Curcumin Enhanced Cholesterol Efflux by Upregulating ABCA1 Expression Through AMPK-SIRT1-LXRα Signaling in THP-1 Macrophage-Derived Foam Cells

Zou

et al. 2020

Preprint

Abbreviations:ABCA1: ATP-binding cassette subfamily A member 1 ABCG1: ATP-binding cassette subfamily G member 1 ABCG5: ATP-binding cassette subfamily G member 5 AMPK: adenosine monophosphate activated protein kinases CE: cholesterol ester CER: Cholesterol esterification rate LXRα: liver X receptor alpha pAMPK: phosphorylated-AMPK RCT: cholesterol reverse transport SR-BI: scavenger receptor class B type I TC: total cholesterol Abstract Cholesterol efflux from macrophages is the first step of cholesterol reverse transport (RCT), whose increase inhibits cholesterol accumulation and foam cell formation to suppress atherogenesis. Liver X receptor alpha (LXRα) and adenosine monophosphate activated protein kinases (AMPK) both have the pivotal role in cholesterol homeostasis. However the association between these two molecules in cell model of atherosclerosis is poorly understood.Hesperetin has been reported to possess several protective effects for cardiovascular diseases, while little is known about the role of hesperetin and its underlying mechanism on macrophage foam cell formation. In this study, we sought to investigate the potential effects of hesperetin in cholesterol efflux by using human macrophage derived foam cells, focusing on liver X receptor alpha (LXRα) and adenosine monophosphate activated protein kinases (AMPK) implication. Hesperetin treatment concentration-dependently reduced foam cell formation, intracellular cholesterol level and cholesterol esterification rate, and enhanced cholesterol efflux in THP-1 macrophages. Hesperetin upregulated the protein levels of LXRα and its targets including ABCA1, ABCG1 as well as SR-BI, and phosphorylated-AMPK.Meanwhile, hesperetin-induced upregulation of LXRα expression was enhanced by AMPK agonist and inhibited by AMPK inhibitor. Furthermore, hesperetin increased mRNA level of LXRα and its target genes, all which were depressed by AMPKα1/α2 small interfering RNA (siRNA) transfection. In conclusion, we founded for the first time that hesperetin could active AMPK. And this activation upregulated LXRα and its targets including ABCA1, ABCG1 and SR-BI, which significantly inhibited foam cell formation and promoted cholesterol efflux in THP-1 macrophages. Our results highlight the therapeutic potential of hespretin for the possible reduction in foam cell formation. This new mechanism could contribute the anti-atherogenic effects of hesperetin.

Section: Discussionsupporting

confidence: 93%

Hesperetin inhibits foam cell formation in macrophages via activating LXRα signal in an AMPK dependent manner

Zou

et al. 2020

Preprint

International Journal of Molecular Medicine

“…HPLC analysis was conducted as previously described (15). Sterol analyses were performed using a HPLC system (2790; controlled with Empower Pro software; Waters Corp., Milford, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Cellular cholesterol efflux analysis was conducted as previously described (15). In brief, the THP-1 cells were cultured with 0.2 µ l Ci/ml of [ 3 H]cholesterol and ox-LDL (50 µ g/ml) for 48 h, followed by treatment with allicin.…”

Section: Methodsmentioning

confidence: 99%

Allicin induces the upregulation of ABCA1 expression via PPARγ/LXRα signaling in THP-1 macrophage-derived foam cells

Lin

Liu

et al. 2017

Self Cite

Allicin is considered anti-atherosclerotic due to its antioxidant and anti-inflammatory effects, which makes it an important drug for the prevention and treatment of atherosclerosis. However, the effects of allicin on foam cells are unclear. Thus, in this study, we examined the effects of allicin on lipid accumulation via peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα) in THP-1 macrophage-derived foam cells. THP-1 cells were exposed to 100 nM phorbol myristate acetate (PMA) for 24 h, and then to oxydized low-density lipoprotein (ox-LDL; 50 mg/ml) to induce foam cell formation. The results of Oil Red O staining and high-performance liquid chromatography (HPLC) revealed showed that pre-treatment of the foam cells with allicin decreased total cholesterol, free cholesterol (FC) and cholesterol ester levels in cells, and also decreased lipid accumulation. Moreover, allicin upregulated ATP binding cassette transporter A1 (ABCA1) expression and promoted cholesterol efflux. However, these effects were significantly abolished by transfection with siRNA targeting ABCA1. Furthermore, PPARγ/LXRα signaling was activated by allicin treatment. The allicin-induced upregulation of ABCA1 expression was also abolished by PPARγ inhibitor (GW9662) and siRNA or LXRα siRNA co-treatment. Overall, our data demonstrate that the allicin-induced upregulation of ABCA1 promotes cholesterol efflux and reduces lipid accumulation via PPARγ/LXRα signaling in THP-1 macrophage-derived foam cells.

“…AMP-activated protein kinase (AMPK)-dependent ABCA1 expression also involves the mammalian target of rapamycin (mTOR) pathway and inhibits the extracellular-signal regulated kinase (ERK). AMPK-induced ABCA1 expression leads to cholesterol efflux from human macrophages (49). Through the ERK1/2 pathway, intracellular ABCA1 exerts a protective effect against oxidative stress caused by ischemia.…”

Section: Association Of Abca1 With Apoptosis and Autophagy In Prostatmentioning

confidence: 99%

ATP‑binding cassette transporter A1: A promising therapy target for prostate cancer (Review)

Xiong

Huang

et al. 2017

mol clin onc

Abstract. ATP-binding cassette transporter A1 (ABCA1) has been found to mediate the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I (apoA-I), and is essential for the synthesis of high-density lipoprotein.Mutations of the ABCA1 gene may induce Tangier disease and familial hypoalphalipoproteinemia; they may also lead to loss of cellular cholesterol homeostasis in prostate cancer, and increased intracellular cholesterol levels are frequently found in prostate cancer cells. Recent studies have demonstrated that ABCA1 may exert anticancer effects through cellular cholesterol efflux, which has been attracting increasing attention in association with prostate cancer. The aim of the present review was to focus on the current views on prostate cancer progression and the various functions of ABCA1, in order to provide new therapeutic targets for prostate cancer.