Suppression of Rat Thromboxane Synthase Gene Transcription by Peroxisome Proliferator-activated Receptor γ in Macrophages via an Interaction with NRF2

Ikeda, Yukio; Sugawara, Akira; Taniyama, Yoshihiro; Uruno, Akira; Igarashi, Kazuhiko; Arima, Shuji; Ito, Sadayoshi; Takeuchi, Kazuhisa

doi:10.1074/jbc.m002319200

Cited by 94 publications

(64 citation statements)

References 46 publications

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“…Nrf2 is a key transcription factor controlling antioxidant gene expression and that regulates antioxidant defence in Mu, implicating upregulation of CD36 in oxidative stress [43]. The recent study reporting that PPARc inhibits Nrf2-induced expression of the gene encoding thromboxane synthase in Mu, suggests that the transcriptional regulators PPARc and Nrf2 may interact [44]. Future studies in vitro using PPARc-deficient Mu should enable us to determine whether Nrf2 modulates CD36 gene expression in these PPARc-deficient cells.…”

Section: Discussionmentioning

confidence: 99%

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

et al. 2007

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The class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure to soluble mediators. We demonstrate here that CD36 expression is induced in human monocytes following exposure to IL-13, a Th2 cytokine, via the peroxisome proliferator-activated receptor (PPAR)c pathway. Induction of CD36 protein was paralleled by an increase in CD36 mRNA. The PPARc pathway was demonstrated using transfection of a PPARc expression plasmid into the murine macrophage cell line RAW264.7, expressing very low levels of PPARc, and in peritoneal macrophages from PPARc-conditional null mice. We also show that CD36 induction by IL-13 via PPARc is dependent on phospholipase A2 activation and that IL-13 induces the production of endogenous 15-deoxy-D 12,14 -prostaglandin J 2 , an endogenous PPARc ligand, and its nuclear localization in human monocytes. Finally, we demonstrate that CD36 and PPARc are involved in IL-13-mediated phagocytosis of Plasmodium falciparum-parasitized erythrocytes. These results reveal a novel role for PPARc in the alternative activation of monocytes by IL-13, suggesting that endogenous PPARc ligands, produced by phospholipase A2 activation, could contribute to the biochemical and cellular functions of CD36.Leukocyte signaling * These 2 authors contributed equally to this work. IntroductionThe innate immune system protects the host in the early phase of infection. Circulating monocytes and tissue macrophages (Mu) mediate much of this innate immune response [1]. The strategy of recognition in the innate response is mediated by the coordinated action of pathogen-associated molecular patterns and pattern recognition receptors. Scavenger receptors and mannose receptor are important pattern recognition receptors in monocytes/Mu [2,3]. The modulation of the expression of these receptors may be critical in the role of these cells in antigen processing, scavenging, and host defence against pathogens. Several members of the scavenger receptor family, including Mu class A scavenger receptors and CD36, have been identified as receptors for modified lipoproteins on Mu, and their relevance to lipid uptake has been demonstrated in vitro and in vivo [4]. The scavenger receptor CD36, an 88-kDa integral membrane protein, is a class B scavenger receptor expressed on a wide variety of cells, in particular on monocytes and monocytederived Mu [5,6]. CD36 is known as a receptor for the uptake of oxidatively modified low-density lipoprotein (LDL) [7] and is also able to bind anionic phospholipid phosphatidylserine [8]. This scavenger receptor is implicated in the clearance of apoptotic cells [9]. Recently, McGilvray and colleagues [10] described a CD36-dependent nonopsonic phagocytosis of erythrocytes containing P. falciparum, by monocytes and culture-derived Mu, and a decrease in the parasiteinduced TNF secretion by monocytes/Mu. These processes were accentuated by CD36 up-regulation by peroxisome proliferator-acti...

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Section: Discussionmentioning

confidence: 99%

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

et al. 2007

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“…5 PPAR-␥ also suppresses thromboxane synthase gene expression, which also could contribute to the reduction in hypertension. 50 Furthermore, the expression of CD22, CD44, CD53, and CD68 was decreased in diet-restricted DKO mice. The latter is particularly interesting because overexpression of the receptor for advanced glycation end products in diabetic CD68…”

Section: Oxidative Stress Inflammation and Reduced Atherosclerosismentioning

confidence: 99%

Weight Loss–Associated Induction of Peroxisome Proliferator–Activated Receptor-α and Peroxisome Proliferator–Activated Receptor-γ Correlate With Reduced Atherosclerosis and Improved Cardiovascular Function in Obese Insulin-Resistant Mice

