PPAR Research最新文献

{"title":"Diet Modifies Pioglitazone's Influence on Hepatic PPAR<i>γ</i>-Regulated Mitochondrial Gene Expression.","authors":"Sakil Kulkarni,&nbsp;Jiansheng Huang,&nbsp;Eric Tycksen,&nbsp;Paul F Cliften,&nbsp;David A Rudnick","doi":"10.1155/2020/3817573","DOIUrl":"https://doi.org/10.1155/2020/3817573","url":null,"abstract":"Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio's beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio's direct impact on hepatocellular gene expression might also be a determinant of this drug's ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio's PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio's hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio's liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio's influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug's influence on such regulation.","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2020-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/3817573","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38411035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retracted: Rosiglitazone Suppresses the Growth and Invasiveness of SGC-7901 Gastric Cancer Cells and Angiogenesis In Vitro via PPAR<i>γ</i> Dependent and Independent Mechanisms.","authors":"","doi":"10.1155/2020/9469261","DOIUrl":"https://doi.org/10.1155/2020/9469261","url":null,"abstract":"<p><p>[This retracts the article DOI: 10.1155/2008/649808.].</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/9469261","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38398612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Emerging Role of PPAR Beta/Delta in Tumor Angiogenesis.","authors":"Siyue Du,&nbsp;Nicole Wagner,&nbsp;Kay-Dietrich Wagner","doi":"10.1155/2020/3608315","DOIUrl":"https://doi.org/10.1155/2020/3608315","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2020-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/3608315","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38318567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPARD May Play a Protective Role against the Development of Schizophrenia.","authors":"Xinrong Li,&nbsp;Sha Liu,&nbsp;Karan Kapoor,&nbsp;Yong Xu","doi":"10.1155/2020/3480412","DOIUrl":"https://doi.org/10.1155/2020/3480412","url":null,"abstract":"<p><p>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; <i>p</i> = 0.23) and increased in the CHR group (LFC = 0.65; <i>p</i> = 0.20). However, there was a significant difference between the EOS group and the CHR group (LFC = -0.99; <i>p</i> = 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.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2020-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/3480412","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38292540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox Regulation of PPAR<i>γ</i> in Polarized Macrophages.","authors":"Verena Trümper,&nbsp;Ilka Wittig,&nbsp;Juliana Heidler,&nbsp;Florian Richter,&nbsp;Bernhard Brüne,&nbsp;Andreas von Knethen","doi":"10.1155/2020/8253831","DOIUrl":"https://doi.org/10.1155/2020/8253831","url":null,"abstract":"<p><p>The peroxisome proliferator-activated receptor (PPAR<i>γ</i>) 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-<i>γ</i>- (IFN<i>γ</i>-) and interleukin-4- (IL4-) polarized macrophages (M<i>Φ</i>) initiates posttranslational modifications of PPAR<i>γ</i>, 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 M<i>Φ</i>, while the redox status of PPAR<i>γ</i> 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 PPAR<i>γ</i> were highly oxidized, accompanied by phosphorylation of serine 82 in response to LPS/IFN<i>γ</i>, 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 PPAR<i>γ</i>-dependent reporter gene transactivation supporting a functional shift of PPAR<i>γ</i> associated with the M<i>Φ</i> phenotype. These data suggest distinct mechanisms for regulating PPAR<i>γ</i> function based on the redox state of M<i>Φ</i>.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/8253831","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38185675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The PPAR <i>Ω</i> Pocket: Renewed Opportunities for Drug Development.","authors":"Åsmund Kaupang, Trond Vidar Hansen","doi":"10.1155/2020/9657380","DOIUrl":"10.1155/2020/9657380","url":null,"abstract":"<p><p>The past decade of PPAR<i>γ</i> research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPAR<i>γ</i> ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPAR<i>γ</i> ligands, capable of isolating central therapeutic effects of PPAR<i>γ</i> modulation, while displaying markedly lower toxicities than previous generations of PPAR<i>γ</i> 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 PPAR<i>α</i> and PPAR<i>β/δ</i>. 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 <i>Ω</i> pockets of PPAR<i>α</i> and PPAR<i>β/δ</i>. 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 PPAR<i>α</i> and PPAR<i>β/δ</i>. