Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: a potential anti-atherogenic function?

ABSTRACT: Apolipoprotein J (apo J) is a secreted glycoprotein of which the exact function remains a matter for speculation. Apo J has been implicated in such diverse processes as sperm maturation, regulation of complement activation, programmed cell death, tissue remodelling and lipid transport. In this study a possible role for apo J in lipid transport was explored. Mouse peritoneal macrophages were incubated with acetylated low-density lipoprotein (AcLDL) to produce foam cells containing cholesterol and cholesteryl esters. Incubation of the foam cells with physiological concentrations of purified apo J led to a dose-dependent export of cholesterol. The appearance of cholesterol in the medium was associated predominantly with a decline in intracellular cholesteryl esters rather than intracellular free cholesterol. The kinetics of cholesterol release to apo J were similar to apo A-I, an established promoter of cholesterol efflux. Apo J was also shown to induce phospholipid efflux from cells, whereas the cholesterol exported to the medium was associated with the apo J. Studies using foam cells from apo E-null mice showed that the cholesterol exported to the medium was independent of apo E production by the cells. These results present the first evidence that apo J can promote cholesterol efflux from foam cells and indicates that it might have a function in cellular cholesterol homoeostasis in both normal and pathological situations.

SUBMITTER: Gelissen IC

PROVIDER: S-EPMC1219343 | biostudies-other | 1998 Apr

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice.

Project description:Increasing evidence suggests that adenosine monophosphate-activated protein kinase (AMPK) exerts protective effects for cardiovascular diseases apart from the regulation of energy homeostasis. However, the role of AMPK and its underlying mechanism on macrophage foam cell formation are poorly understood. In this study, we sought to investigate the potential effects of AMPK in modulating cholesterol deposition by using murine macrophage-derived foam cells. Incubation with 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) markedly attenuated the cholesterol ester accumulation in oxidized low density lipoprotein-loaded macrophages. Notably, AICAR treatment significantly increased ATP-binding cassette transporters G1 (Abcg1) mRNA and protein levels without affecting mRNA and protein expression of ABCA1, scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI (SR-BI), and cholesterol synthesis-related genes. The up-regulation of Abcg1 by AICAR was independent of the liver X receptor/retinoid X receptor pathway but dependent on ERK activation. AICAR elevates Abcg1 expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the Abcg1 mRNA 3'-UTR responsible for the regulatory effect of AICAR. Prevention of ABCG1 expression by small interfering RNA abolished the AICAR-mediated attenuation on foam cell formation. Furthermore, increased ABCG1 expression and reduced lipid accumulation were demonstrated in AICAR-treated macrophages isolated from apolipoprotein E-deficient mice (apoE(-/-) mice). AICAR treatment also inhibited atherosclerotic plaque formation in apoE(-/-) mice. Our findings elucidate a precise mechanism involved in the prevention of atherogenesis by AMPK.

| S-EPMC2963409 | biostudies-literature

Cholesterol Acceptors Regulate the Lipidome of Macrophage Foam Cells.

Project description:Arterial foam cells are central players of atherogenesis. Cholesterol acceptors, apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), take up cholesterol and phospholipids effluxed from foam cells into the circulation. Due to the high abundance of cholesterol in foam cells, most previous studies focused on apoA-I/HDL-mediated free cholesterol (FC) transport. However, recent lipidomics of human atherosclerotic plaques also identified that oxidized sterols (oxysterols) and non-sterol lipid species accumulate as atherogenesis progresses. While it is known that these lipids regulate expression of pro-inflammatory genes linked to plaque instability, how cholesterol acceptors impact the foam cell lipidome, particularly oxysterols and non-sterol lipids, remains unexplored. Using lipidomics analyses, we found cholesterol acceptors remodel foam cell lipidomes. Lipid subclass analyses revealed various oxysterols, sphingomyelins, and ceramides, species uniquely enriched in human plaques were significantly reduced by cholesterol acceptors, especially by apoA-I. These results indicate that the function of lipid-poor apoA-I is not limited to the efflux of cholesterol and phospholipids but suggest that apoA-I serves as a major regulator of the foam cell lipidome and might play an important role in reducing multiple lipid species involved in the pathogenesis of atherosclerosis.

| S-EPMC6695943 | biostudies-literature

Upconversion nanoparticle-mediated photodynamic therapy induces autophagy and cholesterol efflux of macrophage-derived foam cells via ROS generation.