et al. 2004

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Background-Weight loss in obese insulin-resistant but not in insulin-sensitive persons reduces coronary heart disease risk. To what extent changes in gene expression are related to atherosclerosis and cardiovascular function is unknown. Methods and Results-We studied the effect of diet restriction-induced weight loss on gene expression in the adipose tissue, the heart, and the aortic arch and on atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia, and insulin resistance are associated with hypertension, impaired left ventricular function, and accelerated atherosclerosis in those mice. Compared with lean mice, peroxisome proliferator-activated receptors (PPAR)-␣ and PPAR-␥ expression was downregulated in obese double-knockout mice. Diet restriction caused a 45% weight loss, an upregulation of PPAR-␣ and PPAR-␥, and a change in the expression of genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress, and inflammation, most of which are under the transcriptional control of these PPARs. Changes in gene expression were associated with increased insulin sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. PPAR-␣ and PPAR-␥ expression was inversely related to plaque volume and to oxidized LDL content in the plaques. Conclusions-Induction of PPAR-␣ and PPAR-␥ in adipose tissue, heart, and aortic arch is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight loss. Improved lipid metabolism and insulin signaling is associated with decreased tissue deposition of oxidized LDL that increases cardiovascular risk in persons with the metabolic syndrome. Key Words: atherosclerosis Ⅲ circadian rhythm Ⅲ genes Ⅲ lipoproteins Ⅲ obesity I nsulin resistance is now receiving increasing attention not only as a precursor to type 2 diabetes but also as a predictor of increased risk of cardiovascular disease. 1 Fat distributed in the abdominal region is a risk factor for type 2 diabetes and cardiovascular disease and is associated closely with insulin resistance. 2 Weight loss in insulin-resistant but not in insulinsensitive obese persons reduces their risk of coronary heart disease (CHD). 3 It is not known, however, to what extent changes in the intra-abdominal adipose gene expression profile are important for the reduction of the risk. 4 Several adipokines, and more specifically peroxisome proliferator-activated receptors (PPARs), regulate a number of the processes that contribute to the development of atherosclerosis, including dyslipidemia, arterial hypertension, endothelial dysfunction, insulin resistance, and vascular remodeling. Adipokines are preferentially expressed in intraabdominal adipose tissue, and the secretion of proinflammatory adipokines is elevated with increasing adiposity. Approaches to re...

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“…Cloning of the 5Ј-Flanking Region of the AceCS1 Gene-The 5Ј-flanking region (5ЈFL) of the AceCS1 gene was cloned by polymerase chain reaction (PCR) using Genome Walker kits (CLONTECH) as described previously (23). Briefly, the first PCR was conducted with a combination of adaptor primer 1 (provided in the kit) and AceCS1 cDNA primer 1 (5Ј-GCTTCCACTGCCGCTCTTGCGCCG-3Ј) using a mouse genomic library provided in the kit as a template.…”

Section: Methodsmentioning

confidence: 99%

Transcriptional Regulation of the Murine Acetyl-CoA Synthetase 1 Gene through Multiple Clustered Binding Sites for Sterol Regulatory Element-binding Proteins and a Single Neighboring Site for Sp1

Ikeda

Yamamoto

Okamura

et al. 2001

Journal of Biological Chemistry

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Cytosolic acetyl-CoA synthetase (AceCS1) activates acetate to supply the cells with acetyl-CoA for lipid synthesis. The cDNA for the mammalian AceCS1 has been isolated recently, and the mRNA was shown to be negatively regulated by sterols in cultured cells. In the current study, we describe the molecular mechanisms directing the sterol-regulated expression of murine AceCS1 by cloning and functional studies of the 5-flanking region of the AceCS1 gene. An AceCS1 promoter-reporter gene (ϳ2.1 kilobase pairs) was negatively regulated when sterols were added to the medium of cultured cells, and the promoter was markedly induced by co-transfection of a plasmid that expresses the transcriptionally active nuclear form of either sterol regulatory element-binding protein (SREBP)-1a or -2 in HepG2 cells. Sequence analysis suggested that the AceCS1 promoter contains an E-box, two putative CCAAT-boxes, eight sterol regulatory element (SRE) motifs, and six GC-boxes. Gel shift assays demonstrated that all eight SRE motifs bound purified SREBP-1a in vitro with similar affinity. Luciferase reporter gene assays revealed that sterol regulation was critically dependent on three closely spaced SRE motifs and an adjacent GC-box. However, mutation of two putative upstream CCAAT-boxes did not affect SREBP dependent activation. Electrophoretic mobility "supershift" analyses confirmed that both Sp1 and Sp3 bound to the critical GC-box. In addition, transfection studies in Drosophila SL2 cells demonstrated that SREBP synergistically activated the AceCS1 promoter along with Sp1 or Sp3 but not with nuclear factor-Y.

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Suppression of Rat Thromboxane Synthase Gene Transcription by Peroxisome Proliferator-activated Receptor γ in Macrophages via an Interaction with NRF2

Cited by 94 publications

References 46 publications

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

Weight Loss–Associated Induction of Peroxisome Proliferator–Activated Receptor-α and Peroxisome Proliferator–Activated Receptor-γ Correlate With Reduced Atherosclerosis and Improved Cardiovascular Function in Obese Insulin-Resistant Mice

Transcriptional Regulation of the Murine Acetyl-CoA Synthetase 1 Gene through Multiple Clustered Binding Sites for Sterol Regulatory Element-binding Proteins and a Single Neighboring Site for Sp1

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