Phospholipids as modulators of hepatic recognition of chylomicron remnants. Observations with emulsified lipoprotein lipids.
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ABSTRACT:
SUBMITTER: Borensztajn J
PROVIDER: S-EPMC1131612 | biostudies-other | 1990 Jul
REPOSITORIES: biostudies-other
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Project description:Rat lymph chylomicrons were treated with Pronase resulting in particles completely devoid of surface apoproteins. On re-incubation with serum, the Pronase-treated chylomicrons re-acquired, by transfer from other lipoproteins, all apoproteins except apoprotein B, which is water-insoluble and non-transferable. When two groups of rats were injected with [3H]cholesterol-labelled control or Pronase-treated chylomicrons, radioactivity was incorporated into the liver of both groups at similar rates. It is concluded that the remnants of the control and Pronase-treated chylomicrons formed in the vascular space were recognized and taken up by liver cells by a process that does not require apoprotein B.
| S-EPMC1158391 | biostudies-other
Project description:Lipoprotein lipase (LPL) has been proposed to play a role in the uptake of chylomicron remnants by hepatocytes by mediating the binding of these lipoproteins to cell-surface glycosaminoglycans and to the low-density-lipoprotein receptor-related protein (LRP). This proposal is based on studies that examined the binding of chylomicrons to HepG2 cells, fibroblasts and Chinese hamster ovary cells in culture, in the presence of large amounts of LPL [Beisiegel (1995) Curr. Opin. Lipidol. 6, 117-122]. We have investigated whether LPL attached to the surface of chylomicrons enhances the binding and uptake of these lipoproteins to isolated hepatocytes maintained in culture. Bovine milk LPL was bound to mouse chylomicrons, double-labelled in vivo with [3H]retinol (in retinyl esters) and with [14C]palmitic acid (in triacylglycerols), collected from the mesenteric lymph of normal mice and from mice lacking the apoprotein E (apo E) gene. Normal chylomicrons (containing apo E) and apo E-free chylomicrons, with or without bound LPL, were incubated with cultured hepatocytes isolated from mice lacking the apo E gene. At 0 degree C LPL did not enhance the binding of the normal or apo E-free chylomicrons by the hepatocytes. When incubations were performed at 37 degrees C the triacylglycerols of normal and apo E-free chylomicrons were hydrolysed by LPL and there was a significant uptake of [14C]fatty acids and [3H]retinol by the hepatocytes. The addition of heparin or lactoferrin, a known inhibitor of hepatic uptake of chylomicron remnants, to the incubation medium inhibited the uptake of [3H]retinol, present in the lipoprotein core, but not the uptake of the [14C]fatty acids. We conclude that: (1) LPL attached to chylomicrons in amounts sufficient to effectively hydrolyse their core triacylglycerols does not enhance the binding of these lipoproteins to the surface of isolated hepatocytes; (2) the recognition and uptake of chylomicrons by hepatocytes requires that these lipoproteins be first hydrolysed by LPL; and (3) the uptake of lipolysed chylomicrons (remnants) by hepatocytes does not require the mediation of apo E.
| S-EPMC1217584 | biostudies-other
Project description:The hepatic metabolism of [1-14C]oleate- and [1,2-3H]cholesterol-dual-labelled chylomicron remnants derived from olive, corn, palm and fish oil and butter fat was compared by adding each lipoprotein separately to the perfusate of isolated livers from rats fed on a normal diet. Labelled remnants from butter fat and fish oil were removed more rapidly from the perfusate than remnants derived from olive, corn and palm oil. The oxidation of labelled remnant fatty acid from olive oil, fish oil or butter fat was four to seven times greater than that from corn and palm oil. Labelled fatty acid in fish oil remnants was incorporated into phospholipid significantly more efficiently than the labelled fatty acid in olive, corn or palm oil remnants, with butter fat giving an intermediate value. For all the remnants, there was a significant amount of hydrolysis of labelled esterified cholesterol by the liver which was dependent on the magnitude of hepatic uptake of each type of remnant. The recovery of remnant [3H]cholesterol label in the bile was 50% less with palm oil remnants than with all the other remnants studied. The results indicate that the fatty acid composition of chylomicron remnants has a major impact on their uptake and metabolism by the liver.
| S-EPMC1135973 | biostudies-other
Project description: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 Vascular Endothelial Growth Factor (VEGF) 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 (Vegfd-/-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 syndecan 1 (SDC1), 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 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.
2018-08-16 | GSE108959 | GEO
Project description:1. Rats pretreated with Triton WR-1339 to prevent the formation of remnants were injected with [3H]cholesterol-labelled remnants, intact chylomicrons or chylomicrons depleted of most of their surface phospholipids by treatment with phospholipase A2. Within 5 min about 80% of the injected label of remnants and phospholipid-depleted chylomicrons was incorporated into the livers compared with less than 10% of the injected radioactivity of intact chylomicrons. A similar rapid hepatic uptake of radioactivity occurred when rats not pretreated with Triton were injected with [3H]cholesterol-labelled phospholipid-depleted chylomicrons. This rapid hepatic uptake of phospholipid-depleted chylomicrons occurred apparently without any alteration in the apoprotein composition of the particles. 2. The participation of hepatocytes in the uptake of remnants and phospholipid-depleted chylomicrons was examined. Both types of particles were taken up by the hepatocytes. However, small chylomicrons (Sf less than 400) were taken up more efficiently than were large chylomicrons (Sf greater than 400), but neither was taken up as efficiently as the remnants. 3. The results of this study lend support to the hypothesis that phospholipid-depleted chylomicrons and chylomicron remnants are taken up by the liver by a similar mechanism, which depends on the loss of surface phospholipids.