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38185630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPARG Could Work as a Valid Therapeutic Strategy for the Treatment of Lung Squamous Cell Carcinoma.","authors":"Shunbin Shi,&nbsp;Guiping Yu,&nbsp;Bin Huang,&nbsp;Yedong Mi,&nbsp;Yan Kang,&nbsp;Julia Pia Simon","doi":"10.1155/2020/2510951","DOIUrl":"https://doi.org/10.1155/2020/2510951","url":null,"abstract":"<p><p>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, <i>p</i> 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.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2020-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/2510951","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38072978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Literature-Based Knowledge Database and Expression Data to Explore Molecular Pathways Connecting PPARG and Myocardial Infarction.","authors":"Rongyuan Cao,&nbsp;Yan Dong,&nbsp;Kamil Can Kural","doi":"10.1155/2020/1892375","DOIUrl":"https://doi.org/10.1155/2020/1892375","url":null,"abstract":"<p><p>Peroxisome proliferator-activated receptor <i>γ</i> (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; <i>p</i> < 1.84<i>e</i> - 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 (<i>p</i> < 0.05), and inhibit two MI-upregulated markers (RELA and MYD88), which showed increased expression levels in MI cases (<i>p</i> = 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.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2020-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/1892375","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38072977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of Hepatocyte-Specific PPAR<i>γ</i> Expression Ameliorates Early Events of Steatohepatitis in Mice Fed the Methionine and Choline-Deficient Diet.","authors":"Jose Cordoba-Chacon","doi":"10.1155/2020/9735083","DOIUrl":"https://doi.org/10.1155/2020/9735083","url":null,"abstract":"<p><p>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 (PPAR<i>γ</i>, <i>Pparg</i>) and the fatty acid translocase (CD36, <i>Cd36</i>) 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 PPAR<i>γ</i> and CD36 expression to the development of early events induced by the MCD diet. Specifically, mice with adult-onset, hepatocyte-specific PPAR<i>γ</i> knockout with and without hepatocyte CD36 overexpression were fed a MCD diet for three weeks. Hepatocyte PPAR<i>γ</i> 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 PPAR<i>γ</i> and CD36. The expression of PPAR<i>γ</i> and CD36 in hepatocytes may be relevant in the regulation of some features of NAFLD and steatohepatitis.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2020-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/9735083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37937500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPAR-Gamma Agonist Pioglitazone Reduced CD68+ but Not CD163+ Macrophage Dermal Infiltration in Obese Psoriatic Patients.","authors":"Ya O Yemchenko, V I Shynkevych, K Ye Ishcheikin, I P Kaidashev","doi":"10.1155/2020/4548012","DOIUrl":"10.1155/2020/4548012","url":null,"abstract":"<p><strong>Background: </strong>Macrophages are of great importance in the development of obesity and psoriasis. Signaling via PPAR-<i>γ</i> in certain macrophage populations is associated with M2-like features and anti-inflammatory profile. In this research, we evaluated the anti-inflammatory action of pioglitazone by the immunohistochemical study of M1 and M2 macrophages in psoriasis-affected skin in obese patients.</p><p><strong>Methods: </strong>We used immunohistochemistry to characterize CD68+ and CD163+ macrophages and pathomorphological description of skin biopsy, obtained from 6 obese psoriatic patients before and after treatment with 15, 30, and 45 mg pioglitazone, once a day during 6 months. Two patients with conventional therapy and without pioglitazone served as control.</p><p><strong>Results: </strong>Generally, CD163+ cell quantities in psoriasis-affected skin significantly dominated over CD68+ before and after all treatment regiments. Among patients who received pioglitazone, some of them clearly responded to treatment from lowest to highest doses by decreasing CD68+ cells. In the group with 30 mg pioglitazone regiment, we detected a significant reduction of CD68+ cells in dermal infiltrates: CI 95% (16-32) before versus CI 95% (2-7) after treatment. Pioglitazone dose escalation led to certain normalization of skin morphology.</p><p><strong>Conclusion: </strong>The immunohistochemical study allows us to show the anti-inflammatory effect of pioglitazone in psoriatic obese patients, which can be mediated by reducing the number of СD68+ macrophages, but not СD163+ macrophages, in the affected dermis.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2020-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37937499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}