scholarly journals Lipoprotein-heparin-fibronectin-denatured collagen complexes enhance cholesteryl ester accumulation in macrophages.

1984 ◽  
Vol 99 (4) ◽  
pp. 1266-1274 ◽  
Author(s):  
D J Falcone ◽  
N Mated ◽  
H Shio ◽  
C R Minick ◽  
S D Fowler
Keyword(s):  
Extracellular Matrix ◽  
Cholesteryl Ester ◽  
Lipid Accumulation ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Cholesteryl Oleate ◽  
Peritoneal Macrophages ◽  
Ldl Catabolism ◽  
Cellular Lipid Accumulation

The sequestration of low-density lipoprotein (LDL) by components of the vascular extracellular matrix has long been recognized as a contributing factor to lipid accumulation during atherogenesis. The effects, however, that components of the extracellular matrix might have on LDL catabolism by scavenger cells have been little investigated. For these purposes we have prepared insoluble complexes of LDL, heparin, fibronectin, and denatured collagen (gelatin) and examined their effects on lipid accumulation, LDL uptake and degradation, and cholesteryl ester synthesis in mouse peritoneal macrophages. The results of these experiments have demonstrated that the cholesteryl ester content of macrophages incubated with a particular suspension of LDL, heparin, fibronectin, and collagen complexes is four- to fivefold that of cells incubated with LDL alone. The uptake of complexes containing 125I-LDL is rapid; however, in contrast to either endocytosed 125I-LDL or 125I-acetyl LDL, the degradation of complex-derived LDL is impaired. In addition, the uptake of complex-derived LDL stimulates the incorporation of [14C]oleic acid into cholesteryl oleate, however, the stimulation was a small fraction of that observed in cells incubated with acetyl LDL. Ultrastructurally, macrophages incubated with LDL, heparin, fibronectin, and collagen complexes did not contain many lipid droplets, but rather their cytoplasm is filled with phagosomes containing material similar in appearance to LDL-matrix complexes. These results indicate that components of the extracellular matrix can alter the catabolism of LDL by scavenger cells, suggesting that they may play a role in cellular lipid accumulation in the atherosclerotic lesion.

Cholesteryl ester transfer protein (CETP) increases postprandial triglyceridaemia and delays triacylglycerol plasma clearance in transgenic mice

2009 ◽  
Vol 419 (3) ◽  
pp. 629-634 ◽  
Author(s):  
Alessandro G. Salerno ◽  
Patrícia R. Patrício ◽  
Jairo A. Berti ◽  
Helena C. F. Oliveira
Keyword(s):  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Plasma Clearance ◽  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Kinetic Studies ◽  
Cholesteryl Oleate ◽  
Liver Uptake ◽  
Transfer Protein

The CETP (cholesteryl ester transfer protein) is a plasma protein synthesized in several tissues, mainly in the liver; CETP reduces plasma HDL (high-density lipoprotein) cholesterol and increases the risk of atherosclerosis. The effect of CETP levels on postprandial intravascular metabolism of TAGs (triacylglycerols) is an often-overlooked aspect of the relationship between CETP and lipoprotein metabolism. Here, we tested the hypothesis that CETP delays the plasma clearance of TAG-rich lipoprotein by comparing human CETP expressing Tg (transgenic) and non-Tg mice. After an oral fat load, the postprandial triglyceridaemia curve was markedly increased in CETP-Tg compared with non-Tg mice (280±30 versus 190±20 mg/dl per 6 h respectively, P<0.02). No differences in intestinal fat absorption and VLDL (very-low-density lipoprotein) secretion rates were observed. Kinetic studies of double-labelled chylomicron-like EMs (emulsions) showed that both [3H]triolein and [14C]cholesteryl oleate FCRs (fractional clearance rates) were significantly reduced (∼20%) in CETP-Tg mice. Furthermore, TAG from lipid EM pre-incubated with CETP-Tg plasma had plasma clearance and liver uptake significantly lower than the non-Tg plasma-treated lipid EM. In addition, reductions in post-heparin plasma LPL (lipoprotein lipase) activity (50%) and adipose tissue mRNA abundance (39%) were verified in CETP-Tg mice. Therefore we conclude that CETP expression in Tg mice delays plasma clearance and liver uptake of TAG-rich lipoproteins by two mechanisms: (i) transferring TAG to HDLs and increasing CE content of the remnant particles and (ii) by diminishing LPL expression. These findings show that the level of CETP expression can influence the responsiveness to dietary fat and may lead to fat intolerance.

