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The Role of PPARγ in the Transcriptional Control by Agonists and Antagonists.

Tsukahara T - PPAR Res (2012)

Bottom Line: We recently observed that cPA negatively regulates PPARγ function by stabilizing the binding of the corepressor protein, silencing mediator of retinoic acid and thyroid hormone receptor.We then analyzed the molecular mechanism of cPA's action on PPARγ.In this paper, we summarize the current knowledge on the mechanism of PPARγ-mediated transcriptional activity and transcriptional repression in response to novel lipid-derived ligands, such as cPA.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Physiology and Bio-System Control, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.

ABSTRACT
In recent years, peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to be a target for the treatment of type II diabetes. Furthermore, it has received attention for its therapeutic potential in many other human diseases, including atherosclerosis, obesity, and cancers. Recent studies have provided evidence that the endogenously produced PPARγ antagonist, 2,3-cyclic phosphatidic acid (cPA), which is similar in structure to lysophosphatidic acid (LPA), inhibits cancer cell invasion and metastasis in vitro and in vivo. We recently observed that cPA negatively regulates PPARγ function by stabilizing the binding of the corepressor protein, silencing mediator of retinoic acid and thyroid hormone receptor. We also showed that cPA prevents neointima formation, adipocyte differentiation, lipid accumulation, and upregulation of PPARγ target gene transcription. We then analyzed the molecular mechanism of cPA's action on PPARγ. In this paper, we summarize the current knowledge on the mechanism of PPARγ-mediated transcriptional activity and transcriptional repression in response to novel lipid-derived ligands, such as cPA.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of the PPARγ signaling. cPA is generated intracellularly in a stimulus-coupled manner by the PLD2 enzyme (1). cPA inhibits PPARγ activation and stabilizes binding of PPARγ corepressor SMRT (2). Agonists (LPA, alkyl-LPA, and rosiglitazone) activate PPARγ and promote downstream signals, whereas cPA negatively regulates PPARγ. cPA stabilizes PPARγ-SMRT corepressor complex and inhibits PPARγ-mediated postsignal transduction (3).
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fig2: Schematic diagram of the PPARγ signaling. cPA is generated intracellularly in a stimulus-coupled manner by the PLD2 enzyme (1). cPA inhibits PPARγ activation and stabilizes binding of PPARγ corepressor SMRT (2). Agonists (LPA, alkyl-LPA, and rosiglitazone) activate PPARγ and promote downstream signals, whereas cPA negatively regulates PPARγ. cPA stabilizes PPARγ-SMRT corepressor complex and inhibits PPARγ-mediated postsignal transduction (3).

Mentions: Our recent report used a corepressor 2-hybrid assay to show that cPA negatively regulates PPARγ function by stabilizing the SMRT-PPARγ complex (Figure 2) and blocks rosiglitazone-stimulated adipogenesis and lipid accumulation in 3T3-L1 and RAW246.7 macrophage-like cells [14]. This ligand-dependent corepressor exchange results in transcriptional repression of genes involved in the control of insulin action as well as a diverse range of other functions [98]. We also demonstrated that activation of PLD2-mediated cPA production by insulin or topical application of cPA together with PPARγ agonists prevents neointima formation, adipocytic differentiation, lipid accumulation, and upregulation of PPARγ target genes [13, 14]. Atherosclerosis is the leading cause of death among cardiovascular diseases. Neointima formation is a common feature of an atherosclerotic artery and is characterized by smooth muscle cell (SMC) proliferation and extracellular matrix deposition in the vascular intimal layer. Yoshida et al. first reported that LPA and species containing unsaturated LPA (16 : 1, 18 : 1 and 18 : 2) induced neointima formation when injected into the rat carotid artery [99]. Furthermore, LPA and alkyl-LPA induced neointima formation through the activation of PPARγ, whereas cPA inhibited PPARγ-mediated arterial wall remodeling in a noninjury infusion model [13, 14]. These results suggest that PPARγ is required for LPA-induced neointima formation. PPARγ antagonists should continue to be developed, as they have the clinical potential for preventing neointimal vascular lesions.


