scholarly journals Transforming Growth Factor-β (TGF-β) Activates Cytosolic Phospholipase A2α (cPLA2α)-mediated Prostaglandin E2(PGE)2/EP1and Peroxisome Proliferator-activated Receptor-γ (PPAR-γ)/Smad Signaling Pathways in Human Liver Cancer Cells

2004 ◽  
Vol 279 (43) ◽  
pp. 44344-44354 ◽  
Author(s):  
Chang Han ◽  
A. Jake Demetris ◽  
Youhua Liu ◽  
James H. Shelhamer ◽  
Tong Wu
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Liver Cancer Cells ◽  
Ppar Γ ◽  
Cytosolic Phospholipase ◽  
Human Liver Cancer ◽  
Cytosolic Phospholipase A2α ◽  
Human Liver Cancer Cells

Disruption of transforming growth factor-β signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-γ in rat hepatic stellate cells

2007 ◽  
Vol 292 (1) ◽  
pp. G113-G123 ◽  
Author(s):  
Shizhong Zheng ◽  
Anping Chen
Keyword(s):  
Gene Expression ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Gene Promoter ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Activation of hepatic stellate cells (HSC), the major effectors of hepatic fibrogenesis, is coupled with sequential alterations in gene expression, including an increase in receptors for transforming growth factor-β (TGF-β) and a dramatic reduction in the peroxisome proliferator-activated receptor-γ (PPAR-γ). The relationship between them remains obscure. We previously demonstrated that curcumin induced gene expression of PPAR-γ in activated HSC, leading to reducing cell proliferation, inducing apoptosis and suppressing expression of extracellular matrix genes. The underlying molecular mechanisms are largely unknown. We recently observed that stimulation of PPAR-γ activation suppressed gene expression of TGF-β receptors in activated HSC, leading to the interruption of TGF-β signaling. This observation supported our assumption of an antagonistic relationship between PPAR-γ activation and TGF-β signaling in HSC. In this study, we further hypothesize that TGF-β signaling might negatively regulate gene expression of PPAR-γ in activated HSC. The present report demonstrates that exogenous TGF-β1 inhibits gene expression of PPAR-γ in activated HSC, which is eliminated by the pretreatment with curcumin likely by interrupting TGF-β signaling. Transfection assays further indicate that blocking TGF-β signaling by dominant negative type II TGF-β receptor increases the promoter activity of PPAR-γ gene. Promoter deletion assays, site-directed mutageneses, and gel shift assays localize two Smad binding elements (SBEs) in the PPAR-γ gene promoter, acting as curcumin response elements and negatively regulating the promoter activity in passaged HSC. The Smad3/4 protein complex specifically binds to the SBEs. Overexpression of Smad4 dose dependently eliminates the inhibitory effects of curcumin on the PPAR-γ gene promoter and TGF-β signaling. Taken together, these results demonstrate that the interruption of TGF-β signaling by curcumin induces gene expression of PPAR-γ in activated HSC in vitro. Our studies provide novel insights into the molecular mechanisms of curcumin in the induction of PPAR-γ gene expression and in the inhibition of HSC activation.

scholarly journals Hypoxia-induced inhibition of lung development is attenuated by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone

2011 ◽  
Vol 301 (1) ◽  
pp. L125-L134 ◽  
Author(s):  
Teodora Nicola ◽  
Namasivayam Ambalavanan ◽  
Wei Zhang ◽  
Masheika L. James ◽  
Virender Rehan ◽  
...  
Keyword(s):  
Lung Development ◽  
Transforming Growth Factor ◽  
Neutralizing Antibody ◽  
Transforming Growth Factor Β ◽  
Lung Compliance ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Alveolar Development ◽  
Lung Histology