Project description:Macrophage-derived foam cells are a major component of atherosclerotic plaques and have an important role in the progression of atherosclerotic plaques, thus posing a great threat to human health. Photodynamic therapy (PDT) has emerged as a therapeutic strategy for atherosclerosis. Here, we investigated the effect of PDT mediated by upconversion fluorescent nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) on the cholesterol efflux of THP-1 macrophage-derived foam cells and explored the possible mechanism of this effect. First, we found that PDT notably enhanced the cholesterol efflux and the induction of autophagy in both THP-1 and peritoneal macrophage-derived foam cells. The autophagy inhibitor 3-methyladenine and an ATG5 siRNA significantly attenuated PDT-induced autophagy, which subsequently suppressed the ABCA1-mediated cholesterol efflux. Furthermore, the reactive oxygen species (ROS) produced by PDT were responsible for the induction of autophagy, which could be blocked by the ROS inhibitor N-acetyl cysteine (NAC). NAC also reversed the PDT-induced suppression of p-mTOR and p-Akt. Therefore, our findings demonstrate that PDT promotes cholesterol efflux by inducing autophagy, and the autophagy was mediated in part through the ROS/PI3K/Akt/mTOR signaling pathway in THP-1 and peritoneal macrophage-derived foam cells.

| S-EPMC5520901 | biostudies-literature

Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase.

Project description:The lipid droplet (LD) is the major site of cholesterol storage in macrophage foam cells and is a potential therapeutic target for the treatment of atherosclerosis. Cholesterol, stored as cholesteryl esters (CEs), is liberated from this organelle and delivered to cholesterol acceptors. The current paradigm attributes all cytoplasmic CE hydrolysis to the action of neutral CE hydrolases. Here, we demonstrate an important role for lysosomes in LD CE hydrolysis in cholesterol-loaded macrophages, in addition to that mediated by neutral hydrolases. Furthermore, we demonstrate that LDs are delivered to lysosomes via autophagy, where lysosomal acid lipase (LAL) acts to hydrolyze LD CE to generate free cholesterol mainly for ABCA1-dependent efflux; this process is specifically induced upon macrophage cholesterol loading. We conclude that, in macrophage foam cells, lysosomal hydrolysis contributes to the mobilization of LD-associated cholesterol for reverse cholesterol transport.

| S-EPMC3257518 | biostudies-literature

C-reactive protein inhibits cholesterol efflux from human macrophage-derived foam cells.

Project description:ObjectiveThe objective of this study was to determine the effects and potential mechanisms of C-reactive protein (CRP) on cholesterol efflux from human macrophage foam cells, which may play a critical role in atherogenesis.Methods and resultsHuman THP-1 monocytes and peripheral blood mononuclear cells (PBMCs) were preincubated with acetylated LDL and [3H]-cholesterol to form foam cells, which were then treated with apolipoprotein A-I (apoA-I) or HDL for cholesterol efflux assay. Clinically relevant concentrations of CRP significantly reduced cholesterol efflux from THP-1 and PBMCs to apoA-I or HDL. CRP significantly decreased the expression of ATP-binding membrane cassette transporter A-1 (ABCA1) and ABCG1, whereas it increased superoxide anion production. Furthermore, CRP substantially activated ERK1/2 in THP-1-derived foam-like cells. Reducing superoxide anion by antioxidant seleno-L-methionine or SOD mimetic (MnTBAP) effectively abolished the CRP-induced decrease in cholesterol efflux and the expression of ABCA1 and ABCG1. Inhibiting ERK1/2 activation by its specific inhibitor PD98059 or by a dominant negative mutant of ERK2 could also block CRPs action on THP-1 cells.ConclusionsCRP inhibits cholesterol efflux from human foam cells derived from THP-1 and PBMCs in vitro though oxidative stress, ERK1/2 activation, and downregulation of intracellular cholesterol transport molecules ABCA1 and ABCG1.

| S-EPMC2927966 | biostudies-literature

The pro-fibrotic and anti-inflammatory foam cell macrophage paradox.

Project description:The formation of foamy macrophages by sequestering extracellular modified lipids is a key event in atherosclerosis. However, there is controversy about the effects of lipid loading on macrophage phenotype, with in vitro evidence suggesting either pro- or anti-inflammatory consequences. To investigate this in vivo we compared the transcriptomes of foamy and non-foamy macrophages that accumulate in experimental subcutaneous granulomas in fat-fed ApoE null mice or normal chow-fed wild-type mice, respectively. Consistent with previous studies in peritoneal macrophages from LDL receptor null mice (Spann et al., 2012 [1]), we found that anti-inflammatory LXR/RXR pathway genes were over-represented in the foamy macrophages, but there was no change in M1 or M2 phenotypic markers. Quite unexpectedly, however, we found that genes related to the induction of fibrosis had also been up-regulated (Thomas et al., 2015 [2]). The progression of the foamy macrophages along anti-inflammatory and pro-fibrotic pathways was confirmed using immunohistochemistry (described fully in our primary research article (Thomas et al., 2015 [2]). Here we provide additional details on production of the macrophages and their transcriptomic comparison, with the raw and processed microarray data deposited in GEO (accession number GSE70126). Our observations on these cells are indeed paradoxical, because foamy macrophages have long been implicated in promoting inflammation, extracellular matrix degradation and atherosclerotic plaque rupture, which must be provoked by additional local mediators. Our findings probably explain how very early macrophage-rich lesions maintain their structural integrity.

