The Peroxisome Proliferator-activated Receptor δ Promotes Lipid Accumulation in Human Macrophages

Vosper, Helen; Patel, Lisa; Graham, Tracey L.; Khoudoli, Guennadi A.; Hill, Alexander J.; Macphee, Colin H.; Pinto, Ivan L.; Smith, Stephen A.; Suckling, Keith E.; Wolf, C. Roland; Palmer, Colin N.A.

doi:10.1074/jbc.m108482200

Cited by 250 publications

(165 citation statements)

References 49 publications

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“…ND indicates not detected; C18:3n-6/C18:2n-6, ⌬6 desaturase index; C20:4n-6/C20:3n-6, ⌬5 desaturase index. PPAR␥ in liver and adipose tissue, respectively, 39,40 and by PPAR␦ in macrophages 41 and skeletal muscle, 42 underscoring the complexity of the PPAR system in which the responses to a certain ligand may differ between different cell types and tissues. Several studies have suggested antiinflammatory effects after PPAR␣ 14,15 and PPAR␥ activation, 16 although the antiinflammatory properties of PPAR␥ are more controversial.…”

Section: Discussionmentioning

confidence: 99%

Tetradecylselenoacetic Acid, a PPAR Ligand With Antioxidant, Antiinflammatory, and Hypolipidemic Properties

Dyrøy

Røst

Pettersen

et al. 2007

ATVB

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Objective-Antioxidants protect against oxidative stress and inflammation, which, in combination with hyperlipidemia, are important mediators of atherogenesis. Here we present a selenium-substituted fatty acid, tetradecylselenoacetic acid (TSA), which is hypothesized to have antioxidant, antiinflammatory, and hypolipidemic properties. Methods and Results-We show that TSA exerts antioxidant properties by delaying the onset of oxidation of human low density lipoprotein (LDL), by reducing the uptake of oxidized LDL in murine macrophages, and by increasing the mRNA level of superoxide dismutase in rat liver. TSA also showed antiinflammatory effects by suppressing the release of interleukin (IL)-2 and -4, and by increasing the release of IL-10 in human blood leukocytes. In addition, TSA decreased the plasma triacylglycerol level and increased the mitochondrial fatty acid ␤-oxidation in rat liver. In pigs, TSA seemed to reduce coronary artery intimal thickening after percutaneous coronary intervention. In HepG2 cells TSA activated all peroxisome proliferator-activated receptors (PPARs) in a dose-dependent manner. Conclusions-Our data suggest that TSA exert potent antioxidant, antiinflammatory, and hypolipidemic properties, potentially involving PPAR-related mechanisms. Based on these effects, it is tempting to hypothesize that TSA could be an interesting antiatherogenic approach to atherosclerotic disorders. A therosclerosis is regarded as an inflammatory disorder of the vascular wall, where multiple factors contribute to a persistent and self-perpetual inflammation within the atherosclerotic lesions. [1][2][3][4][5] There is also a consensus that atherosclerosis represents a state of elevated oxidative stress characterized by lipid and protein oxidation in the vascular wall. 6 Enhanced inflammation and oxidative stress seem to represent a vicious circle in atherogenesis, and therapeutic options directed against these processes seems like a reasonable approach in the management of atherosclerotic disorders.We have previously shown that tetradecylthioacetic acid (TTA), a modified fatty acid with a sulfur atom in the third position of the carbon backbone, promotes mitochondrial and peroxisomal proliferation, and decreases serum lipid levels in animal models. 7-9 TTA also shows antioxidant effects in vitro 10 and encompasses antiinflammatory properties in human leukocytes. 11 The pleiotropic effects of TTA seem to involve activation of peroxisome proliferator-activated receptors (PPARs), 12,13 which are receptors that serves as an important link between lipid metabolism and inflammation. 14 -17 Tetradecylselenoacetic acid (TSA) is a novel fatty acid which in comparison to TTA has a selenium atom instead of a sulfur atom in third position of the carbon backbone. As with TTA, 18 this modification makes TSA resistant to fatty acid ␤-oxidation. A previous in vitro study has demonstrated that TSA is a stronger antioxidant than TTA. 19 Based on these findings and its relation to TTA, we hypothesized that TSA also exerts poten...

