Paraoxonase 1‐treated ox<scp>LDL</scp> promotes cholesterol efflux from macrophages by stimulating the <scp>PPAR</scp>γ–<scp>LXR</scp>α–<scp>ABCA</scp>1 pathway

Ikhlef, Souade; Berrougui, Hicham; Simo, Olivier Kamtchueng; Khalil, Abdelouahed

doi:10.1002/1873-3468.12198

Cited by 27 publications

(29 citation statements)

References 65 publications

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“…that apigenin can influence lipid metabolism by activating PPARγ [51]. As PPARγ/LXRα pathway has been well demonstrated in the regulation of ABCA1 expression [6,52,53], this pathway may also be responsible for apigenin-induced up-regulation of ABCA1 expression and cholesterol efflux, which still warrants further investigation. In addition to lipid disorder, persistent and chronic inflammation within vessel walls also gives a great impetus to AS progression [54].…”

Section: Discussionmentioning

confidence: 90%

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

Ren

Jiang

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: The development of atherosclerosis is accompanied by escalating inflammation and lipid accumulation within blood vessel walls. ABCA1 plays a crucial role in mediating cholesterol efflux from macrophages, which protects against atherogenesis. This research was designed to explore the effects and underlying mechanisms of apigenin (4’, 5, 7-trihydroxyflavone) on ABCA1-mediated cellular cholesterol efflux and LPS-stimulated inflammation in RAW264.7 macrophages and apoE^-/- mice. Methods: Expression of genes or proteins was examined by RT-PCR or western blot analysis. Liquid scintillation counting was used to detect percent cholesterol efflux. Cellular cholesterol content was measured using HPLC assay. The secretion levels of pro-inflammatory cytokines were quantified by ELISA assay. Atherosclerotic lesion sizes were determined with Oil Red O staining. The contents of macrophages and smooth muscle cells in atherosclerotic lesion were evaluated using immunohistochemistry. Plasma TC, TG, HDL-C and LDL-C levels in apoE^-/- mice were evaluated using commercial test kits. Results: Apigenin potently increased ABCA1 expression through miR-33 repression in a dose- and time-dependent manner. Treatment with apigenin significantly increased ABCA1-mediated cholesterol efflux, and reduced TC, FC and CE levels in macrophage-derived foam cells. In LPS-treated macrophages, the expression levels of TLR-4, MyD88 and p-IκB-α as well as nuclear NF-κB p65 were decreased by the addition of apigenin. Moreover, apigenin markedly decreased secretion levels of several pro-inflammatory cytokines. Lastly, in LPS-challenged apoE^-/- mice, apigenin administration augmented ABCA1 expression, decreased the contents of macrophages and smooth muscle cells in atherosclerotic lesion, reduced miR-33, TLR-4, and NF-κB p65 levels, improved plasma lipid profile and relieved inflammation, which results in less atherosclerotic lesion size. Conclusions: Taken together, these results suggest that apigenin may attenuate atherogenesis through up-regulating ABCA1-mediated cholesterol efflux and inhibiting inflammation.

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Section: Discussionmentioning

confidence: 90%

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

Ren

Jiang

Zhou

et al. 2018

Cell Physiol Biochem

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“…Chawla et al [32] reported that the absence of macrophage PPARγ-LXRα-ABCA1 pathway disrupts cholesterol efflux and aggravates atherogenesis in vivo . Ikhlef et al [64] determined that oxLDL–paraoxonase 1 (PON1) potently amplified cholesterol efflux through the PPARγ-LXRα-ABCA1/G1 pathway in J774 macrophages compared to ox-LDL alone. Besides, salvianolic acid B (Sal B) can also promote the efflux of excess cellular cholesterol from THP-1 cell lines by activating the PPARγ-LXRα-ABCA1 pathway [65].…”

Section: Discussionmentioning

confidence: 99%

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

Jiang

Ren

Chen

et al. 2017

Cell Physiol Biochem

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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.

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“…Lysophosphatidylcholine (LysoPC) plays a role in HDL-PON1-induced cholesterol efflux (26). Incubation of oxLDL with PON1 has been shown to liberate LysoPC.…”

Section: Hdl Pon1 and Reverse Cholesterol Transportmentioning

confidence: 99%

“…Incubation of oxLDL with PON1 has been shown to liberate LysoPC. Treatment of J774A.1 macrophages with the oxLDL-PON1 complex increased apoA-I-mediated cholesterol efflux compared to oxLDL in the absence of PON1 (26). Purified LysoPC mimicked effects of oxLDL-PON1 on macrophage cholesterol efflux.…”

Section: Hdl Pon1 and Reverse Cholesterol Transportmentioning

confidence: 99%

“…Purified LysoPC mimicked effects of oxLDL-PON1 on macrophage cholesterol efflux. Additional studies revealed that oxLDL-PON1 increased expression of liver X receptor (LXR) and peroxisome proliferator-activated receptor γ (PPARγ), known inducers of ABCA1 and ABCG1 (26). Inactivation of PON1 was associated with inhibition of macrophage ABCA1/ABCG1 expression.…”

Section: Hdl Pon1 and Reverse Cholesterol Transportmentioning

confidence: 99%

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Cholesterol reduction and macrophage function: role of paraoxonases

White¹,

Anantharamaiah

2017

Current Opinion in Lipidology

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Purpose of review Unregulated uptake of oxidized LDL by macrophages to form foam cells is the hallmark for atherosclerosis. The paraoxonase (PON) family of enzymes play a critical role in attenuating atherosclerotic lesion formation by hydrolyzing lipid peroxides (LOOHs) and preventing the oxidation of LDL particles and by enhancing HDL-mediated cholesterol efflux. Findings in recent years suggest novel mechanisms by which PON isoforms interact with macrophages to regulate cholesterol metabolism and cellular function. Recent findings The association of PON with HDL particles facilitates binding of the particle to macrophages and ABCA1-dependent cholesterol efflux. The hydrolysis of membrane phospholipids by PON generates lysophosphatidylcholine which is shown to regulate expression of cholesterol transport proteins. The PON family also regulates multiple aspects of macrophage function. PON attenuates inflammation and prevents induction of apoptosis via activation of an SR-B1-dependent signaling mechanism. PON limits macrophage-dependent oxidant formation by preventing activation of the membrane-associated NADPH oxidase and by stabilizing mitochondria. PON also promotes the differentiation of macrophages to an anti-inflammatory phenotype. This function appears to be independent of PON enzymatic activity and, rather, is dependent on the ability of endogenous sulfhydryls to neutralize pro-inflammatory peroxides. Summary In recent years, the therapeutic efficacy of HDL-based therapies has been subject to dispute. Pharmacological approaches that target an increase in the expression and/or activity of PON may facilitate macrophage cholesterol metabolism and attenuate inflammatory injury.

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Paraoxonase 1‐treated oxLDL promotes cholesterol efflux from macrophages by stimulating the PPARγ–LXRα–ABCA1 pathway

Cited by 27 publications

References 65 publications

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation

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

Cholesterol reduction and macrophage function: role of paraoxonases

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