nor modified by inhibitors of these two processes, respectively. The latter observation contrasts with previous reports of chylomicron remnant internalisation by macrophages of other species.

Apolipoprotein E (APOE) and warfarin dosing in an Italian population

Sirs, Despite large interindividual differences in dose requirement and a narrow therapeutic range, warfarin is still the most widely prescribed anticoagulant for thromboembolic therapy. However, the problems with dose titration, especially during the initial phase of treatment, lead to a high risk of either severe bleeding or the failure to prevent thromboembolism [1]. A working knowledge of warfarin interactive pathways and of the human genome will facilitate the determination of genetic factors that cause variable response to this drug. Warfarin acts through the inhibition of vitamin K reductase in the vitamin K cycle, thereby preventing the activation of clotting factors II, VII, IX and X and proteins C, S and Z [2, 3]. However, vitamin K1 can be reduced through another pathway, and a high intake of vitamin K1 may reverse the anticoagulant effect of warfarin [3–5]. Vitamin K1 is absorbed from the small intestine together with dietary fat, transported by chylomicrons in the blood and subsequently cleared by the liver through an apolipoprotein E (APOE) receptorspecific uptake [3, 6]. The major isoforms of apolipoprotein E are encoded by the three APOE alleles E2, E3 and E4 [7]. Individuals carrying the APOE*E4 allele have a more rapid uptake of chylomicron remnants following a meal than those that do not [8], and they also have lower serum concentrations of vitamin K1 following an overnight fast [6, 9, 10]. These findings suggest that carriers of APOE*E4 have a more rapid uptake of vitamin K1, leading to an enhanced availability of reduced vitamin K for the activation of clotting factors and proteins in the liver. Warfarin is administered as a racemate of Rand Senantiomers [11]. Cytochrome P450 2C9 (CYP2C9) is the main enzyme responsible for the metabolism of the more active S-warfarin [12], and genetic variability in CYP2C9 has a significant effect on warfarin dose requirement [13]. We have recently published a study on warfarin-treated Swedish patients showing that CYP2C9*1/*1 extensive metabolisers that are homozygous for APOE*E4 require higher warfarin doses than patients carrying other APOE alleles [14]. This study was repeated using 145 Italian patients, most of whom had participated in a previously published study on warfarin pharmacokinetics [15]. The local Ethics Committee (Comitato Etico dell’Azienda Ospedaliera di Padova) gave permission for the APOE genotyping. The warfarin patients had stable prothrombin time international normalised ratios (PT INR), and no interfering drugs were allowed during the study. Two APOE single nucleotide polymorphisms (SNPs) at nucleotide positions 334 and 472 were investigated using TaqMan (Applied Biosystems, Foster City, Calif.), and the ABI PRISM 7000 Sequence Detection System (Applied Biosystems) [14]. Twenty patients carried one APOE*E4 allele (E2/E4, n=1 and E3/E4, n=19), 105 were homozygous for E3 and 20 were heterozygous E2/E3. No one was homozygous for APOE*E4. There were no significant differences in age, gender, bodyweight or PT INR among the APOE genotype groups. We found that the weekly warfarin dose requirement did not vary between patients with different APOE genotypes (analysis of variance: p=0.5937; Fig. 1a). To test the contribution of other important factors, we combined the POE genotype with the CYP2C9 genotype, age, bodyweight and PT INR in a multiple regression model and found that CYP2C9 H. Kohnke AE M. G. Scordo AE M. Wadelius (&) Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden E-mail: mia.wadelius@medsci.uu.se Tel.: +46-18-6114945

Spillover of Dietary Fatty Acids and Use of Serum Nonesterified Fatty Acids for the Synthesis of VLDL-Triacylglycerol Under Two Different Feeding Regimens

The present study quantified dietary fatty acid flux in healthy men (n = 6) who were fed a liquid formula through a duodenal feeding tube (continuous feeding group) or who consumed the same formula in meals (meal feeding group). A triacylglycerol (TAG) stable isotope was added to the formula to determine the entry of dietary fatty acids into the serum and its clearance to the liver and resecretion into serum via VLDL. The contribution of dietary fatty acids to serum nonesterified fatty acids (NEFAs) was higher with meal feeding (24.4 +/- 2.6%) compared with continuous feeding (10.8 +/- 2.9%, P < 0.01) and, when multiplied by the NEFA concentration, resulted in similar absolute fatty acid spillover. Diet-derived NEFAs subsequently represented 10.6 +/- 1.2% and 4.7 +/- 1.3% of hepatic VLDL-TAG (meal feeding vs. continuous feeding, respectively, P = 0.004). Chylomicron remnant uptake by the liver contributed 9.3 +/- 1.9% of fatty acids to hepatic VLDL-TAG synthesis with meal feeding compared with continuous feeding (4.4 +/- 0.8%, P < 0.03). These data suggest that the extent of dietary fatty acid recycling via serum NEFAs and VLDL-TAG is determined by the rate of delivery of dietary fat to the intestine. The inefficient removal of dietary fat from the circulation may maintain VLDL-TAG production but may also result in prolonged postprandial lipemia.

