Molecular mechanism for nobiletin to enhance ABCA1/G1 expression in mouse macrophages

Tsuboi, Tomoe; Lu, Rui; Yonezawa, Takayuki; Watanabe, Akio; Woo, Je‐Tae; Abe-Dohmae, Sumiko; Yokoyama, Shinji

doi:10.1016/j.atherosclerosis.2020.01.024

Cited by 34 publications

(20 citation statements)

References 37 publications

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“…Additionally, the expression of ABCA1/G1 and EEPD1 was significantly reduced or increased after transfecting with miR-320b mimics or inhibitor in macrophages. LXR was reported to directly upregulate ABCA1/G1 abundance in macrophages 19,45,46) MiR-320b Alters Plasma Pro-Inflammatory Cytokines Levels in Apoe / Mice ELISA assay was conducted to determine the effects of miR-320b on the expression levels of proinflammatory cytokines, and the concentration of MCP-1, IL-6, and CXCL5 was significantly increased by 81.7%, 80.4%, and 20.6%, respectively, in AAV2-miR-320b group compared with that in the controls (Fig. 5C).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-320b Modulates Cholesterol Efflux and Atherosclerosis

Lü

Yang

et al. 2022

JAT

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ATP-binding cassette (ABC) transporters and endonuclease-exonuclease-phosphatase family domain containing 1 (EEPD1) are reported to regulate cellular cholesterol efflux in macrophages. Bioinformatics analysis has revealed that ABCG1 and EEPD1 might be potential targets of microRNA (miR)-320b. This study aimed to elucidate the roles of miR-320b in cholesterol efflux from macrophages and the pathogenesis of atherosclerosis.Methods: Microarray was conducted to profile microRNA (miRNA) expression, and quantitative real-time PCR (qPCR) was used to validate the differentially expressed miRNAs in peripheral blood mononuclear cells of coronary artery disease (CAD) patients and healthy controls. Luciferase assay was conducted to evaluate the activity of reporter construct containing the 3´-untranslated region (3´-UTR) of target genes. Besides, NBDcholesterol efflux induced by high-density lipoprotein (HDL) and lipid-free apolipoprotein A1 (apoA1) was detected using fluorescence intensity, respectively. Apoe / mice were injected with adeno-associated virus (AAV)2-miR-320b or control via tail vein, thereafter fed with 14 week atherogenic diet to study the roles of miR-320b in vivo.Results: MiR-320b was highly expressed in CAD patients compared with that in the healthy controls in both the microarray analysis and qPCR analysis. In vitro study showed that miR-320b decreased HDL-and apoA1mediated cholesterol efflux from macrophages partly by directly targeting ABCG1 and EEPD1 genes and partly via suppressing the LXR -ABCA1/G1 pathway. Consistently, in vivo administration of AAV2-miR-320b into Apoe / mice attenuated cholesterol efflux from peritoneal macrophages, which showed reduced expression of ABCA1/G1 and EEPD1, and increased lipid LDL-C level, with a down-regulation of hepatic LDLR and ABCA1. AAV2-miR-320b treatment also increased atherosclerotic plaque size and lesional macrophage content and enhanced pro-inflammatory cytokines levels through the elevated phosphorylation level of nuclear factor-B p65 in macrophages. Conclusion:We identify miR-320b as a novel modulator of macrophage cholesterol efflux and that it might be a promising therapeutic target for atherosclerosis treatment.feature at the early stage of atherosclerotic plaque development 2,3) . Besides, the transformation of monocyte-derived macrophages into foam cells is directly linked to disturbed cholesterol influx, endogenous synthesis, and efflux 4,5) , which not only accumulates lipid but also produces various chemokines and cytokines to induce inflammation 2) .

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Section: Discussionmentioning

confidence: 99%

MicroRNA-320b Modulates Cholesterol Efflux and Atherosclerosis

Lü

Yang

et al. 2022

JAT

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“…Intracellular cholesterol homeostasis is regulated by cholesterol synthesis, endocytosis mediated by LDL receptor, and cholesterol efflux mediated by HDL apolipoprotein in most cells [ 37 ]. Furthermore, ABCA1 and ABCG1 mediate cholesterol efflux from cells to apolipoprotein A-I (ApoA-I) and HDL [ 18 , 38 ]. ApoE, a 34 kDa glycoprotein, is implicated in the formation of HDL, acting both as a ligand for receptor-mediated lipoprotein clearance and a receptor for cholesterol efflux from peripheral cells [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…PGC-1 α activates a variety of nuclear receptors, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), and farnesoid X receptors (FXRs) [ 15 , 16 ]. LXR, a member of the nuclear receptor superfamily, is highly involved in cholesterol efflux from cells by regulating the expression of ATP-binding cassette subfamily A member 1 (ABCA1) and ABCG1 [ 17 , 18 ]. A previous study indicated that expression of the downstream ABCA1 gene is upregulated by activating LXR, which promotes cholesterol influx to high-density lipoprotein (HDL), and attenuates cholesterol deposition in the kidney [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Morroniside Promotes PGC-1α-Mediated Cholesterol Efflux in Sodium Palmitate or High Glucose-Induced Mouse Renal Tubular Epithelial Cells