Abstract 3968: Bone Marrow Derived Growth Differentiation Factor-15 (GDF-15) Protects from Macrophage Accumulation and Effects Atherosclerotic Lesion Stabilisation in Low-Density Lipoprotein Receptor-Null Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Michael R Preusch ◽  
Jens Strelau ◽  
Matthias Baeuerle ◽  
Erwin Blessing ◽  
Marc Bischof ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Peritoneal Macrophages ◽  
Lesion Size ◽  
Fibrous Cap ◽  
Atherosclerotic Lesions ◽  
Density Lipoprotein Receptor ◽  
Macrophage Accumulation

Atherosclerosis is considered to be a chronic inflammatory disease. Macrophages are the prime sources of a variety of inflammatory cytokines and growth factors, which contribute to the initiation and progression of atherosclerotic lesions. The cytokine growth differentiation factor-15 (GDF-15) is a newly discovered member of the transforming growth factor-beta cytokine. GDF-15 participates in vascular inflammation and is mostly expressed by macrophages within the lesions. In this study the impact of GDF-15 deficiency in bone marrow-derived cells on atherogenesis in a mouse model was examined. Bone marrow from GDF15 −/−or GDF-15 +/+ mice was transplanted into lethally irradiated low-density lipoprotein receptor (LDLR−/−) mice (n=38). Twentyfour weeks after administration of a high-fat/high-cholesterol Western type diet atherosclerotic lesion size within the aortic root as well as macrophage content was quantified and compared. In addition features of lesion destabilisation like size of the necrotic core, thinning of the fibrous cap, intra-plaque hemorrhage and calcification were evaluated. In an in-vitro experiment peritoneal macrophages from transplanted mice were harvested and stimulated with tumor necrosis factor alpha (TNFα). Transplantation of GDF-15 −/− bone marrow cells resulted in an enhanced macrophage accumulation within the atherosclerotic lesions (ratio mac/lesion 0.51 versus 0.31; p<0.05) and a significant thinning of the fibrous cap (30.5 versus 48.5 μm; p<0.05). Cell culture experiments demonstrated that macrophages from GDF-15 −/− mice had a much higher induction of ICAM-1 and MCP-1 after stimulation with TNFα in comparison to wildtype peritoneal macrophages. However no difference in lesion size could be reported. Furthermore, there was no difference in plasma lipid levels and body weight. Our data indicates that bone marrow derived GDF-15 protects from macrophage accumulation within atherosclerotic lesions and promotes lesion stabilisation possibly due to inhibition of adhesion molecules and MCP-1.

scholarly journals Receptor activities for low-density lipoprotein and acetylated low-density lipoprotein in a mouse macrophage cell line (IC21) and in human monocyte-derived macrophages.

1981 ◽  
Vol 154 (6) ◽  
pp. 1852-1867 ◽  
Author(s):  
M G Traber ◽  
V Defendi ◽  
H J Kayden
Keyword(s):  
Cholesteryl Ester ◽  
Cholesterol Synthesis ◽  
Low Density Lipoprotein ◽  
Primary Cultures ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Simian Virus 40 ◽  
Human Monocyte ◽  
Peritoneal Macrophages ◽  
Low Density

IC21 macrophages, a permanent culture of a line of cells derived from a single colony of mouse peritoneal macrophages transformed with simian virus 40, demonstrate most of the characteristics of lipoprotein metabolism that have been described for primary cultures of rodent or canine peritoneal macrophages. IC21 macrophages have low but demonstrable low-density lipoprotein (LDL) receptor activity. They actively degrade acetylated LDL (AcLDL), which has a negative charge and is not recognized by the LDL receptor. Incubation of IC21 macrophages with human lipoprotein-depleted serum leads to a marked increase in cholesterol synthesis, as measured by incorporation of labeled acetate into sterols. Sterol synthesis is inhibited by further incubation with AcLDL; incubation with LDL also decreases cholesterol synthesis with an accumulation of radioactivity from acetate in sterol intermediates, which indicates that some uptake of LDL occurs. Incubation with AcLDL but not LDL leads to a marked stimulation of cholesterol esterification, as measured by labeled oleic acid incorporation into cholesteryl esters, and a concomitant increase in cellular cholesteryl ester content. IC21 macrophages as compared with human monocyte-derived macrophages are shown to have marked difference in their abilities to degrade native LDL and AcLDL. Human monocyte-derived macrophages degrade LDL at low concentrations at a rate sevenfold greater than do IC21 macrophages. The rate of cholesteryl ester synthesis after LDL receptor induction and incubation with LDL increases linearly with LDL concentration in HMD macrophages, but no increase was found in similarly incubated IC21 macrophages. IC21 macrophages degrade AcLDL at a rate two- to fourfold greater than do human monocyte-derived macrophages.