The Role of PPARγ in the Transcriptional Control by Agonists and Antagonists.

Tsukahara T - PPAR Res (2012)

Schematic diagram of the PPARγ signaling. cPA is generated intracellularly in a stimulus-coupled manner by the PLD2 enzyme (1). cPA inhibits PPARγ activation and stabilizes binding of PPARγ corepressor SMRT (2). Agonists (LPA, alkyl-LPA, and rosiglitazone) activate PPARγ and promote downstream signals, whereas cPA negatively regulates PPARγ. cPA stabilizes PPARγ-SMRT corepressor complex and inhibits PPARγ-mediated postsignal transduction (3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368591&req=5

fig2: Schematic diagram of the PPARγ signaling. cPA is generated intracellularly in a stimulus-coupled manner by the PLD2 enzyme (1). cPA inhibits PPARγ activation and stabilizes binding of PPARγ corepressor SMRT (2). Agonists (LPA, alkyl-LPA, and rosiglitazone) activate PPARγ and promote downstream signals, whereas cPA negatively regulates PPARγ. cPA stabilizes PPARγ-SMRT corepressor complex and inhibits PPARγ-mediated postsignal transduction (3).
Mentions: Our recent report used a corepressor 2-hybrid assay to show that cPA negatively regulates PPARγ function by stabilizing the SMRT-PPARγ complex (Figure 2) and blocks rosiglitazone-stimulated adipogenesis and lipid accumulation in 3T3-L1 and RAW246.7 macrophage-like cells [14]. This ligand-dependent corepressor exchange results in transcriptional repression of genes involved in the control of insulin action as well as a diverse range of other functions [98]. We also demonstrated that activation of PLD2-mediated cPA production by insulin or topical application of cPA together with PPARγ agonists prevents neointima formation, adipocytic differentiation, lipid accumulation, and upregulation of PPARγ target genes [13, 14]. Atherosclerosis is the leading cause of death among cardiovascular diseases. Neointima formation is a common feature of an atherosclerotic artery and is characterized by smooth muscle cell (SMC) proliferation and extracellular matrix deposition in the vascular intimal layer. Yoshida et al. first reported that LPA and species containing unsaturated LPA (16 : 1, 18 : 1 and 18 : 2) induced neointima formation when injected into the rat carotid artery [99]. Furthermore, LPA and alkyl-LPA induced neointima formation through the activation of PPARγ, whereas cPA inhibited PPARγ-mediated arterial wall remodeling in a noninjury infusion model [13, 14]. These results suggest that PPARγ is required for LPA-induced neointima formation. PPARγ antagonists should continue to be developed, as they have the clinical potential for preventing neointimal vascular lesions.

Bottom Line: We recently observed that cPA negatively regulates PPARγ function by stabilizing the binding of the corepressor protein, silencing mediator of retinoic acid and thyroid hormone receptor.We then analyzed the molecular mechanism of cPA's action on PPARγ.In this paper, we summarize the current knowledge on the mechanism of PPARγ-mediated transcriptional activity and transcriptional repression in response to novel lipid-derived ligands, such as cPA.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Physiology and Bio-System Control, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.

ABSTRACT
In recent years, peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to be a target for the treatment of type II diabetes. Furthermore, it has received attention for its therapeutic potential in many other human diseases, including atherosclerosis, obesity, and cancers. Recent studies have provided evidence that the endogenously produced PPARγ antagonist, 2,3-cyclic phosphatidic acid (cPA), which is similar in structure to lysophosphatidic acid (LPA), inhibits cancer cell invasion and metastasis in vitro and in vivo. We recently observed that cPA negatively regulates PPARγ function by stabilizing the binding of the corepressor protein, silencing mediator of retinoic acid and thyroid hormone receptor. We also showed that cPA prevents neointima formation, adipocyte differentiation, lipid accumulation, and upregulation of PPARγ target gene transcription. We then analyzed the molecular mechanism of cPA's action on PPARγ. In this paper, we summarize the current knowledge on the mechanism of PPARγ-mediated transcriptional activity and transcriptional repression in response to novel lipid-derived ligands, such as cPA.

No MeSH data available.


Related in: MedlinePlus