Gao

Liu

Shen

et al. 2021

BioMed Research International

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Lipid deposition is an etiology of renal damage caused by lipid metabolism disorder in diabetic nephropathy (DN). Thus, reducing lipid deposition is a feasible strategy for the treatment of DN. Morroniside (MOR), an iridoid glycoside isolated from the Chinese herb Cornus officinalis Sieb. et Zucc., is considered to be an effective drug in inhibiting oxidative stress, reducing inflammatory response, and countering apoptosis. To explore the protective mechanism of MOR in attenuating renal lipotoxicity in DN, we investigated the effect of MOR on an in vitro model of lipid metabolism disorder of DN established by stimulating mouse renal tubular epithelial cells (mRTECs) with sodium palmitate (PA) or high glucose (HG). Oil Red O and filipin cholesterol staining assays were used to determine intracellular lipid accumulation status. Results revealed that PA or HG stimulation inhibited the expressions of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), liver X receptors (LXR), ATP-binding cassette subfamily A member 1 (ABCA1), ABCG1, and apolipoprotein E (ApoE) in mRTECs as evidenced by western blot and quantitative real-time PCR, resulting in increased intracellular lipid deposition. Interestingly, MOR upregulated expressions of PGC-1α, LXR, ABCA1, ABCG1, and ApoE, thus reducing cholesterol accumulation in mRTECs, suggesting that MOR might promote cholesterol efflux from mRTECs via the PGC-1α/LXR pathway. Of note, silencing PGC-1α reversed the promotive effect of MOR on PA- or HG-induced cellular cholesterol accumulation. In conclusion, our results suggest that MOR has a protective effect on mRTECs under high lipid or high glucose conditions, which may be related to the promotion of intracellular cholesterol efflux mediated by PGC-1α.

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“…This phenomenon was similar to the finding reported by Chawla et al, which showed that PPARγ stimulated the transcription of LXRα in macrophages ( Chawla et al, 2001 ). Furthermore, there was other evidence which demonstrated that LXRα antagonist inhibited the transcription of PPARγ ( Tsuboi et al, 2020 ). They proposed that LXRα and PPARγ formed a loop pathway to amplify the signals, which was further confirmed by our results.…”

Section: Discussionmentioning

confidence: 99%

Atrial Natriuretic Peptide Inhibited ABCA1/G1-dependent Cholesterol Efflux Related to Low HDL-C in Hypertensive Pregnant Patients

et al. 2021

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Objective: It has been reported that atrial natriuretic peptide (ANP) regulates lipid metabolism by stimulating adipocyte browning, lipolysis, and lipid oxidation, and by impacting the secretion of adipokines. In our previous study, we found that the plasma ANP concentration of hypertensive disorders of pregnancy (HDP) was significantly increased in comparison to that of normotensive pregnancy patients. Thus, this study’s objective was to investigate the lipid profile in patients with HDP and determine the effects of ANP on the cholesterol efflux in THP-1 macrophages.Methods: A total of 265 HDP patients and 178 normotensive women as the control group were recruited. Clinical demographic characteristics and laboratory profile data were collected. Plasma total triglycerides (TGs), total cholesterol (TC), low-density cholesterol (LDL-C), and high-density cholesterol (HDL-C) were compared between the two groups. THP-1 monocytes were incubated with different concentrations of ANP. ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) mRNA and protein were evaluated. ABCA1- and ABCG1-mediated cholesterol efflux to apolipoprotein A-Ⅰ (apoA-Ⅰ) and HDL, respectively, were measured by green fluorescent labeled NBD cholesterol. Natriuretic peptide receptor A (NPR-A) siRNA and specific agonists of the peroxisome proliferator–activated receptor-γ (PPAR-γ) and liver X receptor α (LXRα) were studied to investigate the mechanism involved.Results: Plasma TG, TC, LDL-C, and LDL-C/HDL-C were significantly increased, and HDL-C was significantly decreased in the HDP group in comparison to the control (all p < 0.001). ANP inhibited the expression of ABCA1 and ABCG1 at both the mRNA and protein levels in a dose-dependent manner. The functions of ABCA1- and ABCG1-mediated cholesterol efflux to apoA-I and HDL were significantly decreased. NPR-A siRNA further confirmed that ANP binding to its receptor inhibited ABCA1/G1 expression through the PPAR-γ/LXRα pathway.Conclusions: ABCA1/G1 was inhibited by the stimulation of ANP when combined with NPR-A through the PPAR-γ/LXRα pathway in THP-1 macrophages. The ABCA1/G1-mediated cholesterol efflux was also impaired by the stimulation of ANP. This may provide a new explanation for the decreased level of HDL-C in HDP patients.

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Molecular mechanism for nobiletin to enhance ABCA1/G1 expression in mouse macrophages

Cited by 34 publications

References 37 publications

MicroRNA-320b Modulates Cholesterol Efflux and Atherosclerosis

MicroRNA-320b Modulates Cholesterol Efflux and Atherosclerosis

Morroniside Promotes PGC-1α-Mediated Cholesterol Efflux in Sodium Palmitate or High Glucose-Induced Mouse Renal Tubular Epithelial Cells

Atrial Natriuretic Peptide Inhibited ABCA1/G1-dependent Cholesterol Efflux Related to Low HDL-C in Hypertensive Pregnant Patients

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