scholarly journals Shen-Hong-Tong-Luo Formula Attenuates Macrophage Inflammation and Lipid Accumulation through the Activation of the PPAR-γ/LXR-α/ABCA1 Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-19
Author(s):  
Zepeng Zhang ◽  
Lu Zhai ◽  
Jing Lu ◽  
Sanmiao Sun ◽  
Dandan Wang ◽  
...  
Keyword(s):  
Protective Effect ◽  
Lipid Accumulation ◽  
High Performance ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Peritoneal Macrophages ◽  
Inflammatory Factors ◽  
Network Pharmacology ◽  
Ppar Γ ◽  
Primary Mouse

Atherosclerosis (AS) is the killer of human health and longevity, which is majorly caused by oxidized lipoproteins that attack macrophages in the endarterium. The Shen-Hong-Tong-Luo (SHTL) formula has shown great clinical efficacy and vascular protective effect for over 30 years in China, to attenuate AS progression. However, its pharmacological mechanism needs more investigation. In this study, we first investigated the chemical composition of SHTL by fingerprint analysis using high-performance liquid chromatography. In primary mouse peritoneal macrophages induced by lipopolysaccharide (LPS), we found that SHTL pretreatment suppressed reactive oxygen species accumulation and reversed the increases of the inflammatory factors, TNF-α and IL-6. Moreover, lipid accumulation induced by oxidized low-density lipoprotein (Ox-LDL) in macrophages was inhibited by SHTL. Additionally, network pharmacology was used to predict the potential targets of SHTL as the PPAR-γ/LXR-α/ABCA1 signaling pathway, which was validated in macrophages and ApoE-/- mice by histopathological staining, qPCR, and Western blot analysis. Importantly, the protective effect of SHTL in the LPS- and Ox-LDL-induced macrophages against inflammation and lipid accumulation was attenuated by GW9662, a PPAR-γ antagonist, which confirmed the prediction results of network pharmacology. In summary, these results indicated that SHTL pretreatment reduced inflammation and lipid accumulation of macrophages by activating the PPAR-γ/LXR-α/ABCA1 pathway, which may provide a new insight into the mechanism of SHTL in the suppression of AS progression.

scholarly journals Sterol O-acyltransferase 2 chaperoned by apolipoprotein J facilitates hepatic lipid accumulation following viral and nutrient stresses

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hung-Yu Sun ◽  
Tzu-Ying Chen ◽  
Yu-Ching Tan ◽  
Chun-Hsiang Wang ◽  
Kung-Chia Young
Keyword(s):  
Cholesteryl Ester ◽  
Lipid Accumulation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Apolipoprotein J

AbstractThe risks of non-alcoholic fatty liver disease (NAFLD) include obese and non-obese stresses such as chronic hepatitis C virus (HCV) infection, but the regulatory determinants remain obscure. Apolipoprotein J (ApoJ) served as an ER-Golgi contact-site chaperone near lipid droplet (LD), facilitating HCV virion production. We hypothesized an interplay between hepatic ApoJ, cholesterol esterification and lipid deposit in response to NAFLD inducers. Exposures of HCV or free-fatty acids exhibited excess LDs along with increased ApoJ expression, whereas ApoJ silencing alleviated hepatic lipid accumulation. Both stresses could concomitantly disperse Golgi, induce closer ApoJ and sterol O-acyltransferase 2 (SOAT2) contacts via the N-terminal intrinsically disordered regions, and increase cholesteryl-ester. Furthermore, serum ApoJ correlated positively with cholesterol and low-density lipoprotein levels in normal glycaemic HCV patients, NAFLD patients and in mice with steatosis. Taken together, hepatic ApoJ might activate SOAT2 to supply cholesteryl-ester for lipid loads, thus providing a therapeutic target of stress-induced steatosis.

scholarly journals Autophagy Induction Protects against 7-Oxysterol-induced Cell Death via Lysosomal Pathway and Oxidative Stress

2016 ◽  
Vol 9 ◽  
pp. JCD.S37841 ◽  
Author(s):  
Xi-Ming Yuan ◽  
Nargis Sultana ◽  
Nabeel Siraj ◽  
Liam J. Ward ◽  
Bijar Ghafouri ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Lipid Accumulation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Autophagic Vacuole ◽  
Cellular Lipid ◽  
Autophagy Induction ◽  
Cellular Lipid Accumulation ◽  
And Oxidative Stress

