The critical role of ABCG1 and PPARγ/LXRα signaling in TLR4 mediates inflammatory responses and lipid accumulation in vascular smooth muscle cells

Cao, Xiao-Jie; Zhang, Lili; Chen, Chunhai; Wang, Qingsong; Guo, Lei; Ma, Qibin; Deng, Ping; Zhu, Gang; Li, Bing-Hu; Pi, Yan; Long, Chun-Yan; Zhang, Lei; Yu, Zhengping; Zhou, Zhou; Li, Jingcheng

doi:10.1007/s00441-016-2518-3

Cited by 26 publications

(23 citation statements)

References 38 publications

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“…CRP is produced by different cells, including smooth muscle cells, macrophages, lymphocytes and adipocytes, and activates the classical complement pathway [8].Thiazolidinediones insignificantly decreased TNF alfa levels in Type 2 DM patients or had no effect on TNF-α and sCD40L; our data are consistent with the Manning et al's study [12,13]. Recently, Cao X et al suggested that Toll-like receptor 4 (TLR4) played a critical role in vascular inflammation, lipid accumulation, and atherosclerosis development [14]. Activation of TLR4 signaling via oxidized low-density lipoprotein (oxLDL) inhibited expression of peroxisome proliferator-activated receptor gamma (PPARγ), liver X receptor alpha (LXRα) and ABCG1.…”

Section: Discussionsupporting

confidence: 91%

“…PPARγ activation by Rosiglitazone induced LXRα and ABCG1 expression and reduced TLR4 induced inflammation. Cao et al showed that Rosiglitazone treatment inhibited IL-6 and MCP-1 mRNA expression but not that of TNF-α [14]. It has been suggested that the anti-inflammatory effect of PPARγ activators was related to PPARγ-dependent or PPARγ-independent mechanisms [14,15].…”

Section: Discussionmentioning

confidence: 99%

“…Cao et al showed that Rosiglitazone treatment inhibited IL-6 and MCP-1 mRNA expression but not that of TNF-α [14]. It has been suggested that the anti-inflammatory effect of PPARγ activators was related to PPARγ-dependent or PPARγ-independent mechanisms [14,15]. Dzienis-Straczkowska et al (2003) indicated that soluble-TNFα receptors, especially sTNFR2, might be a better marker of TNFα action in insulin-resistant states than the plasma TNFα level itself [16].…”

Section: Discussionmentioning

confidence: 99%

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Effect of PPAR-γ agonists on macrophage activation in type2 diabetes mellitus

Sözmen¹,

Karakaş²,

Topçugil³

et al. 2018

Ann Clin Anal Med

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Effect of (PPAR-γ) agonists on macrophage activationEffect of PPAR-γ agonists on macrophage activation in type2 diabetes mellitus DOI: 10.4328 AbstractAim: Recently, it has been proposed that inflammation triggered by macrophages as the pathogenic mechanism linked to the development of obesity-related insulin resistance. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists which increase the insulin receptor sensitivity, might improve glycemic control by enhancing insulin sensitivity and ameliorate the impaired lipid profile. In this study, we assessed the effect of rosiglitazone (PPAR-γ agonist) on the insulin resistance and inflammatory markers. Material and Method: Thirty patients (11 men, 19 women) with type II diabetes mellitus (DM) were taken into the study. They were treated by rosiglitazone in a dose of 4mg/day as well as a diet for 12 weeks. Results: Rosiglitazone treatment significantly decreased HbA1c (p<0,01), IR-HOMA, hsCRP (p<0,01), triglyceride levels (p<0,05), CETP activity (p<0,01) and basal serum oxidation (TBARS levels, p<0,05). However, Chitotriosidase activity significantly increased after Rosiglitazone treatment (p<0,01). TNF, IL-6, sTNFR1, and sTNFR2 levels showed no statistically significant difference compared to their basal levels. Discussion: Rosiglitazone might treat diabetes by mediating glucose/lipid metabolism and preventing lipid oxidation in patients with DM. On the other hand, it has a dual role on inflammation; while it might induce macrophage activation suggesting its pro-inflammatory effect, it might also reduce the CRP levels by lowering gene expression suggesting its anti-inflammatory effect.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effect of PPAR-γ agonists on macrophage activation in type2 diabetes mellitus