Interplay Between Apolipoprotein E and Scavenger Receptor Class B Type I Controls Coronary Atherosclerosis and Lifespan in the Mouse

The mouse has become a standard model for the study of atherosclerosis induced by extreme dyslipidemia in genetically modified strains such as the apolipoprotein E (apoE)–deficient or the LDL-receptor–deficient mouse. Although the process of plaque formation appears to repeat the fundamental steps of the human disease, it has been notoriously difficult to reproduce in the mouse the clinical consequences of atherosclerosis, such as myocardial infarction and stroke, that so commonly in patients signal plaque rupture or total lumen occlusion.1 The apoE-deficient mouse is a particularly interesting model because of its susceptibility to atherosclerotic lesions spanning from the aortic sinus to the abdominal aorta and involving the brachiocephalic and carotid arteries as well.2,3 It has recently been reported that the brachiocephalic plaque in the apoE-deficient mouse is prone to rupture on feeding a high-fat diet for periods as short as 8 weeks,4 but even in this setting of exaggerated hypercholesterolemia, the aortic sinus and coronary tree do not appear to be susceptible to plaque rupture. Scavenger receptor class B type I (SR-BI) is a scavenger-type receptor expressed by many tissues and accepted by consensus to represent the docking receptor for HDL in the liver. SR-BI-deficient mice have raised HDL levels and increased atherosclerosis susceptibility on fat feeding.5 ApoE and SR-BI are both expressed, among other cells, by the hepatocyte and the macrophage. ApoE is an efficient ligand for receptor-mediated lipoprotein removal by the liver, but it is also a strong acceptor of cellular cholesterol. As such, it may control the rate of foam cell formation in the vessel wall. Similarly, SR-BI channels cholesterol in and out of the cell, and its abundant expression by the macrophage may regulate cholesterol homeostasis in arterial foam cells. Although apoE and SR-BI play crucial roles in lipoprotein metabolism and have been …

Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice

The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma. Whereas LDLR deficiency in mice results in the accumulation of plasma LDL-sized lipoproteins, VLDLR or LRP deficiency alone only minimally affects plasma lipoproteins. To investigate the combined effect of the absence of these receptors on TG-rich lipoprotein levels, we have generated unique VLDLR, LDLR, and LRP triple-deficient mice. Compared with wild-type mice, these mice markedly accumulated plasma lipids and lipases. These mice did not show aggravated hyperlipidemia compared with LDLR and LRP double-deficient mice, but plasma TG was increased after high-fat diet feeding. In addition, these mice showed a severely decreased postprandial TG clearance typical of VLDLR-deficient (VLDLR-/-) mice. Collectively, although VLDLR deficiency in LRP- and LDLR-/- mice does not aggravate hyperlipidemia, these triple-deficient mice represent a unique model of markedly delayed TG clearance on a hyperlipidemic background.

Endotoxin promotes preferential periportal upregulation of VLDL secretion in the rat liver

Zonation affects liver parenchymal cell function and metabolism as well as nonparenchymal cell activation, but whether VLDL production is zonated has yet to be elucidated. Infection induces enhanced VLDL secretion by the liver. Ex vivo studies were undertaken to examine the liver heterogeneity for VLDL formation and secretion and their in vivo response to endotoxin. Highly pure periportal (PP) and perivenous (PV) hepatocytes were isolated from fasted lipopolysaccharide-treated, fasted, and fed rats. They were used to assess their capacity to release VLDL-apolipoprotein B (apoB) and lipid classes in relation to de novo lipid synthesis and the expression of genes crucial to VLDL production. Despite the common superior ability of PP hepatocytes for lipid release and zonal differences in lipid synthesis, zonated secretion of VLDL particles was observed in septic but not in normal fed or fasted livers. The endotoxin-induced apoB secretion was more accentuated in PP hepatocytes; this was accompanied by a preferential PP increase in apoB and microsomal triglyceride transfer protein mRNA levels, whereas lipogenesis indicators were, if anything, similarly modified in hepatocytes of either acinar origin. We conclude that PP and PV hepatocytes exhibited similar capabilities for VLDL formation/secretion in normal conditions; however, the endotoxic pressure did zonate periportally.

