The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR)

Peraza, Marjorie A.; Burdick, Andrew D.; Marin, Holly E.; Gonzalez, Frank J.; Peters, Jeffrey M.

doi:10.1093/toxsci/kfj062

Cited by 240 publications

(171 citation statements)

References 303 publications

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“…As a nuclear receptor involved in multiple physiological regulations (Cheng et al, 2004;Kim et al, 2004;Piqueras et al, 2007), PPAR-b is an ideal drug target for the treatment of diseases. Studies have shown a wide range of PPAR-b agonists, including eicosanoids, fatty acids and some synthetic compounds (for example, GW501516); GW501516 is currently in a phase II clinical trial for dyslipidemia (Barish et al, 2006;Peraza et al, 2006;Takahashi et al, 2006). Because of its protective role in the carcinogenesis and progression of colon cancer as suggested in this study, PPAR-b may be a potential drug target for colon cancer.…”

Section: Studies Have Identified Ilk As a Direct Target Of Ppar-b (mentioning

confidence: 82%

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

et al. 2009

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The role of peroxisome proliferator-activated receptor-b/ d (PPAR-b/d) in the pathogenesis of colon cancer remains highly controversial. This study specifically silenced the PPAR-b expression in three colon cancer cell lines with different metastatic potentials. Although PPAR-b knockdown resulted in more malignant morphological changes, bigger colony sizes and lower carcinoembryonic antigen (CEA) secretion, and enhanced the cell-fibronectin adhesion, cell invasion and migration were unaffected. These effects were stronger in poorly metastatic cell lines compared with highly metastatic ones. Simultaneously, PPAR-b knockdown decreased the mRNAs encoding adipocyte differentiation-related protein and liver fatty acid binding protein, and increased the mRNA of ILK, whereas the mRNAs encoding integrin-b1 and angiopoietin-like 4 were unchanged. Using immunohistochemistry, we determined that the intensity of PPAR-b expression was stronger in rectal cancers with better differentiation than in those with poor differentiation, and was stronger in early-stage tumors than in advanced ones. Together, these findings consistently indicate that PPAR-b may facilitate differentiation and inhibit the cell-fibronectin adhesion of colon cancer, having a role as an inhibitor in the carcinogenesis and progression of colorectal cancer. Interestingly, PPAR-b seems to have a more important role in poorly metastatic cells than in highly metastatic ones.

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Section: Studies Have Identified Ilk As a Direct Target Of Ppar-b (mentioning

confidence: 82%

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

et al. 2009

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“…Ligands for PPARs exhibit potent anti-inflammatory effects related to innate and adaptive immunity in various disease models, including IBD and EAE. However, use of PPAR ligands as therapeutics is limited by their adverse side effects (Peraza et al, 2006). Combinations of PPAR and RXR agonists may produce synergistic effects with reduced side effects .…”

Section: Discussionmentioning

confidence: 99%

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Choi¹,

Bothwell

2012

Molecules and Cells

149

111

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Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4 + T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

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“…In addition to transcriptionally-mediate events, ligands for PPARs can also cause changes in the phosphorylation of proteins that can also modulate cell cycle, and these events can be mediated by both receptor-dependent and receptor-independent mechanisms (reviewed in [40]). To begin to examine the changes in phosphorylation-dependent signaling, global analysis of phosphorylated cell cycle proteins was performed using the Kinexus KPSS 10.0 Screen.…”

Section: Gw0742 Inhibits Mapk Signaling In N/tert-1 Keratinocytesmentioning

confidence: 99%

Ligand activation of peroxisome proliferator-activated receptor-β/δ(PPARβ/δ) inhibits cell growth of human N/TERT-1 keratinocytes

Burdick¹,

Bility

Girroir³

et al. 2007

Cellular Signalling

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The functional role of peroxisome proliferator-activated receptor-β (PPARβ; also referred to as PPARδ) in epidermal cell growth remains controversial. Recent evidence suggests that ligand activation of PPARβ/δ increases cell growth and inhibits apoptosis in epidermal cells. In contrast, other reports suggest that ligand activation of PPARβ/δ leads to the induction of terminal differentiation and inhibition of cell growth. In the present study, the effect of the highly specific PPARβ/δ ligand GW0742 on cell growth was examined using a human keratinocyte cell line (N/ TERT-1) and mouse primary keratinocytes. Ligand activation of PPARβ/δ with GW0742 prevented cell cycle progression from G1 to S phase and attenuated cell proliferation in N/TERT-1 cells. Despite specifically activating PPARβ/δ as revealed by target gene induction, no changes in PTEN, PDK and ILK expression or downstream phosphorylation of Akt were found in either N/TERT-1 cells or primary keratinocytes. Further, altered cell growth resulting from serum withdrawal and the induction of caspase-3 activity by ultraviolet radiation were unchanged in the absence of PPARβ/δ expression and/or the presence of GW0742. While no changes in the expression of mRNAs encoding cell cycle control proteins were found in response to GW0742, a significant decrease in the level of ERK phosphorylation was observed. Results from these studies demonstrate that ligand activation of PPARβ/δ does not lead to an anti-apoptotic effect in either human or mouse keratinocytes, but rather, leads to inhibition of cell growth likely through the induction of terminal differentiation.

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The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR)

Cited by 240 publications

References 303 publications

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Ligand activation of peroxisome proliferator-activated receptor-β/δ(PPARβ/δ) inhibits cell growth of human N/TERT-1 keratinocytes

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