7-Oxysterols are major toxic components in oxidized low-density lipoprotein and human atheroma lesions, which cause lysosomal membrane permeabilization (LMP) and cell death. Autophagy may function as a survival mechanism in this process. Here, we investigated whether 7-oxysterols mixed in an atheroma-relevant proportion induce autophagy, whether autophagy induction influences 7-oxysterol-mediated cell death, and the underlying mechanisms, by focusing on cellular lipid levels, oxidative stress, and LMP in 7-oxysterol-treated macrophages. We found that 7-oxysterols induced cellular lipid accumulation, autophagy dysfunction, and cell death in the form of both apoptosis and necrosis. Exposure to 7-oxysterols induced autophagic vacuole synthesis in the form of increased autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and LC3-phosphatidylethanolamine conjugate (LC3-II) and autophagic vacuole formation. This led to an accumulation of p62, indicating a reduction in autophagic vacuole degradation. Importantly, autophagy induction significantly reduced 7-oxysterol-mediated cell death by diminishing LMP and oxidative stress. Moreover, autophagy induction minimized cellular lipid accumulation induced by 7-oxysterols. These findings highlight the importance of autophagy in combating cellular stress, LMP, and cell death in atherosclerosis. Therefore, activation of the autophagy pathway may be a potential therapeutic strategy for prevention of necrotic core formation in atherosclerotic lesions.

scholarly journals Leonurine Prevents Atherosclerosis Via Promoting the Expression of ABCA1 and ABCG1 in a Pparγ/Lxrα Signaling Pathway-Dependent Manner

2017 ◽  
Vol 43 (4) ◽  
pp. 1703-1717 ◽  
Author(s):  
Ting Jiang ◽  
Kun Ren ◽  
Qian Chen ◽  
Heng Li ◽  
Rong Yao ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Cholesterol Efflux ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Dependent Manner ◽  
Protein Levels ◽  
Cellular Lipid Accumulation ◽  
Oil Red O Staining ◽  
Oil Red O

Background/Aims: Previous studies have demonstrated that leonurine, a unique alkaloid compound of Herba leonuri, can exert anti-oxidative and anti-inflammatory effects on the development of atherosclerosis (AS). This study was designed to investigate the effects of leonurine on cholesterol efflux from THP-1 macrophage-derived foam cells and development of atherosclerotic lesions in apoE-/- mice, and further determine the potential mechanisms. Methods: Human THP-1 cells were fully differentiated into foam cells by the pre-treatment with phorbol-12-myristate-13-acetate (PMA) and oxidized density lipoproteins (ox-LDL). After cells were incubated with various concentrations of leonurine, Oil Red O staining and high-performance liquid chromatography (HPLC) assays were utilized to detect cellular lipid accumulation and cholesterol content, respectively. Cellular cholesterol efflux was determined by liquid scintillation counting. The mRNA and protein levels of ATP-binding cassette transporter A1/G1 (ABCA1/G1), peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptor α (LXRα) in foam cells were assessed using real-time quantitative PCR (RT-qPCR) and western blot analyses, respectively. Plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) levels in apoE-/- mice were evaluated using enzymatic methods. The atherosclerotic lesion sizes and collagen contents in aortic roots were determined by Oil Red O and Masson’s trichrome staining, respectively. Results: Oil Red O staining and liquid scintillation counting assays showed that leonurine significantly inhibited lipid accumulation and promoted 3H-cholesterol efflux in human THP-1 macrophage-derived foam cells in a concentration-dependent manner. Besides, both the mRNA and protein levels of ABCA1/G1, PPARγ and LXRα were enhanced by leonurine, which were attenuated by LXRα siRNA or PPARγ siRNA transfection. Finally, leonurine improved plasma lipid profile, decreased atherosclerotic lesion sizes, increased collagen contents and amplified PPARγ, LXRα and ABCA1/G1 expressions in aortic roots of apoE-/- mice. Conclusions: Leonurine can promote cholesterol efflux and alleviate cellular lipid accumulation by magnifying the expression of ABCA1/G1 in a PPARγ/LXRα signaling pathway-dependent manner in human THP-1 macrophage-derived foam cells and abate atherogenesis in apoE-/- mice, which may offer a promising therapeutic intervention of leonurine in protecting against AS.

Batroxobin Accelerates Lipid Accumulation of Peroxidized Low Density Lipoprotein in Mouse Peritoneal Macrophages

Pathobiology ◽  
1996 ◽  
Vol 64 (5) ◽  
pp. 275-278
Author(s):  
Shengyuan Yu ◽  
Peigen Kuang ◽  
Takemichi Kanazawa ◽  
Kogo Onodera ◽  
Hirohumi Metoki ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Peritoneal Macrophages ◽  
Low Density ◽  
Mouse Peritoneal Macrophages
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