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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

Structural formulas of LPA, alkyl-LPA, cPA,and rosiglitazone. LPA is made up of a glycerol backbone with a hydroxyl group, a phosphate group, and a long-chain saturated or unsaturated fatty acid. Alkyl-LPA is an alkyl-ether analog of LPA. Alkyl-LPA shows a higher potency than LPA at the intracellular LPA receptor PPARγ. cPA is a naturally occurring acyl analog of LPA. cPA is a weak agonist of plasma membrane LPA receptors, whereas cPA is an inhibitor of PPARγ. Rosiglitazone is a thiazolidinedione (TZD) class of antidiabetics and is full agonist of PPARγ.
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fig1: Structural formulas of LPA, alkyl-LPA, cPA,and rosiglitazone. LPA is made up of a glycerol backbone with a hydroxyl group, a phosphate group, and a long-chain saturated or unsaturated fatty acid. Alkyl-LPA is an alkyl-ether analog of LPA. Alkyl-LPA shows a higher potency than LPA at the intracellular LPA receptor PPARγ. cPA is a naturally occurring acyl analog of LPA. cPA is a weak agonist of plasma membrane LPA receptors, whereas cPA is an inhibitor of PPARγ. Rosiglitazone is a thiazolidinedione (TZD) class of antidiabetics and is full agonist of PPARγ.

Mentions: In the last decade, both synthetic and natural PPARγ agonists have been explored for their biological and physiological functions [33]. Synthetic PPARγ agonists, which include rosiglitazone (Avandia) (Figure 1) [34, 35], troglitazone (Rezulin, withdrawn by the FDA due to causing liver failure) [36, 37], and pioglitazone (Actos; Takeda Pharmaceutical Ltd.) [38, 39], have provided insight into the therapeutic potential of PPARγ. These compounds are specific PPARγ ligands with Kds in the 40–500 nM range [34, 40]. They are effective as insulin-sensitizing agents, reducing insulin resistance and lowering plasma glucose levels in patients with type II diabetes (previously known as noninsulin-dependent diabetes mellitus, NIDDM). Recently, these drugs have also been found to be effective in regulating cell proliferation and differentiation [25]. PPARγ activation by its ligands can induce growth arrest, differentiation, and apoptosis of cancer cells. Similarly, PPARγ heterozygous knockout mice have increased susceptibility to chemical carcinogens [41]. Nevertheless, these reports remain controversial and are not well supported. For instance, low concentrations of PPARγ ligands increase cell proliferation, while high concentrations inhibit cell growth in MDA-MB-231 breast cancer cells [42]. The effective clinical dose of rosiglitazone used in diabetes is 0.11 mg/kg/day [43]. In contrast, the antitumor activity of rosiglitazone in mice requires 100–150 mg/kg/day [43], which is 1,000-fold higher. Therefore, the dosage of PPARγ agonists for cancer therapy must be carefully defined in clinical trials. A recent report suggested that physiological agonists included polyunsaturated acids, such as eicosapentaenoic acid (EPA) [44], linoleic acid [45], and oxidized fatty acid metabolites, cyclopentenone prostaglandin 15-deoxy-Δ12,14 (15d-PGJ2) [46], 8(S)-hydroxyeicosatetraenoic acid (8(S)-HETE) [47], and the lipoxygenase product, 9-hydroxyoctadecadienoic acid (HODE) [23]. These results were surprising, because these compounds are known to mediate their biological effects through interacting with cell-surface GPCRs, including prostaglandin D2 receptors (DP)1-2 and G protein-coupled receptor 44 (GPR44), prostaglandin E receptors (EP)1-4, prostaglandin F receptor (FP), prostacyclin receptors (IP)1-2, and thromboxane receptors (TP). However, in 1995, Forman et al. first reported that the prostaglandin J2 derivative, 15d-PGJ2, was a natural intracellular agonist of PPARγ as well as a factor of adipocyte determination [46]. 15d-PGJ2 is a product of the cyclooxygenase pathway and is the final metabolite of prostaglandin D2 (PGD2). Some J-series prostaglandins have been found to bind to PPARγ in the low micromolar range [48]. Although 15d-PGJ2 was initially identified as a high-affinity endogenous ligand (Kd = 300 nM) [46], the physiological role of 15d-PGJ2 remains unclear. In particular, its concentration in vivo is much lower than that required for its biological functions [49]. Furthermore, apoptosis induced by 15-PGJ2 occurs independently of PPARγ activation and may result from a loss of mitochondrial membrane potential and the formation of reactive oxygen species (ROS) [50, 51].


