Sesamol and sesame (Sesamum indicum) oil enhance macrophage cholesterol efflux via up-regulation of PPARγ1 and LXRα transcriptional activity in a MAPK-dependent manner

2014 ◽  
Vol 54 (5) ◽  
pp. 691-700 ◽  
Author(s):  
Amin F. Majdalawieh ◽  
Hyo-Sung Ro
Keyword(s):  
Cholesterol Efflux ◽  
Transcriptional Activity ◽  
Sesamum Indicum ◽  
Dependent Manner ◽  
Macrophage Cholesterol Efflux

The Anti-Atherogenic Properties of Sesamin are Mediated via Improved Macrophage Cholesterol Efflux Through PPARγ1-LXRα and MAPK Signaling

2014 ◽  
Vol 84 (1-2) ◽  
pp. 79-91 ◽  
Author(s):  
Amin F. Majdalawieh ◽  
Hyo-Sung Ro
Keyword(s):  
Cholesterol Efflux ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Macrophage Cholesterol Efflux

Background: Foam cell formation resulting from disrupted macrophage cholesterol efflux, which is triggered by PPARγ1 and LXRα, is a hallmark of atherosclerosis. Sesamin and sesame oil exert anti-atherogenic effects in vivo. However, the exact molecular mechanisms underlying such effects are not fully understood. Aim: This study examines the potential effects of sesamin (0, 25, 50, 75, 100 μM) on PPARγ1 and LXRα expression and transcriptional activity as well as macrophage cholesterol efflux. Methods: PPARγ1 and LXRα expression and transcriptional activity are assessed by luciferase reporter assays. Macrophage cholesterol efflux is evaluated by ApoAI-specific cholesterol efflux assays. Results: The 50 μM, 75 μM, and 100 μM concentrations of sesamin up-regulated the expression of PPARγ1 (p< 0.001, p < 0.001, p < 0.001, respectively) and LXRα (p = 0.002, p < 0.001, p < 0.001, respectively) in a concentration-dependent manner. Moreover, 75 μM and 100 μM concentrations of sesamin led to 5.2-fold (p < 0.001) and 6.0-fold (p<0.001) increases in PPAR transcriptional activity and 3.9-fold (p< 0.001) and 4.2-fold (p < 0.001) increases in LXR transcriptional activity, respectively, in a concentration- and time-dependent manner via MAPK signaling. Consistently, 50 μM, 75 μM, and 100 μM concentrations of sesamin improved macrophage cholesterol efflux by 2.7-fold (p < 0.001), 4.2-fold (p < 0.001), and 4.2-fold (p < 0.001), respectively, via MAPK signaling. Conclusion: Our findings shed light on the molecular mechanism(s) underlying sesamin’s anti-atherogenic effects, which seem to be due, at least in part, to its ability to up-regulate PPARγ1 and LXRα expression and transcriptional activity, improving macrophage cholesterol efflux. We anticipate that sesamin may be used as a therapeutic agent for treating atherosclerosis.

Abstract 28: Adiponectin Stimulates Cholesterol Efflux Efficiently in Human THP-1 Macrophages and Modulates HDL-apoA-I Biogenesis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Karina Gasbarrino ◽  
Anouar Hafiane ◽  
Jacques Genest ◽  
Stella Styliani Daskalopoulou
Keyword(s):  
Cholesterol Efflux ◽  
Protective Role ◽  
Time Dependent ◽  
Fixed Dose ◽  
Dependent Manner ◽  
Molecular Weight Range ◽  
Macrophage Cholesterol Efflux ◽  
20 Nm ◽  
Dose Dependent

