Airway Remodeling ; physiology ; Animals ; Asthma ; metabolism ; Disease Models, Animal ; PPAR gamma ; biosynthesis ; Rats

Obesity is a leading risk factor for insulin resistance, hypertension, hyperlipidemia, and cardiovascular complications, collectively referred to as metabolic diseases. Given the prevalence of obesity and its associated medical problems, new strategies are required to prevent or treat obesity and obesity-related metabolic effects. Here we summarize contributors of obesity, and molecular mechanisms controlling adipogenesis from studies in mammalian systems. We also discuss the possibilities of using Drosophila as a genetic model system to advance our understanding of players in fat biology.
Animals ; Drosophila/*physiology ; Humans ; Metabolic Syndrome X/*etiology/metabolism/prevention & control ; Obesity/*complications/metabolism/prevention & control ; PPAR gamma/metabolism/physiology

BACKGROUNDMicroRNAs (miRNAs) function as essential posttranscriptional modulators of gene expression, and are involved in a wide range of physiologic and pathologic states, including cancer. Numerous miRNAs are deregulated in hepatocellular carcinoma (HCC). This study aimed to investigate the role of miR-27a in the development of HCC.

METHODSThe expression of MiR-27a was measured by quantitative real-time polymerase chain reaction (qRT-PCR). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to examine changes in the viability of HepG2, Bel-7402, Bel-7404 hepatoma cell lines associated with up-regulation or down-regulation of miR-27a. A dual-luciferase activity assay was used to verify a target gene of miR-27a. Immunohistochemistry, qRT-PCR, Western blotting analysis, and cell cycle and apoptosis flow cytometric assays were used to elucidate the mechanism by which miR-27a modulates liver cancer cell proliferation.

RESULTSThe expression of miR-27a was significantly increased in HCC tissues and HepG2, Bel-7402, Bel-7404 hepatoma cell lines (P < 0.05). We also found that the down-regulation of miR-27a in HepG2 cells dramatically inhibited proliferation, blocked the G1 to S cell cycle transition and induced apoptosis (P < 0.05). In addition, miR-27a directly targeted the 3'- untranslated region of peroxisome proliferator-activated receptor &gamma; (PPAR-&gamma;), and ectopic miR-27a expression suppressed PPAR-&gamma; expression on the mRNA and protein levels. The rosiglitazone-induced overexpression of PPAR-&gamma; attenuated the effect of miR-27a in HCC cells.

CONCLUSIONSOur findings suggested that miRNA-27a promoted HCC cell proliferation by regulating PPAR-&gamma; expression. MiR-27a may provide a potential therapeutic strategy for HCC treatment.

Carcinoma, Hepatocellular ; genetics ; metabolism ; Cell Proliferation ; genetics ; physiology ; Gene Expression Regulation, Neoplastic ; Hep G2 Cells ; Humans ; Liver Neoplasms ; genetics ; metabolism ; MicroRNAs ; genetics ; physiology ; PPAR gamma ; metabolism

Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a nuclear receptor superfamily; members of which play key roles in the control of body metabolism principally by acting on adipose tissue. Ligands of PPARgamma, such as thiazolidinediones, are widely used in the treatment of metabolic syndromes and type 2 diabetes mellitus (T2DM). Although these drugs have potential benefits in the treatment of T2DM, they also cause unwanted side effects. Thus, understanding the molecular mechanisms governing the transcriptional activity of PPARgamma is of prime importance in the development of new selective drugs or drugs with fewer side effects. Recent advancements in molecular biology have made it possible to obtain a deeper understanding of the role of PPARgamma in body homeostasis. The transcriptional activity of PPARgamma is subject to regulation either by interacting proteins or by modification of the protein itself. New interacting partners of PPARgamma with new functions are being unveiled. In addition, post-translational modification by various cellular signals contributes to fine-tuning of the transcriptional activities of PPARgamma. In this review, we will summarize recent advancements in our understanding of the post-translational modifications of, and proteins interacting with, PPARgamma, both of which affect its transcriptional activities in relation to adipogenesis.
Gene Expression Regulation ; Homeostasis ; *Models, Genetic ; PPAR gamma/genetics/metabolism/*physiology ; *Protein Processing, Post-Translational ; Sumoylation ; Transcription Factors/metabolism/physiology ; Ubiquitination