Sözmen¹,

Karakaş²,

Topçugil³

et al. 2018

Ann Clin Anal Med

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“…Toll-like receptor 4 (TLR4), a typical representative of pattern recognition receptors in innate immune responses, which can activate the transcription factors nuclear factor-κB (NF-κB) leading to the production of proinflammatory cytokines [ 49 ]. Toll-like receptor 4 mainly regulates ABCG1 , which is a key gene that mediates inflammation and cellular lipid accumulation [ 50 ]. Toll-like receptor 4 induces inflammation and lipid accumulation in VSMCs by downregulating ABCG1 expression through the Peroxisome proliferator activated receptor gamma (PPAR γ)/liver X receptor alpha (LXRα) signaling pathway [ 51 ].…”

Section: Atherosclerosis Related Inflammatory Signaling Pathwaysmentioning

confidence: 99%

Research Progress on the Relationship between Atherosclerosis and Inflammation

et al. 2018

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Atherosclerosis is a chronic inflammatory disease; unstable atherosclerotic plaque rupture, vascular stenosis, or occlusion caused by platelet aggregation and thrombosis lead to acute cardiovascular disease. Atherosclerosis-related inflammation is mediated by proinflammatory cytokines, inflammatory signaling pathways, bioactive lipids, and adhesion molecules. This review discusses the effects of inflammation and the systemic inflammatory signaling pathway on atherosclerosis, the role of related signaling pathways in inflammation, the formation of atherosclerosis plaques, and the prospects of treating atherosclerosis by inhibiting inflammation.

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“…In recent years, there has been an increasing body of evidence pointing to the possibility that metals can alter epigenetic factors and cardiovascular risk [4]. Among the metal-DMR genes, we identified three genes encoding atherosclerosis-effector proteins (IRF1, PF4 and TLR4), which are either involved in unbalanced lipid metabolism or chronic inflammation of the arterial wall [66][67][68]. Others genes, including SMAD3, HLA-C, GNAS or SDK1, have been previously reported as differentially methylated in CVDs [11,13,34,35], and some of these had a strong and medium-strong score of relationship with atherosclerosis in our ANN analysis.…”

Section: Discussionmentioning

confidence: 99%

In silico epigenetics of metal exposure and subclinical atherosclerosis in middle aged men: pilot results from the Aragon Workers Health Study

Riffo‐Campos

Fuentes-Trillo

Tang

et al. 2018

Phil. Trans. R. Soc. B

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We explored the association of metal levels with subclinical atherosclerosis and epigenetic changes in relevant biological pathways. Whole blood DNA Infinium Methylation 450 K data were obtained from 23 of 73 middle age men without clinically evident cardiovascular disease (CVD) who participated in the Aragon Workers Health Study in 2009 (baseline visit) and had available baseline urinary metals and subclinical atherosclerosis measures obtained in 2010-2013 (follow-up visit). The median metal levels were 7.36 µg g, 0.33 µg g, 0.11 µg g and 0.07 µg g, for arsenic (sum of inorganic and methylated species), cadmium, antimony and tungsten, respectively. Urine cadmium and tungsten were associated with femoral and carotid intima-media thickness, respectively (Pearson's = 0.27; = 0.03 in both cases). Among nearest genes to identified differentially methylated regions (DMRs), 46% of metal-DMR genes overlapped with atherosclerosis-DMR genes ( < 0.001). Pathway enrichment analysis of atherosclerosis-DMR genes showed a role in inflammatory, metabolic and transport pathways. In protein-to-protein interaction networks among proteins encoded by 162 and 108 genes attributed to atherosclerosis- and metal-DMRs, respectively, with proteins known to have a role in atherosclerosis pathways, we observed hub proteins in the network associated with both atherosclerosis and metal-DMRs (e.g. and ), and also hub proteins associated with metal-DMRs only but with relevant connections with atherosclerosis effectors (e.g., ,, and). Our integrative analysis demonstrates the feasibility of identifying epigenomic regions linked to environmental exposures and potentially involved in relevant pathways for human diseases. While our results support the hypothesis that metal exposures can influence health due to epigenetic changes, larger studies are needed to confirm our pilot results.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

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The critical role of ABCG1 and PPARγ/LXRα signaling in TLR4 mediates inflammatory responses and lipid accumulation in vascular smooth muscle cells

Cited by 26 publications

References 38 publications

Effect of PPAR-γ agonists on macrophage activation in type2 diabetes mellitus

Effect of PPAR-γ agonists on macrophage activation in type2 diabetes mellitus

Research Progress on the Relationship between Atherosclerosis and Inflammation

In silico epigenetics of metal exposure and subclinical atherosclerosis in middle aged men: pilot results from the Aragon Workers Health Study

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