Hypoxia enhances transforming growth factor-β (TGF-β) signaling, inhibiting alveolar development and causing abnormal pulmonary arterial remodeling in the newborn lung. We hypothesized that, during chronic hypoxia, reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling may contribute to, or be caused by, excessive TGF-β signaling. To determine whether PPAR-γ was reduced during hypoxia, C57BL/6 mice were exposed to hypoxia from birth to 2 wk and evaluated for PPAR-γ mRNA and protein. To determine whether rosiglitazone (RGZ, a PPAR-γ agonist) supplementation attenuated the effects of hypoxia, mice were exposed to air or hypoxia from birth to 2 wk in combination with either RGZ or vehicle, and measurements of lung histology, function, parameters related to TGF-β signaling, and collagen content were made. To determine whether excessive TGF-β signaling reduced PPAR-γ, mice were exposed to air or hypoxia from birth to 2 wk in combination with either TGF-β-neutralizing antibody or vehicle, and PPAR-γ signaling was evaluated. We observed that hypoxia reduced PPAR-γ mRNA and protein, in association with impaired alveolarization, increased TGF-β signaling, reduced lung compliance, and increased collagen. RGZ increased PPAR-γ signaling, with improved lung development and compliance in association with reduced collagen and TGF-β signaling. However, no reduction was noted in hypoxia-induced pulmonary vascular remodeling. Inhibition of hypoxia-enhanced TGF-β signaling increased PPAR-γ signaling. These results suggest that hypoxia-induced inhibition of lung development is associated with a mutually antagonistic relationship between reduced PPAR-γ and increased TGF-β signaling. PPAR-γ agonists may be of potential therapeutic significance in attenuating TGF-β signaling and improving alveolar development.

The effect of high glucose and PPAR-γ agonists on PPAR-γ expression and function in HK-2 cells

2004 ◽  
Vol 287 (3) ◽  
pp. F528-F534 ◽  
Author(s):  
U. Panchapakesan ◽  
C. A. Pollock ◽  
X. M. Chen
Keyword(s):  
Cell Growth ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Human Kidney ◽  
Transforming Growth Factor Β ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Monocyte Chemoattractant Protein 1 ◽  
Ppar Γ ◽  
Proximal Tubular

Peroxisome proliferator-activated receptor-γ (PPAR-γ) are ligand-activated transcription factors that regulate cell growth, inflammation, lipid metabolism, and insulin sensitivity. PPAR-γ in the human kidney has been described. However, the role of PPAR-γ in proximal tubular cells with respect to cell growth and inflammation in diabetic nephropathy is largely unknown. We evaluated the effect of high (30 mM) d-glucose, thiazolidinedione pioglitazone (10 μM), and the selective PPAR-γ agonist L-805645 (8 μM) on PPAR-γ expression, growth, and inflammatory parameters in the proximal tubular model of HK-2 cells. PPAR-γ was present in HK-2 cells and upregulated with 30 mM d-glucose to 177 ± 31.2% of control ( P < 0.05). PPAR-γ activation was induced by pioglitazone to a similar level to that observed by exposure to high glucose but maximally induced by the selective agonist L-805645. However, L-805645 reduced cell viability in both 5 and 30 mM d-glucose to 73.8 ± 3.1 and 77.6 ± 1.4% of control (both P < 0.0001). In parallel, thymidine incorporation was reduced with L-805645 in both 5 and 30 mM d-glucose to 33.3 ± 3.4 and 37.9 ± 2.2%, respectively (both P < 0.0001). Flow cytometry demonstrated increased apoptosis and G1 phase arrest in association with an increase in p21cip1/waf1 in cells exposed to L-805645. Exposure to 30 mM d-glucose did not significantly change AP-1 promoter activity (89.0 ± 5.5% of control); however, the addition of L-805645 significantly reduced it to 62.2 ± 2.7% of control ( P < 0.0001). Thirty nanomolar d-glucose induced transforming growth factor-β1 to 137.7 ± 16.9% of control ( P < 0.05), and L-805645 was able to suppress this to 68.7 ± 5.7% of control ( P < 0.01 vs. d-glucose). Exposure to 30 mM d-glucose reduced monocyte chemoattractant protein 1 levels to 78.6 ± 7.1% ( P < 0.05) of control, with the reduction more marked in the presence of either pioglitazone ( P < 0.01) or L-805645 ( P < 0.01). In summary, high glucose upregulates PPAR-γ and when significantly induced demonstrates anti-proliferative and anti-inflammatory effects.