BACKGROUND/AIMS: Saccharomyces boulardii (S. boulardii) has been reported to be beneficial in the treatment of inflammatory bowel disease, however, little is known about its mechanism of action. Peroxisome proliferator- activated receptor-gamma (PPAR-gamma) is recently found to regulate inflammation in intestinal epithelial cells. We hypothesized that the anti-inflammatory effects of S. boulardii are mediated, in part, through PPAR-gamma. To test this hypothesis, we examined the ability of S. boulardii to modulate the expression of PPAR-gamma in human colon cells. METHODS: Effects of S. boulardii on survival and proliferation of HT-29 human colon cells were assessed by MTT and [3H]thymidine incorporation assays. PPAR-gamma expression was assessed by Western blot and RT-PCR. Induction of interleukin-8 (IL-8) expression by tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), or lipopolysaccharide (LPS) was assessed by RT-PCR. RESULTS: S. boulardii did not affect viability and proliferation of HT-29 cells. S. boulardii up-regulated PPAR-gamma expression at both mRNA and protein levels. Pretreatment of HT-29 cells with S. boulardii blocked PPAR-gamma down-regulation by TNF-alpha, IL-1beta, or LPS, whereas it ameliorated IL-8 response to these proinflammatory factors. CONCLUSIONS: S. boulardii stimulates PPAR-gamma expression and reduces response of human colon cells to proinflammatory cytokines.
Cell Proliferation ; Colon/*metabolism ; *Gene Expression ; HT29 Cells ; Humans ; Interleukin-1/metabolism ; Interleukin-8/metabolism ; Lipopolysaccharides/pharmacology ; PPAR gamma/genetics/*metabolism ; Saccharomyces/*physiology

In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.
Animals ; Brain Neoplasms ; metabolism ; therapy ; Dacarbazine ; analogs & derivatives ; pharmacology ; Down-Regulation ; drug effects ; Glioma ; metabolism ; therapy ; Humans ; PPAR gamma ; metabolism ; Temozolomide ; Wnt Signaling Pathway ; drug effects ; physiology

BACKGROUNDPeroxisome proliferator-activated receptor-gamma (PPARgamma) is a kind of ligand-activated transcription factors binding to peroxisome proliferator response element (PPRE), a specific recognition site. It is thought to play a critical role in glucose and lipid metabolism and in inflammation control. The aim of this study was to establish a new cellular model for the quick screening of lipid-lowering drugs, which may be effective as PPAR-gamma ligands on the PPRE-mediated pathway regulatory system.

METHODSTwo plasmids were constructed: pXOE-PPARgamma, in which the human PPARgamma gene was in the downstream of TFIIIA gene promoter, and pLXRN-PPRE-d2EGFP, in which the enhanced green fluorescent protein (EGFP) gene was subcloned into PPRE. The xenopus oocytes were injected with these two plasmids, and consequently treated with prostaglandin E1, pioglitazone, and different kinds of lipid-lowering drugs. After 3 days, the oocytes were observed under a fluorescence microscope. To confirm the drug action,we injected pXOE-PPARgamma plasmid into the oocytes, which then treated with prostaglandin E1 and Hawthorn flavonoids. The mass of expressed lipoprotein lipase (LPL) in the cells was determined by enzyme labeling linked immunosorbent assay (ELISA).

RESULTSThe expression of EGFP was only induced by prostagalandin E1, pioglitazone, Hawthorn flavonoids. A concentration-response relationship was seen between expressed EGFP and Hawthorn flavonoids. The levels of LPL in both Hawthorn flavonoids groups and PPARgamma ligand prostagalandin E1 group injected with pXOE-PPARgamma plasmid increased significantly (< 0.001) compared with controls, and a concentration-response relationship was observed between LPL mass and Hawthorn flavonoids.

CONCLUSIONSIt is possible to establish a PPRE regulatory EGFP reporter system in xenopus oocytes to monitor the activity of PPARgamma ligand. Hawthorn flavonoids can increase the expression of gene downsteam of PPRE by effect on the PPRE pathway regulatory system.

Alprostadil ; pharmacology ; Animals ; Crataegus ; Female ; Hypolipidemic Agents ; pharmacology ; Lipoprotein Lipase ; biosynthesis ; Medicine, Chinese Traditional ; Oocytes ; metabolism ; PPAR gamma ; physiology ; Peroxisome Proliferators ; pharmacology ; Plasmids ; Response Elements ; physiology ; Xenopus

OBJECTIVEPPAR-gamma is associated with the differentiation, apoptosis, proliferation and cytokine secretion of immunologic cells. This study investigated peripheral blood lymphoblastic PPAR-gamma mRNA expression and its correlation with plasma IL-13 contents in children with acute idiopathic thrombocytopenic purpura (ITP).

METHODSFifty-three children with acute ITP who were in line with the standard test between September 2007 and July 2008 were enrolled. Fifty healthy children during the same period were used as the control group. PPAR-gamma mRNA expression in peripheral blood lymphocytes were detected by RT-PCR. Plasma IL-13 contents were detected using ELISA.

RESULTSPPAR-gamma mRNA expression in peripheral blood lymphocytes from acute ITP children were significantly higher than that in the control group (0.78 +/- 0.03 vs 0.52 +/- 0.05; P< 0.05). Plasma IL-13 contents in children with acute ITP were also significantly higher than those in the control group (160.21 +/- 34.26 pg/mL vs 121.42 +/- 12.69 pg/mL; P< 0.05). There was a positive correlation between plasma IL-13 level and lymphoblastic PPAR-gamma mRNA expression in children with ITP (r=0.89, P< 0.05).

