Thiazolidinedione Activation of Peroxisome Proliferator-activated Receptor γ Can Enhance Mitochondrial Potential and Promote Cell Survival

Wang, Y. Lynn; Frauwirth, Kenneth A.; Rangwala, Shamina M.; Lazar, Mitchell A.; Thompson, Craig B.

doi:10.1074/jbc.m204279200

Cited by 104 publications

(100 citation statements)

References 42 publications

(49 reference statements)

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“…35 Together, these findings support the hypothesis that RSG is increasing efficiency and the number of brain mitochondria, thereby increasing glucose utilization and improving cognition in AD patients. It is interesting to speculate why APOE e4-positive patients may not have responded to RSG as well as APOE e4-negative patients.…”

Section: Discussionsupporting

confidence: 67%

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

et al. 2006

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Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N ¼ 511), and results were also stratified by apolipoprotein E (APOE) genotype (n ¼ 323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE e4 allele status and ADAS-Cog (P ¼ 0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE e4-negative patients on 8 mg RSG (P ¼ 0.024; not corrected for multiplicity). APOE e4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P ¼ 0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE e4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE e4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.

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Section: Discussionsupporting

confidence: 67%

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

et al. 2006

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“…Our results are in line with other reports indicating PPAR-␥-independent anti-inflammatory and proapoptotic effects of cyclopentenone PGs (22, 31-34, 36, 38). Wang et al (12) reported that PPAR-␥ might even favor T lymphocyte survival by enhancing mitochondrial transmembrane potential. Several authors (10,12,14) report about the induction of apoptosis in primary T cells by 15d-PGJ 2 .…”

Section: Discussionmentioning

confidence: 99%

“…Wang et al (12) reported that PPAR-␥ might even favor T lymphocyte survival by enhancing mitochondrial transmembrane potential. Several authors (10,12,14) report about the induction of apoptosis in primary T cells by 15d-PGJ 2 . However, in two recent A, A total of 10 7 human primary CD3 ϩ cells were pretreated for 1 h with medium or 100 M zVAD-fmk.…”

Section: Discussionmentioning

confidence: 99%

Cyclopentenone Prostaglandins Induce Lymphocyte Apoptosis by Activating the Mitochondrial Apoptosis Pathway Independent of External Death Receptor Signaling

Nencioni

Lauber

Grünebach³

et al. 2003

The Journal of Immunology

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15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2) is a naturally occurring cyclopentenone metabolite of PGD2 that possesses both peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent and PPAR-γ-independent anti-inflammatory properties. Recent studies suggest that cyclopentenone PGs may play a role in the down-regulation of inflammation-induced immune responses. In this study, we report that 15d-PGJ2 as well as synthetic PPAR-γ agonists inhibit lymphocyte proliferation. However, only 15d-PGJ2, but not the specific PPAR-γ activators, induce lymphocyte apoptosis. We found that blocking of the death receptor pathway in Fas-associated death domain−/− or caspase-8−/− Jurkat T cells has no effect on apoptosis induction by 15d-PGJ2. Conversely, overexpression of Bcl-2 or Bcl-xL completely inhibits the initiation of apoptosis, indicating that 15d-PGJ2-mediated apoptosis involves activation of the mitochondrial pathway. In line with these results, 15d-PGJ2 induces mitochondria disassemblage as demonstrated by dissipation of mitochondrial transmembrane potential (Δψm) and cytochrome c release. Both of these events are partially inhibited by the broad spectrum caspase inhibitor benzyloxycarbonil-Val-Ala-Asp-fluoromethylketone, suggesting that caspase activation may amplify the mitochondrial alterations initiated by 15d-PGJ2. We also demonstrate that 15d-PGJ2 potently stimulates reactive oxygen species production in Jurkat T cells, and Δψm loss induced by 15d-PGJ2 is prevented by the reactive oxygen species scavenger N-acetyl-l-cysteine. In conclusion, our data indicate that cyclopentenone PGs like 15d-PGJ2 may modulate immune responses even independent of PPAR-γ by activating the mitochondrial apoptosis pathway in lymphocytes in the absence of external death receptor signaling.

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“…One study demonstrated that treatment with high doses of TZDs enhanced T-cell apoptosis (Harris and Phipps, 2001). However, PPARγ activation also resulted in increased survival under conditions of cytokine withdrawal or serum starvation (Jo et al, 2006;Wang et al, 2002). Recent studies have more precisely analyzed the function of PPARγ in CD4 T-cell-targeted PPARγ-deficient mice.…”

Section: Ppars In T Cells and Autoimmunitymentioning

confidence: 99%

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

Choi¹,

Bothwell

2012

Molecules and Cells

140

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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Thiazolidinedione Activation of Peroxisome Proliferator-activated Receptor γ Can Enhance Mitochondrial Potential and Promote Cell Survival

Cited by 104 publications

References 42 publications

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

Cyclopentenone Prostaglandins Induce Lymphocyte Apoptosis by Activating the Mitochondrial Apoptosis Pathway Independent of External Death Receptor Signaling

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

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