| S-EPMC1163576 | biostudies-other
Project description:Apoprotein-free heparin-binding and non-binding chylomicrons were used as substrates to test the effects on lipoprotein lipase activity of (a) chylomicron protein I; (b) the mixture of proteins I, II and apoprotein E and (c) human beta 2-glycoprotein I. No activation of the enzyme was observed with any of those apoproteins. When rats were injected simultaneously with [3H]cholesterol-labelled heparin-binding chylomicrons (containing proteins I and II) and [14C]cholesterol-labelled non-binding chylomicrons, no differences were detected between the rates of removal from circulation of those two types of particles. Clearance of chylomicrons from circulation was accompanied by the incorporation of 3H and 14C labels into the livers at similar rates. It is concluded that proteins I, II and apoprotein E have no effect on the degradation of chylomicrons by lipoprotein lipase and that the hepatic recognition of remnants does not appear to be affected by proteins I and II.
| S-EPMC1153116 | biostudies-other
Project description:Rat lymph chylomicrons and chylomicron remnants were treated with trypsin or Pronase. The ability of the resulting apoprotein-free lipoproteins to be taken up by the isolated perfused rat liver, and to bind to isolated rat liver membranes, was examined. Compared with control lipoproteins, the apoprotein-free chylomicrons and remnants retained unaltered their capacity to be differentiated by the intact liver and by the isolated membranes. Further, control remnants and apoprotein-free remnants competed for binding to the isolated membranes. We conclude that apoproteins are not required for the hepatic differentiation between chylomicrons and remnants, and suggest that the lipoprotein phospholipids may play a direct role in this process.
| S-EPMC1151512 | biostudies-other
Project description:Cluster of differentiation 36 (CD36) variants influence fasting lipids and risk of metabolic syndrome, but their impact on postprandial lipids, an independent risk factor for cardiovascular disease, is unclear. We determined the effects of SNPs within a ?410 kb region encompassing CD36 and its proximal and distal promoters on chylomicron (CM) remnants and LDL particles at fasting and at 3.5 and 6 h following a high-fat meal (Genetics of Lipid Lowering Drugs and Diet Network study, n = 1,117). Five promoter variants associated with CMs, four with delayed TG clearance and five with LDL particle number. To assess mechanisms underlying the associations, we queried expression quantitative trait loci, DNA methylation, and ChIP-seq datasets for adipose and heart tissues that function in postprandial lipid clearance. Several SNPs that associated with higher serum lipids correlated with lower adipose and heart CD36 mRNA and aligned to active motifs for PPAR?, a major CD36 regulator. The SNPs also associated with DNA methylation sites that related to reduced CD36 mRNA and higher serum lipids, but mixed-model analyses indicated that the SNPs and methylation independently influence CD36 mRNA. The findings support contributions of CD36 SNPs that reduce adipose and heart CD36 RNA expression to inter-individual variability of postprandial lipid metabolism and document changes in CD36 DNA methylation that influence both CD36 expression and lipids.
| S-EPMC5321222 | biostudies-literature
Project description:Primary hepatocytes treated with nonesterified PUFA have been used as a model for analyzing the inhibitory effects of dietary polyunsaturated fats on lipogenic gene expression. Although nonesterified fatty acids play an important signaling role in starvation, they do not completely recapitulate the mechanism of dietary fat presentation to the liver, which is delivered via chylomicron remnants. To test the effect of remnant TG on lipogenic enzyme expression, chylomicron remnants were generated from the lymph of rats intubated with either safflower oil or lard. The remnants were added to the medium of primary rat hepatocytes in culture and the accumulation of mRNA for genes involved in carbohydrate and lipid metabolism was measured. Both PUFA-enriched remnants and nonesterified PUFA inhibited the expression and maturation of sterol response element binding protein-1c (SREBP-1c) and the expression of lipogenic genes regulated by this transcription factor. These remnants also inhibited the expression of glucose-6-phosphate dehydrogenase (G6PD), a gene regulated at post-transcriptional steps. In contrast, PUFA-enriched remnants did not inhibit the accumulation of mRNA for malic enzyme, glucokinase, and L-pyruvate kinase, whereas nonesterified fatty acids caused a decrease in these mRNA. These genes are regulated independently of SREBP-1c. SFA-enriched remnants did not inhibit lipogenic gene expression, which is consistent with a lack of inhibition of lipogenesis by dietary saturated fats. Thus, the inhibitory action of dietary polyunsaturated fats on lipogenesis involves a direct action of chylomicron remnants on the liver.
| S-EPMC3021438 | biostudies-literature
Project description:BackgroundCurrent guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical trials demonstrate persistent residual ASCVD risk despite aggressive LDL-C lowering.ContentNon-LDL-C lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (TGRLs), and lipoprotein(a), and C-reactive protein as a measure of inflammation are increasingly recognized as associated with residual risk after LDL-C lowering. Eicosapentaenoic acid in statin-treated patients with high triglycerides reduced both triglycerides and ASCVD events. Reducing TGRLs is believed to have beneficial effects on inflammation and atherosclerosis. High lipoprotein(a) concentrations increase ASCVD risk even in individuals with LDL-C < 70 mg/dL. Although statins do not generally lower lipoprotein(a), proprotein convertase subtilisin/kexin type 9 inhibitors reduce lipoprotein(a) and cardiovascular outcomes, and newer approaches are in development. Persistent increases in C-reactive protein after intensive lipid therapy have been consistently associated with increased risk for ASCVD events.SummaryWe review the evidence that biochemical assays to measure TGRLs, lipoprotein(a), and C-reactive protein are associated with residual risk in patients treated to low concentrations of LDL-C. Growing evidence supports a causal role for TGRLs, lipoprotein(a), and inflammation in ASCVD; novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development to reduce residual ASCVD risk.
| S-EPMC7793228 | biostudies-literature