CONCLUSIONSPPAR-gamma mRNA expression in peripheral blood lymphocytes increased and were positively correlated with plasma IL-13 contents in children with acute ITP, suggesting that PPAR-gamma and IL-13 might participate in the pathogenesis of acute ITP.

Acute Disease ; Child ; Child, Preschool ; Female ; Humans ; Interleukin-13 ; blood ; physiology ; Lymphocytes ; metabolism ; Male ; PPAR gamma ; genetics ; physiology ; Purpura, Thrombocytopenic, Idiopathic ; etiology ; immunology ; RNA, Messenger ; analysis

OBJECTIVE: To study the protective effect of enhanced peroxisome proliferator activated receptor γ (PPARγ) pathway against apoptosis of long-term cultured primary nerve cells. METHODS: A natural aging model was established in primary rat nerve cells by long-term culture for 22 days. The cells were divided into control group, 0.1, 1.0, 5.0, and 10 μmol/L GW9662 intervention groups, and 0.1, 1.0, 5.0, and 10 μmol/L pioglitazone intervention groups. The cell viability was assessed using MTT assay and the cell morphological changes were observed after the treatments to determine the optimal concentrations of GW9662 and pioglitazone. Double immunofluorescence labeling and flow cytometry were used to observe the changes in the number of viable cells and cell apoptosis following the treatments; immunocytochemical staining was used to assess the changes in the anti-oxidation ability of the treated cells. RESULTS: The optimal concentrations of GW9662 and pioglitazone determined based on the cell viability and morphological changes were both 1 μmol/L. Compared with the control group, GW9662 treatment significantly lowered while pioglitazone significantly increased the total cell number and nerve cell counts ( < 0.05), and nerve cells in the cell cultures maintained a constant ratio at about 80% in all the groups ( > 0.05). GW9662 significantly enhanced while pioglitazone significantly lowered the cell apoptosis rates compared with the control group ( < 0.05). GW9662 obviously lowered SOD activity and GSH content in G group ( < 0.05) and increased MDA content in the cells ( < 0.05), and pioglitazone resulted in reverse changes in SOD, GSH and MDA contents in the cells ( < 0.05). CONCLUSIONS Activation of PPARγ pathway protects long-term cultured primary nerve cells by enhancing cellular anti-oxidant capacity and reducing cell apoptosis, suggesting a potential strategy for anti-aging treatment of the nervous system through intervention of the PPARγ pathway.
Anilides ; administration & dosage ; pharmacology ; Animals ; Apoptosis ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Cellular Senescence ; physiology ; Neurons ; cytology ; PPAR gamma ; metabolism ; Pioglitazone ; administration & dosage ; pharmacology ; Rats

Oxidized LDL (OxLDL), a causal factor in atherosclerosis, induces the expression of heat shock proteins (Hsp) in a variety of cells. In this study, we investigated the role of CD36, an OxLDL receptor, and peroxisome proliferator-activated receptor gamma (PPAR gamma) in OxLDL-induced Hsp70 expression. Overexpression of dominant-negative forms of CD36 or knockdown of CD36 by siRNA transfection increased OxLDL-induced Hsp70 protein expression in human monocytic U937 cells, suggesting that CD36 signaling inhibits Hsp70 expression. Similar results were obtained by the inhibition of PPAR gamma activity or knockdown of PPAR gamma expression. In contrast, overexpression of CD36, which is induced by treatment of MCF-7 cells with troglitazone, decreased Hsp70 protein expression induced by OxLDL. Interestingly, activation of PPAR gamma through a synthetic ligand, ciglitazone or troglitazone, decreased the expression levels of Hsp70 protein in OxLDL-treated U937 cells. However, major changes in Hsp70 mRNA levels were not observed. Cycloheximide studies demonstrate that troglitazone attenuates Hsp70 translation but not Hsp70 protein stability. PPAR gamma siRNA transfection reversed the inhibitory effects of troglitazone on Hsp70 translation. These results suggest that CD36 signaling may inhibit stress- induced gene expression by suppressing translation via activation of PPAR gamma in monocytes. These findings reveal a new molecular basis for the anti-inflammatory effects of PPAR gamma.
Antigens, CD36/*physiology ; Cell Line, Tumor ; Chromans/pharmacology ; Cycloheximide/pharmacology ; HSP70 Heat-Shock Proteins/*biosynthesis ; Humans ; Lipoproteins, LDL/pharmacology/*physiology ; Monocytes/drug effects/metabolism ; PPAR gamma/agonists/antagonists & inhibitors/*physiology ; Protein Synthesis Inhibitors/pharmacology ; Signal Transduction ; Thiazolidinediones/pharmacology