PPAR Research最新文献

Objective: This study is aimed at using genes related to the peroxisome proliferator-activated receptor (PPAR) pathway to establish a prognostic risk model in kidney renal clear cell carcinoma (KIRC).

Methods: For this study, we first found the PPAR pathway-related genes on the gene set enrichment analysis (GSEA) website and found the KIRC mRNA expression data and clinical data through TCGA database. Subsequently, we used R language and multiple R language expansion packages to analyze the expression, hazard ratio analysis, and coexpression analysis of PPAR pathway-related genes in KIRC. Afterward, using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) website, we established the protein-protein interaction (PPI) network of genes related to the PPAR pathway. After that, we used LASSO regression curve analysis to establish a prognostic survival model in KIRC. Finally, based on the model, we conducted correlation analysis of the clinicopathological characteristics, univariate analysis, and multivariate analysis.

Results: We found that most of the genes related to the PPAR pathway had different degrees of expression differences in KIRC. Among them, the high expression of 27 genes is related to low survival rate of KIRC patients, and the high expression of 13 other genes is related to their high survival rate. Most importantly, we used 13 of these genes successfully to establish a risk model that could accurately predict patients' prognosis. There is a clear correlation between this model and metastasis, tumor, stage, grade, and fustat.

Conclusions: To the best of our knowledge, this is the first study to analyze the entire PPAR pathway in KIRC in detail and successfully establish a risk model for patient prognosis. We believe that our research can provide valuable data for future researchers and clinicians.

[This retracts the article DOI: 10.1155/2008/649808.].

PPARs are ligand-activated transcriptional factors that belong to the nuclear receptor superfamily. Among them, PPAR alpha and PPAR gamma are prone to exert an antiangiogenic effect, whereas PPAR beta/delta has an opposite effect in physiological and pathological conditions. Angiogenesis has been known as a hallmark of cancer, and our recent works also demonstrate that vascular-specific PPAR beta/delta overexpression promotes tumor angiogenesis and progression in vivo. In this review, we will mainly focus on the role of PPAR beta/delta in tumor angiogenesis linked to the tumor microenvironment to further facilitate tumor progression and metastasis. Moreover, the crosstalk between PPAR beta/delta and its downstream key signal molecules involved in tumor angiogenesis will also be discussed, and the network of interplay between them will further be established in the review.

PPARD has been suggested to contribute to the etiology of schizophrenia (SCZ) with the underlying mechanisms largely unknown. Here, we first collected and analyzed the PPARD expression profile from three groups: (1) 18 healthy control (HC) subjects, (2) 14 clinical high-risk (CHR) patients, and (3) 19 early onset of SCZ (EOS) patients. After that, we conducted a systematical pathway analysis to explore the potential mechanisms involved in PPARD exerting influence on the pathological development of SCZ. Compared to the HC group, the expression of PPARD was slightly decreased in the EOS group (LFC = -0.34; p = 0.23) and increased in the CHR group (LFC = 0.65; p = 0.20). However, there was a significant difference between the EOS group and the CHR group (LFC = -0.99; p = 0.015), reflecting the amount of variation in PPARD expression before and after the onset of SCZ. Pathway analysis suggested that overexpression of PPARD may regulate ten proteins or molecules to inhibit the pathological development of SCZ, including the deactivation of eight SCZ promoters and stimulation of two SCZ inhibitors. Our results support the association between PPARD and SCZ. The pathways identified may help in the understanding of the potential mechanisms by which PPARD contributes to the etiology of SCZ.

The peroxisome proliferator-activated receptor (PPARγ) is a central mediator of cellular lipid metabolism and immune cell responses during inflammation. This is facilitated by its role as a transcription factor as well as a DNA-independent protein interaction partner. We addressed how the cellular redox milieu in the cytosol and the nucleus of lipopolysaccharide (LPS)/interferon-γ- (IFNγ-) and interleukin-4- (IL4-) polarized macrophages (MΦ) initiates posttranslational modifications of PPARγ, that in turn alter its protein function. Using the redox-sensitive GFP2 (roGFP2), we validated oxidizing and reducing conditions following classical and alternative activation of MΦ, while the redox status of PPARγ was determined via mass spectrometry. Cysteine residues located in the zinc finger regions (amino acid fragments AA 90-115, AA 116-130, and AA 160-167) of PPARγ were highly oxidized, accompanied by phosphorylation of serine 82 in response to LPS/IFNγ, whereas IL4-stimulation provoked minor serine 82 phosphorylation and less cysteine oxidation, favoring a reductive milieu. Mutating these cysteines to alanine to mimic a redox modification decreased PPARγ-dependent reporter gene transactivation supporting a functional shift of PPARγ associated with the MΦ phenotype. These data suggest distinct mechanisms for regulating PPARγ function based on the redox state of MΦ.