Introduction: Adiponectin (APN) is an anti-inflammatory and anti-atherogenic adipokine that is strongly correlated with circulating HDL levels. However, its role in macrophage lipid metabolism, a crucial process in atherogenesis, remains poorly investigated. We examined the effect of APN on cholesterol efflux from human THP-1 macrophages, elucidated its kinetics, and investigated its role in HDL biogenesis. Methods: APN dose-dependent (0.1 to 60 μM) and time-dependent (0.5 to 24 hours) cholesterol efflux studies were performed in 3 [H]-cholesterol labeled human THP-1 macrophages in the presence of apoA-I. Following efflux studies, the HDL fractions within media were concentrated (10kDa cut-off filter) and subjected to analytical FPLC and 2D-PAGGE technique to reveal HDL species. Results: APN stimulated ABCA1-mediated cholesterol efflux in a dose-dependent and time-dependent manner. Kinetics analysis revealed that increased molar doses of APN and apoA-I had similar Km efficiency of cholesterol efflux but greater velocity ( Km =3.24±0.71 μM, Vmax =4.90±0.07 efflux/6h) when compared to apoA-I alone ( Km =3.33±0.57 μM, Vmax =3.83±0.24 efflux/6h). Importantly, once APN was tested against a fixed dose of apoA-I (10 μg/mL), it promoted cholesterol efflux with Km = 0.17±0.06 μM. This was associated with a 75.7% decrease in intracellular free cholesterol in THP-1 cells in the presence of APN and apoA-I when compared to apoA-I alone (P<0.01). APN alone had no effect on the level of residual efflux (reached a level of 1%). The FPLC cholesterol profiles demonstrated that in the presence of APN and apoA-I there was increased lipidated nascent HDL (nHDL) during the process of cholesterol efflux, compared to apoA-I alone. This was associated with increased size of nHDL-apoA-1 pre-β and α species via 2D-PAGGE analyses. By immunoblotting for apoA-I and APN, APN oligomers exhibited a molecular weight range of 9 to 20 nm, appearing within the size range of nHDL-apoA-I. Conclusion: In addition to promoting macrophage cholesterol efflux in vitro , APN can modulate HDL-apoA-I biogenesis, by increasing the generation of nHDL particles. These findings suggest that APN may be of potential therapeutic value in the modulation of HDL’s protective role in atherosclerosis.

scholarly journals PPARγ1 and LXRα face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1

2010 ◽  
Vol 8 (1) ◽  
pp. nrs.08004 ◽  
Author(s):  
Amin Majdalawieh ◽  
Hyo-Sung Ro
Keyword(s):  
Cholesterol Efflux ◽  
Transcriptional Activity ◽  
Cholesterol Homeostasis ◽  
Peroxisome Proliferator ◽  
Biological Processes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Enhancer Binding Protein ◽  
Liver X Receptor Α ◽  
Macrophage Cholesterol Efflux ◽  
Regulatory Functions

Peroxisome proliferator-activated receptor γ1 (PPARγ1) and liver X receptor α (LXRα) are nuclear receptors that play pivotal roles in macrophage cholesterol homeostasis and inflammation; key biological processes in atherogenesis. The activation of PPARγ1 and LXRα by natural or synthetic ligands results in the transactivation of ABCA1, ABCG1, and ApoE; integral players in cholesterol efflux and reverse cholesterol transport. In this review, we describe the structure, isoforms, expression pattern, and functional specificity of PPARs and LXRs. Control of PPARs and LXRs transcriptional activity by coactivators and corepressors is also highlighted. The specific roles that PPARγ1 and LXRα play in inducing macrophage cholesterol efflux mediators and antagonizing macrophage inflammatory responsiveness are summarized. Finally, this review focuses on the recently reported regulatory functions that adipocyte enhancer-binding protein 1 (AEBP1) exerts on PPARγ1 and LXRα transcriptional activity in the context of macrophage cholesterol homeostasis and inflammation.

scholarly journals Truncated APC regulates the transcriptional activity of β-catenin in a cell cycle dependent manner

2006 ◽  
Vol 16 (2) ◽  
pp. 199-209 ◽  
Author(s):  
Jean Schneikert ◽  
Annette Grohmann ◽  
Jürgen Behrens
Keyword(s):  
Cell Cycle ◽  
Transcriptional Activity ◽  
Dependent Manner ◽  
A Cell ◽  
Cycle Dependent

scholarly journals Serum Amyloid A Promotes Cholesterol Efflux Mediated by Scavenger Receptor B-I

2005 ◽  
Vol 280 (43) ◽  
pp. 35890-35895 ◽  
Author(s):  
Deneys R. van der Westhuyzen ◽  
Lei Cai ◽  
Maria C. de Beer ◽  
Frederick C. de Beer
Keyword(s):  
Acute Phase ◽  
Cholesterol Efflux ◽  
Serum Amyloid A ◽  
Acute Phase Protein ◽  
Scavenger Receptor ◽  
Dependent Manner ◽  
Cellular Cholesterol ◽  
Amyloid A ◽  
Phase Protein ◽  
Cellular Cholesterol Efflux