Biphasic effect of pioglitazone on isolated human endothelial progenitor cells: Involvement of peroxisome proliferator-activated receptor-γ and transforming growth factor-β1

2007 ◽  
Vol 97 (06) ◽  
pp. 988-997 ◽  
Author(s):  
Mihail Hristov ◽  
Denis Gümbel ◽  
Teresa Tejerina ◽  
Santiago Redondo ◽  
Christian Weber
Keyword(s):  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Peroxisome Proliferator ◽  
Endothelial Progenitor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Patients With Diabetes ◽  
Tgf Β1

SummaryEndothelial progenitor cells (EPCs) have been implicated in vascular repair and found to be functionally impaired in patients with diabetes. We evaluated the effects of the anti-diabetic drug pioglitazone on human EPC function and the involvement of PPAR-γ and TGF-β1. EPCs in culture were characterized at day 7 by the development of colony-forming units (CFUs) and flow cytometry assessment of differentiation marker (DiI-ac-LDL/lectin, KDR and CD31). Adhesion on fibronectin and fibrinogen in flow was analyzed as functional parameter. Treatment with pioglitazone for 72 hours increased the number of EPC-CFUs, DiI-ac-LDL+/lectin+, CD31+ and KDR+ EPCs at 1 μM but not at 10 μM. Since pioglitazone did not significantly alter proliferation and apoptosis in cultured EPCs, the increase in EPC number was most likely attributable to augmented adhesion and differentiation. Indeed, pioglitazone increased EPC adhesion in flow at 1 μM, an effect prevented by PPAR-γ and β2-integrin blockade. In contrast, pioglitazone did not promote EPC adhesion at 10 μM; however, increased adhesion became evident by co-incubation with a blocking TGF-β1 antibody. As determined by ELISA, pioglitazone induced a persistent increase in TGF-β1 secretion only at 10 μM when a significantly elevated expression of endoglin, the accessory receptor forTGF-β1, was also observed. Taken together, pioglitazone exerts biphasic effects on the function of isolated EPCs, causing a PPAR-γ-dependent stimulation at 1 μM and a TGF-β1-mediated suppression at 10 μM. These results may help to define optimal therapeutic doses of pioglitazone for improving endothelial dysfunction.

scholarly journals Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements

2017 ◽  
Vol 474 (9) ◽  
pp. 1531-1546 ◽  
Author(s):  
Sowmya P. Lakshmi ◽  
Aravind T. Reddy ◽  
Raju C. Reddy
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Regulatory Elements ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Context Sensitive ◽  
Signaling Mechanisms ◽  
Target Promoter

Transforming growth factor β (TGF-β) contributes to wound healing and, when dysregulated, to pathological fibrosis. TGF-β and the anti-fibrotic nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) repress each other's expression, and such PPARγ down-regulation is prominent in fibrosis and mediated, via previously unknown SMAD-signaling mechanisms. Here, we show that TGF-β induces the association of SMAD3 with both SMAD4, needed for translocation of the complex into the nucleus, and the essential context-sensitive co-repressors E2F4 and p107. The complex mediates TGF-β-induced repression by binding to regulatory elements in the target promoter. In the PPARG promoter, we found that the SMAD3–SMAD4 complex binds both to a previously unknown consensus TGF-β inhibitory element (TIE) and also to canonical SMAD-binding elements (SBEs). Furthermore, the TIE and SBEs independently mediated the partial repression of PPARG transcription, the first demonstration of a TIE and SBEs functioning within the same promoter. Also, TGF-β-treated fibroblasts contained SMAD complexes that activated a SMAD target gene in addition to those repressing PPARG transcription, the first finding of such dual activity within the same cell. These findings describe in detail novel mechanisms by which TGF-β represses PPARG transcription, thereby facilitating its own pro-fibrotic activity.

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