The past decade of PPARγ research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPARγ ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPARγ ligands, capable of isolating central therapeutic effects of PPARγ modulation, while displaying markedly lower toxicities than previous generations of PPARγ ligands. This review examines the emerging framework around the design of these ligands and seeks to unite its principles with the development of new classes of ligands for PPARα and PPARβ/δ. The focus is on the relationships between the binding modes of ligands, their influence on PPAR posttranslational modifications, and gene expression patterns. Specifically, we encourage the design and study of ligands that primarily bind to the Ω pockets of PPARα and PPARβ/δ. In support of this development, we highlight already reported ligands that if studied in the context of this new framework may further our understanding of the gene programs regulated by PPARα and PPARβ/δ. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.

Previous studies showed that PPAR-gamma (PPARG) ligands might serve as potential therapeutic agents for nonsmall cell lung cancer (NSCLC). However, a few studies reported the specific relationship between PPARG and lung squamous cell carcinoma (LSCC). Here, we made an effort to explore the relationship between PPARG and LSCC. First, we used mega-analysis and partial mega-analysis to analyze the effects of PPARG on LSCC by using 12 independent LSCC expression datasets (285 healthy controls and 375 LSCC cases). Then, literature-based molecular pathways between PPARG and LSCC were established. After that, a gene set enrichment analysis (GSEA) was conducted to study the functionalities of PPARG and PPARG-driven triggers within the molecular pathways. Finally, another mega-analysis was constructed to test the expression changes of PPARG and its driven targets. The partial mega-analysis showed a significant downregulated expression of PPARG in LSCC (LFC = -1.08, p value = 0.00073). Twelve diagnostic markers and four prognostic markers were identified within multiple PPARG-LSCC regulatory pathways. Our results suggested that the activation of PPARG expression may inhibit the development and progression of LSCC through the regulation of LSCC upstream regulators and downstream marker genes, which were involved in tumor cell proliferation and protein polyubiquitination/ubiquitination.

Peroxisome proliferator-activated receptor γ (PPARG) might play a protective role in the development of myocardial infarction (MI) with limited mechanisms identified. Genes associated with both PPARG and MI were extracted from Elsevier Pathway Studio to construct the initial network. The gene expression activity within the network was estimated through a mega-analysis with eight independent expression datasets derived from Gene Expression Omnibus (GEO) to build PPARG and MI connecting pathways. After that, gene set enrichment analysis (GSEA) was conducted to explore the functional profile of the genes involved in the PPARG-driven network. PPARG demonstrated a significantly low expression in MI patients (LFC = -0.52; p < 1.84e - 9). Consequently, PPARG could indicatively be promoting three MI inhibitors (e.g., SOD1, CAV1, and POU5F1) and three MI-downregulated markers (e.g., ALB, ACADM, and ADIPOR2), which were deactivated in MI cases (p < 0.05), and inhibit two MI-upregulated markers (RELA and MYD88), which showed increased expression levels in MI cases (p = 0.0077 and 0.047, respectively). These eight genes were mainly enriched in nutrient- and cell metabolic-related pathways and functionally linked by GSEA and PPCN. Our results suggest that PPARG could protect the heart against both the development and progress of MI through the regulation of nutrient- and metabolic-related pathways.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. To date, there is not a specific and approved treatment for NAFLD yet, and therefore, it is important to understand the molecular mechanisms that lead to the progression of NAFLD. Methionine- and choline-deficient (MCD) diets are used to reproduce some features of NAFLD in mice. MCD diets increase the expression of hepatic peroxisome proliferator-activated receptor gamma (PPARγ, Pparg) and the fatty acid translocase (CD36, Cd36) which could increase hepatic fatty acid uptake and promote the progression of NAFLD in mice and humans. In this study, we assessed the contribution of hepatocyte-specific PPARγ and CD36 expression to the development of early events induced by the MCD diet. Specifically, mice with adult-onset, hepatocyte-specific PPARγ knockout with and without hepatocyte CD36 overexpression were fed a MCD diet for three weeks. Hepatocyte PPARγ and/or CD36 expression did not contribute to the development of steatosis induced by the MCD diet. However, the expression of inflammatory and fibrogenic genes seems to be dependent on the expression of hepatocyte PPARγ and CD36. The expression of PPARγ and CD36 in hepatocytes may be relevant in the regulation of some features of NAFLD and steatohepatitis.