Serum amyloid A (SAA) is an acute phase protein whose expression is markedly up-regulated during inflammation and infection. The physiological function of SAA is unclear. In this study, we reported that SAA promotes cellular cholesterol efflux mediated by scavenger receptor B-I (SR-BI). In Chinese hamster ovary cells, SAA promoted cellular cholesterol efflux in an SR-BI-dependent manner, whereas apoA-I did not. Similarly, SAA, but not apoA-I, promoted cholesterol efflux from HepG2 cells in an SR-BI-dependent manner as shown by using the SR-BI inhibitor BLT-1. When SAA was overexpressed in HepG2 cells using adenovirus-mediated gene transfer, the endogenously expressed SAA promoted SR-BI-dependent efflux. To assess the effect of SAA on SR-BI-mediated efflux to high density lipoprotein (HDL), we compared normal HDL, acute phase HDL (AP-HDL, prepared from mice injected with lipopolysaccharide), and AdSAA-HDL (HDL prepared from mice overexpressing SAA). Both AP-HDL and AdSAA-HDL promoted 2-fold greater cholesterol efflux than normal HDL. Lipid-free SAA was shown to also stimulate ABCA1-dependent cholesterol efflux in fibroblasts, in line with an earlier report (Stonik, J. A., Remaley, A. T., Demosky, S. J., Neufeld, E. B., Bocharov, A., and Brewer, H. B. (2004) Biochem. Biophys. Res. Commun. 321, 936–941). When added to cells together, SAA and HDL exerted a synergistic effect in promoting ABCA1-dependent efflux, suggesting that SAA may remodel HDL in a manner that releases apoA-I or other efficient ABCA1 ligands from HDL. SAA also facilitated efflux by a process that was independent of SR-BI and ABCA1. We conclude that the acute phase protein SAA plays an important role in HDL cholesterol metabolism by promoting cellular cholesterol efflux through a number of different efflux pathways.

Abstract 43: Cholesterol Efflux Pathways Suppress Inflammasome Activation in Mice and Humans

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Marit Westerterp ◽  
Panagiotis Fotakis ◽  
Mireille Ouimet ◽  
Andrea E Bochem ◽  
Hanrui Zhang ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Inflammasome Activation ◽  
Loss Of Function ◽  
Caspase 1 ◽  
Macrophage Cholesterol Efflux

Plasma high-density-lipoprotein (HDL) has several anti-atherogenic properties, including its key role in functioning as acceptor for ATP-binding cassette A1 and G1 (ABCA1 and ABCG1) mediated cholesterol efflux. We have shown previously that macrophage Abca1/g1 deficiency accelerates atherosclerosis, by enhancing foam cell formation and inflammatory cytokine expression in atherosclerotic plaques. Macrophage cholesterol accumulation activates the inflammasome, leading to caspase-1 cleavage, required for IL-1β and IL-18 secretion. Several studies have suggested that inflammasome activation accelerates atherogenesis. We hypothesized that macrophage Abca1/g1 deficiency activates the inflammasome. In Ldlr -/- mice fed a Western type diet (WTD), macrophage Abca1/g1 deficiency increased IL-1β and IL-18 plasma levels (2-fold; P <0.001), and induced caspase-1 cleavage. Deficiency of the inflammasome components Nlrp3 or caspase-1 in macrophage Abca1/g1 knockouts reversed the increase in plasma IL-18 levels ( P <0.001), indicating these changes were inflammasome dependent. We found that macrophage Abca1/g1 deficiency induced caspase-1 cleavage in splenic CD115 + monocytes and CD11b + macrophages. While mitochondrial ROS production or lysosomal function were not affected, macrophage Abca1/g1 deficiency led to an increased splenic population of monocytes (2.5-fold; P <0.01). Monocytes secrete ATP, and as a result, ATP secretion from total splenic cells was increased (2.5-fold; P <0.01), likely contributing to inflammasome activation. Caspase-1 deficiency decreased atherosclerosis in macrophage Abca1/g1 deficient Ldlr -/- mice fed WTD for 8 weeks (225822 vs 138606 μm 2 ; P <0.05). Of therapeutic interest, one injection of reconstituted HDL (100 mg/kg) in macrophage Abca1/g1 knockouts decreased plasma IL-18 levels ( P <0.05). Tangier disease patients, with a homozygous loss-of-function for ABCA1, showed increased IL-1β and IL-18 plasma levels (3-fold; P <0.001), suggesting that cholesterol efflux pathways also suppress inflammasome activation in humans. These findings suggest that macrophage cholesterol efflux pathways suppress inflammasome activation, possibly contributing to the anti-atherogenic effects of HDL treatment.

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