New Strategies to Promote Macrophage Cholesterol Efflux

The capacity of macrophages to dispose of cholesterol deposited in the atherosclerotic plaque depends on their ability to activate cholesterol efflux pathways. To develop athero-protective therapies aimed at promoting macrophage cholesterol efflux, cholesterol metabolism in THP-1 monocyte-derived macrophages has been extensively studied, but the intrinsic sensitivity of monocytes and the lack of a standardized procedure to differentiate THP-1 monocytes into macrophages have made it difficult to utilize THP-1 macrophages in the same or similar degree of differentiation across studies. The variability has resulted in lack of understanding of how the differentiation affects cholesterol metabolism, and here we review and investigate the effects of THP-1 differentiation on cholesterol efflux. The degree of THP-1 differentiation was inversely associated with ATP binding cassette A1 (ABCA1) transporter-mediated cholesterol efflux. The differentiation-associated decrease in ABCA1-mediated cholesterol efflux occurred despite an increase in ABCA1 expression. In contrast, DSC1 expression decreased during the differentiation. DSC1 is a negative regulator of the ABCA1-mediated efflux pathway and a DSC1-targeting agent, docetaxel showed high potency and efficacy in promoting ABCA1-mediated cholesterol efflux in THP-1 macrophages. These data suggest that pharmacological targeting of DSC1 may be more effective than increasing ABCA1 expression in promoting macrophage cholesterol efflux. In summary, the comparison of THP-1 macrophage subtypes in varying degrees of differentiation provided new insights into cholesterol metabolism in macrophages and allowed us to identify a viable target DSC1 for the promotion of cholesterol efflux in differentiated macrophages. Docetaxel and other pharmacological strategies targeting DSC1 may hold significant potential for reducing atherogenic cholesterol deposition.

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Rosmarinic Acid Increases Macrophage Cholesterol Efflux through Regulation of ABCA1 and ABCG1 in Different Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms22168791 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8791

Author(s):

Jean-Baptiste Nyandwi ◽

Young Shin Ko ◽

Hana Jin ◽

Seung Pil Yun ◽

Sang Won Park ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Rosmarinic Acid ◽

Cholesterol Efflux ◽

Inflammasome Activation ◽

Atherosclerotic Cardiovascular Disease ◽

Protein Levels ◽

Initial Event ◽

Abca1 Expression ◽

Macrophage Cholesterol Efflux ◽

Underlying Mechanisms

Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.

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W06.172 Paraoxonase 1 (PON1) enhances HDL-mediated macrophage cholesterol efflux via the ABCA1 transporter: A possible role for lysophosphatidylcholine

Atherosclerosis ◽

10.1016/s0021-9150(04)90171-2 ◽

2004 ◽

Vol 5 (1) ◽

pp. 40

Author(s):

M ROSENBLAT

Keyword(s):

Cholesterol Efflux ◽

Paraoxonase 1 ◽

Macrophage Cholesterol Efflux

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

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000195 ◽

2014 ◽

Vol 84 (1-2) ◽

pp. 79-91 ◽

Cited By ~ 7

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 sesamins 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.

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Faculty Opinions recommendation of Overexpression of steroidogenic acute regulatory protein increases macrophage cholesterol efflux to apolipoprotein AI.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2920957.2598056 ◽

2010 ◽

Author(s):

Holly LaVoie ◽

Steven R King

Keyword(s):

Cholesterol Efflux ◽

Regulatory Protein ◽

Steroidogenic Acute Regulatory Protein ◽

Apolipoprotein Ai ◽

Macrophage Cholesterol Efflux ◽

Steroidogenic Acute Regulatory

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Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation

Cells ◽

10.3390/cells10020198 ◽

2021 ◽

Vol 10 (2) ◽

pp. 198

Author(s):

Bailey A. Loving ◽

Maoping Tang ◽

Mikaela C. Neal ◽

Sachi Gorkhali ◽

Robert Murphy ◽

...

Keyword(s):

Lipoprotein Lipase ◽

Cholesterol Efflux ◽

Acid Oxidation ◽

Lipid Uptake ◽

Expression Of Genes ◽

Ppar Signaling ◽

Ppar Agonists ◽

Inflammatory State ◽

Excessive Secretion ◽

Efflux Pathway

Microglia become increasingly dysfunctional with aging and contribute to the onset of neurodegenerative disease (NDs) through defective phagocytosis, attenuated cholesterol efflux, and excessive secretion of pro-inflammatory cytokines. Dysfunctional microglia also accumulate lipid droplets (LDs); however, the mechanism underlying increased LD load is unknown. We have previously shown that microglia lacking lipoprotein lipase (LPL KD) are polarized to a pro-inflammatory state and have impaired lipid uptake and reduced fatty acid oxidation (FAO). Here, we also show that LPL KD microglia show excessive accumulation of LD-like structures. Moreover, LPL KD microglia display a pro-inflammatory lipidomic profile, increased cholesterol ester (CE) content, and reduced cholesterol efflux at baseline. We also show reduced expression of genes within the canonical cholesterol efflux pathway. Importantly, PPAR agonists (rosiglitazone and bezafibrate) rescued the LD-associated phenotype in LPL KD microglia. These data suggest that microglial-LPL is associated with lipid uptake, which may drive PPAR signaling and cholesterol efflux to prevent inflammatory lipid distribution and LD accumulation. Moreover, PPAR agonists can reverse LD accumulation, and therefore may be beneficial in aging and in the treatment of NDs.

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Abstract: P444 TRANS INTESTINAL CHOLESTEROL EFFLUX PATHWAY IS NOT MEDIATED THROUGH HDL

Atherosclerosis Supplements ◽

10.1016/s1567-5688(09)70739-1 ◽

2009 ◽

Vol 10 (2) ◽

pp. e754

Author(s):

C Vrins ◽

M van Eck ◽

R Ottenhoff ◽

P Rensen ◽

A Groen

Keyword(s):

Cholesterol Efflux ◽

Efflux Pathway

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.43 ◽

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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