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

Tsukahara T - PPAR Res (2012)

Structural formulas of LPA, alkyl-LPA, cPA,and rosiglitazone. LPA is made up of a glycerol backbone with a hydroxyl group, a phosphate group, and a long-chain saturated or unsaturated fatty acid. Alkyl-LPA is an alkyl-ether analog of LPA. Alkyl-LPA shows a higher potency than LPA at the intracellular LPA receptor PPARγ. cPA is a naturally occurring acyl analog of LPA. cPA is a weak agonist of plasma membrane LPA receptors, whereas cPA is an inhibitor of PPARγ. Rosiglitazone is a thiazolidinedione (TZD) class of antidiabetics and is full agonist of PPARγ.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368591&req=5

fig1: Structural formulas of LPA, alkyl-LPA, cPA,and rosiglitazone. LPA is made up of a glycerol backbone with a hydroxyl group, a phosphate group, and a long-chain saturated or unsaturated fatty acid. Alkyl-LPA is an alkyl-ether analog of LPA. Alkyl-LPA shows a higher potency than LPA at the intracellular LPA receptor PPARγ. cPA is a naturally occurring acyl analog of LPA. cPA is a weak agonist of plasma membrane LPA receptors, whereas cPA is an inhibitor of PPARγ. Rosiglitazone is a thiazolidinedione (TZD) class of antidiabetics and is full agonist of PPARγ.
Mentions: In the last decade, both synthetic and natural PPARγ agonists have been explored for their biological and physiological functions [33]. Synthetic PPARγ agonists, which include rosiglitazone (Avandia) (Figure 1) [34, 35], troglitazone (Rezulin, withdrawn by the FDA due to causing liver failure) [36, 37], and pioglitazone (Actos; Takeda Pharmaceutical Ltd.) [38, 39], have provided insight into the therapeutic potential of PPARγ. These compounds are specific PPARγ ligands with Kds in the 40–500 nM range [34, 40]. They are effective as insulin-sensitizing agents, reducing insulin resistance and lowering plasma glucose levels in patients with type II diabetes (previously known as noninsulin-dependent diabetes mellitus, NIDDM). Recently, these drugs have also been found to be effective in regulating cell proliferation and differentiation [25]. PPARγ activation by its ligands can induce growth arrest, differentiation, and apoptosis of cancer cells. Similarly, PPARγ heterozygous knockout mice have increased susceptibility to chemical carcinogens [41]. Nevertheless, these reports remain controversial and are not well supported. For instance, low concentrations of PPARγ ligands increase cell proliferation, while high concentrations inhibit cell growth in MDA-MB-231 breast cancer cells [42]. The effective clinical dose of rosiglitazone used in diabetes is 0.11 mg/kg/day [43]. In contrast, the antitumor activity of rosiglitazone in mice requires 100–150 mg/kg/day [43], which is 1,000-fold higher. Therefore, the dosage of PPARγ agonists for cancer therapy must be carefully defined in clinical trials. A recent report suggested that physiological agonists included polyunsaturated acids, such as eicosapentaenoic acid (EPA) [44], linoleic acid [45], and oxidized fatty acid metabolites, cyclopentenone prostaglandin 15-deoxy-Δ12,14 (15d-PGJ2) [46], 8(S)-hydroxyeicosatetraenoic acid (8(S)-HETE) [47], and the lipoxygenase product, 9-hydroxyoctadecadienoic acid (HODE) [23]. These results were surprising, because these compounds are known to mediate their biological effects through interacting with cell-surface GPCRs, including prostaglandin D2 receptors (DP)1-2 and G protein-coupled receptor 44 (GPR44), prostaglandin E receptors (EP)1-4, prostaglandin F receptor (FP), prostacyclin receptors (IP)1-2, and thromboxane receptors (TP). However, in 1995, Forman et al. first reported that the prostaglandin J2 derivative, 15d-PGJ2, was a natural intracellular agonist of PPARγ as well as a factor of adipocyte determination [46]. 15d-PGJ2 is a product of the cyclooxygenase pathway and is the final metabolite of prostaglandin D2 (PGD2). Some J-series prostaglandins have been found to bind to PPARγ in the low micromolar range [48]. Although 15d-PGJ2 was initially identified as a high-affinity endogenous ligand (Kd = 300 nM) [46], the physiological role of 15d-PGJ2 remains unclear. In particular, its concentration in vivo is much lower than that required for its biological functions [49]. Furthermore, apoptosis induced by 15-PGJ2 occurs independently of PPARγ activation and may result from a loss of mitochondrial membrane potential and the formation of reactive oxygen species (ROS) [50, 51].

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