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Section: Discussionmentioning

confidence: 99%

Tetradecylselenoacetic Acid, a PPAR Ligand With Antioxidant, Antiinflammatory, and Hypolipidemic Properties

Dyrøy

Røst

Pettersen

et al. 2007

ATVB

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“…The PPAR␦ ligand GW501516 was reported to increase expression of ABCA1 and induce apoAI-specific cholesterol eff lux from human THP-1 cells. Vosper et al (37) showed that another PPAR␦ ligand induced expression of scavenger receptors (SR-A and CD36) involved in lipid accumulation in macrophages. We observed no changes in LXR␣, ABCA1, ABCG1, or CD36 expression in aorta or peritoneal macrophages after GW0742 treatment (data not shown).…”

Section: Discussionmentioning

confidence: 99%

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

Takata

Liu

Yin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

197

181

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Activation of the nuclear hormone receptor peroxisome proliferatoractivated receptor ␦ (PPAR␦) has been shown to improve insulin resistance, adiposity, and plasma HDL levels. However, its antiatherogenic role remains controversial. Here we report atheroprotective effects of PPAR␦ activation in a model of angiotensin II (AngII)-accelerated atherosclerosis, characterized by increased vascular inflammation related to repression of an antiinflammatory corepressor, B cell lymphoma-6 (Bcl-6), and the regulators of G protein-coupled signaling (RGS) proteins RGS4 and RGS5. In this model, administration of the PPAR␦ agonist GW0742 (1 or 10 mg/kg) substantially attenuated AngII-accelerated atherosclerosis without altering blood pressure and increased vascular expression of Bcl-6, RGS4, and RGS5, which was associated with suppression of inflammatory and atherogenic gene expression in the artery. In vitro studies demonstrated similar changes in AngII-treated macrophages: PPAR␦ activation increased both total and free Bcl-6 levels and inhibited AngII activation of MAP kinases, p38, and ERK1/2. These studies uncover crucial proinflammatory mechanisms of AngII and highlight actions of PPAR␦ activation to inhibit AngII signaling, which is atheroprotective.peroxisome proliferator-activated receptor ␦ ͉ vascular inflammation ͉ macrophage

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“…More recently, expression has been reported on hepatocytes under certain circumstances (Vosper, et al, 2001,Yu, et al, 2001,Zhou, et al, 2006 and smooth muscle cells (Lim, et al, 2006,de Oliveira Silva, Delbosc, Arais, Monnier, Cristol, & Pares-Herbute, 2006, Kwok, Juan, and Ho, 2006. CD36 plays a role in uptake of apoptotic cells (Savill, Hogg, Ren, and Haslett, 1992), shed photoreceptor outer segments , and modified lipoproteins (Endemann, Stanton, Madden, Bryant, White, & Protter, 1993,Podrez, et al,2000, and in recognition of ligands that trigger an innate immune response, including components of gram positive bacteria cell walls (Hoebe, et al, 2005,Stuart, et al, 2005 (as a co-receptor with Toll Like Receptor (TLR) 2), fibrillar amyloid β (Bamberger, Harris, McDonald, Husemann, & Landreth, 2003,El Khoury, et al, 2003, which is a constituent of Alzheimer plaque, and resembles fibrillar amyloid protein (Medeiros, et al, 2004), that may occur in atherosclerotic plaque.…”

Section: Cd36 Structure and Expressionmentioning

confidence: 99%

CD36: Implications in cardiovascular disease

Febbraio

Silverstein

2007

The International Journal of Biochemistry & Cell Biology

213

215

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CD36 is a broadly expressed membrane glycoprotein that acts as a facilitator of fatty acid uptake, a signaling molecule, and a receptor for a wide range of ligands, including apoptotic cells, modified forms of low density lipoprotein, thrombospondins, fibrillar beta-amyloid, components of gram positive bacterial walls and malaria infected erythrocytes. CD36 expression on macrophages, dendritic and endothelial cells, and in tissues including muscle, heart, and fat, suggest diverse roles, and indeed, this is truly a multifunctional receptor involved in both homeostatic and pathologic conditions. Despite an impressive increase in our knowledge of CD36 functions, in depth understanding of the mechanistic aspects of this protein remains elusive. This review focuses on CD36 in cardiovascular disease-what we know, and what we have yet to learn.

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The Peroxisome Proliferator-activated Receptor δ Promotes Lipid Accumulation in Human Macrophages

Cited by 250 publications

References 49 publications

Tetradecylselenoacetic Acid, a PPAR Ligand With Antioxidant, Antiinflammatory, and Hypolipidemic Properties

Tetradecylselenoacetic Acid, a PPAR Ligand With Antioxidant, Antiinflammatory, and Hypolipidemic Properties

PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

CD36: Implications in cardiovascular disease

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