High cholesterol absorption efficiency and rapid biliary secretion of chylomicron remnant cholesterol enhance cholelithogenesis in gallstone-susceptible mice

The study of chylomicron pathway through which it exerts its metabolic effects on biliary cholesterol secretion is crucial for understanding how high dietary cholesterol influences cholelithogenesis. We explored a relationship between cholesterol absorption efficiency and gallstone prevalence in 15 strains of inbred male mice and the metabolic fate of chylomicron and chylomicron remnant cholesterol in gallstone-susceptible C57L and gallstone-resistant AKR mice. Our results show a positive and significant ( P<0.0001, r=0.87) correlation between percent cholesterol absorption and gallstone prevalence rates. Compared with AKR mice, C57L mice displayed significantly greater absorption of cholesterol from the small intestine, more rapid plasma clearance of chylomicrons and chylomicron remnants, higher activities of lipoprotein lipase and hepatic lipase, greater hepatic uptake of chylomicron remnants, and faster secretion of chylomicron remnant cholesterol from plasma into bile. All of these increased susceptibility to cholesterol gallstone formation in C57L mice. We conclude that genetic variations in cholesterol absorption efficiency are associated with cholesterol gallstone formation in inbred mice and cholesterol absorbed from the intestine provides an important source for biliary hypersecretion. Differential metabolism of the chylomicron remnant cholesterol between C57L and AKR mice clearly plays a crucial role in the formation of lithogenic bile and gallstones.

W13.332 Uptake of chylomicron remnants into murine bone marrow in vivo

W13.332 Uptake of chylomicron remnants into murine bone marrow in vivo

W13.332 Uptake of chylomicron remnants into murine bone marrow in vivo

W13.332 Uptake of chylomicron remnants into murine bone marrow in vivo

LDL concentration is correlated with the removal from the plasma of a chylomicron-like emulsion in subjects with coronary artery disease

In animal model studies, the uptake of chylomicron remnants after entering in the space of Disse occurs mainly by low-density lipoprotein (LDL) receptor and LDL receptor-related protein (LRP). In subjects, the relative importance of each one of these receptors for the clearance of chylomicron remnants is not fully understood. In our study, LDL cholesterol and apolipoprotein (apo) B were correlated to the plasma kinetics of a chylomicron-like emulsion in 77 subjects (11 women, mean age 58±12 years) with coronary artery disease (CAD). Their total cholesterol was 227±25 mg/dl, triglyceride 159±25 mg/dl, LDL cholesterol 148±27 mg/dl, HDL cholesterol 40±9 mg/dl, apo A1 1.80±0.53 g/l and apo B 1.65±0.48 g/l. The emulsion was double-labeled with 3H-triolein and 14C-cholesteryl oleate and injected intravenously after 12-h fasting. The decay curves of the radioisotopes were determined from blood samples collected at predetermined intervals during 60 min. A negative correlation between FCR of the emulsion cholesterol esters and LDL cholesterol and apo B plasma concentrations was found ( r=−0.4, P=0.005 and r=−0.3, P=0.01, respectively) whereas FCR of the emulsion triglycerides did not correlate with any of the plasma lipids or apolipoprotein parameters. Concluding, in patients with CAD, LDL catabolic pathway significantly influences the removal from plasma of chylomicron remnants.

Binding and uptake of chylomicron remnants by primary and THP-1 human monocyte-derived macrophages: determination of binding proteins

Binding and uptake of chylomicron remnants by primary and THP-1 human monocyte-derived macrophages: determination of binding proteins

The fatty acid composition of chylomicron remnants influences their binding and internalization by isolated hepatocytes.

The binding and internalization of (125)I-labelled chylomicron remnants derived from palm, olive, corn, or fish oil (rich in saturated, monounsaturated, n-6, or n-3 polyunsaturated fatty acids, respectively) by hepatocytes from rats fed a low-fat diet or a diet supplemented with the corresponding fat for 21 days was investigated. In hepatocytes from rats fed the low-fat diet, the association of radioactivity with the cells at 4 degrees C (a measure of initial binding only) was similar with all types of remnants tested, but was more rapid at 37 degrees C (a measure of binding plus internalization) when fish oil, as compared to olive, corn or palm oil remnants, was used, and similar differences in the internalization of the particles were observed. In contrast, when hepatocytes from rats fed the fat-supplemented diets were used, the rate of association at 37 degrees C of remnants with cells from rats fed palm, corn or fish oil was similar, and higher than that found with cells from animals fed olive oil, and in this case these differences were mainly due to changes in the binding of the particles to the cells at 4 degrees C. Both excess low-density lipoprotein (LDL), which inhibits remnant uptake by the LDL receptor, and lactoferrin, which blocks the LDL receptor-related protein (LRP), were found to decrease the association of the remnants with cells from rats fed the low-fat and high-fat diets. However, in hepatocytes from animals given the low-fat diet, most of the differences between the various types of particle were retained in the presence of lactoferrin, but abolished in the presence of LDL. In contrast, in cells from rats fed the high-fat diets, the differences were reduced by both lactoferrin and LDL. These findings demonstrate that the hepatic uptake of chylomicron remnants is influenced both by the fatty acid composition of the particles, and by longer-term adaptive changes in liver tissue, and suggest that the former effects are mediated mainly by the LDL receptor, while the latter may involve both the LDL receptor and the LRP.