| S-EPMC4664709 | biostudies-literature

Placental secretion of apolipoprotein A1 and E: the anti-atherogenic impact of the placenta.

Project description:High levels of atherogenic lipids in pregnancy are associated with health complications for the mother, the fetus and the newborn. As endocrine secretory tissue, the human placenta releases apolipoproteins (apos), particularly apoA1 and apoE. However, the magnitude and the directionality of the apo secretions remain unknown. We aimed to 1) determine the amount and orientation (apical-maternal versus basal-fetal) of placentally secreted apoA1 and apoE using human perfused placenta and primary trophoblast cell (PTC) culture, 2) compare apoA1 and apoE secretions of PTC with that of hepatocytes and 3) associate the obtained results with human blood levels by determining apoA1 and apoE concentrations in maternal and fetal serum samples. In perfused placenta and serum samples, apoA1 and apoE concentrations were significantly higher at the maternal compared to the fetal side. For apoE a similar trend was found in PTC. For apoA1, the secretion to the apical side declined over time while release to the basal side was stable resulting in significantly different apoA1 concentrations between both sides. Unexpectedly, PTC secreted significantly higher amounts of apoA1 and apoE compared to hepatocytes. Our data indicate that the placenta may play an important role in maternal and fetal cholesterol homeostasis via secretion of anti-atherogenic apos.

| S-EPMC6470155 | biostudies-literature

Ht31, a protein kinase A anchoring inhibitor, induces robust cholesterol efflux and reverses macrophage foam cell formation through ATP-binding cassette transporter A1.

Project description:Macrophage foam cell is the predominant cell type in atherosclerotic lesions. Removal of excess cholesterol from macrophages thus offers effective protection against atherosclerosis. Here we report that a protein kinase A (PKA)-anchoring inhibitor, st-Ht31, induces robust cholesterol/phospholipid efflux, and ATP-binding cassette transporter A1 (ABCA1) greatly facilitates this process. Remarkably, we found that st-Ht31 completely reverses foam cell formation, and this process is ABCA1-dependent. The reversal is also accompanied by the restoration of well modulated inflammatory response to LPS. There is no detectable toxicity associated with st-Ht31, even when cells export up to 20% cellular cholesterol per hour. Using FRET-based PKA biosensors in live cells, we provide evidence that st-Ht31 drives cholesterol efflux by elevating PKA activity specifically in the cytoplasm. Furthermore, ABCA1 facilitates st-Ht31 uptake. This allows st-Ht31 to effectively remove cholesterol from ABCA1-expressing cells. We speculate that de-anchoring of PKA offers a novel therapeutic strategy to remove excess cholesterol from lipid-laden lesion macrophages.

| S-EPMC3030343 | biostudies-literature

Novel technique for generating macrophage foam cells for in vitro reverse cholesterol transport studies.

Project description:Generation of foam cells, an essential step for reverse cholesterol transport studies, uses the technique of receptor-dependent macrophage loading with radiolabeled acetylated LDL. In this study, we used the ability of a biologically relevant detergent molecule, lysophosphatidylcholine (lyso-PtdCho), to form mixed micelles with cholesterol or cholesteryl ester (CE) to generate macrophage foam cells. Fluorescent or radiolabeled cholesterol/lyso-PtdCho mixed micelles were prepared and incubated with RAW 264.7 or mouse peritoneal macrophages. Results showed that such micelles were quite stable at 4°C and retained the solubilized cholesterol during one month of storage. Macrophages incubated with cholesterol or CE (unlabeled, fluorescently labeled, or radiolabeled)/lyso-PtdCho mixed micelles accumulated CE as documented by microscopy, lipid staining, labeled oleate incorporation, and by TLC. Such foam cells unloaded cholesterol when incubated with HDL but not with oxidized HDL. We propose that stable cholesterol or CE/lyso-PtdCho micelles would offer advantages over existing methods.

| S-EPMC3826683 | biostudies-literature

Clusterin/apolipoprotein J, its isoforms and Alzheimer's disease.

Project description: Not available

| S-EPMC10133478 | biostudies-literature