Transcriptional Repression of Atherogenic Inflammation: Modulation by PPARδ

Lee, Chih‐Hao; Chawla, Ajay; Urbiztondo, Ned; Liao, Daiqing; Boisvert, William A.; Evans, Ronald M.

doi:10.1126/science.1087344

Cited by 548 publications

(502 citation statements)

References 21 publications

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“…This idea is supported by the observation that unliganded PPAR␤/␦ can influence inflammation in an opposite fashion as compared with ligand-activated PPAR␤/␦. 66 It also remains possible that the exacerbated hepatotoxicity found in the absence of PPAR␤/␦ expression will not be influenced by administration of a PPAR␤/␦ ligand, as exacerbated intestinal inflammation observed in the absence of PPAR␤/␦ expression is not improved by ligand activation of the receptor. 67 Clearly, further studies are necessary to differentiate between these possibilities.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

et al. 2008

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Potential functional roles for the peroxisome proliferator-activated receptor-␤/␦ (PPAR␤/␦) in skeletal muscle fatty acid catabolism and epithelial carcinogenesis have recently been described. Whereas PPAR␤/␦ is expressed in liver, its function in this tissue is less clear. To determine the role of PPAR␤/␦ in chemically induced liver toxicity, wild-type and PPAR␤/␦-null mice were treated with azoxymethane (AOM) and markers of liver toxicity examined. Bile duct hyperplasia, regenerative hyperplasia, and increased serum alanine aminotransferase (ALT) were found in AOM-treated PPAR␤/␦-null mice, and these effects were not observed in similarly treated wild-type mice. Exacerbated carbon tetrachloride (CCl 4 ) hepatoxicity was also observed in PPAR␤/␦-null as compared with wild-type mice. No differences in messenger RNAs (mRNAs) encoding cytochrome2E1 required for the metabolic activation of AOM and CCl 4 were observed between wild-type or PPAR␤/␦-null mice in response to CCl 4 . Significant differences in the expression of genes reflecting enhanced nuclear factor kappa B (NF-B) activity were noted in PPAR␤/␦-null mice. Conclusion:Results from these studies show that PPAR␤/␦ is protective against liver toxicity induced by AOM and CCl 4 , suggesting that this receptor is hepatoprotective against environmental chemicals that are metabolized in this tissue. (HEPATOLOGY 2008;47:225-235.)

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Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

et al. 2008

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“…Recently, an important role of PPAR␦ in inflammation has also been reported. 17 Thus, based on the data from the HepG2 and rat liver experiments, it is tempting to hypothesize that the antiinflammatory effects of TSA in PBMCs may involve pan-PPAR activation. Nevertheless, although the relative importance of the various PPARs in the TSA mediated effects is not clear, our findings strongly suggest that activation of PPARs could be involved.…”

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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“…In mouse models, genetic deletion of macrophage PPARγ resulted in increased development of atherosclerosis (Chawla et al, 2001), whereas genetic deletion of PPARα (Tordjman et al, 2001) and PPARδ (Lee et al, 2003) led to reduced atherosclerosis. Similarly, PPARα and PPARγ agonists have been shown to significantly reduce atherosclerotic lesions in mice.…”

Section: Pparsmentioning

confidence: 99%

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

2012

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Transcriptional Repression of Atherogenic Inflammation: Modulation by PPARδ

Cited by 548 publications

References 21 publications

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

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

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

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