Dataset Information

Unique Interactome Network Signatures for Peroxisome Proliferator-activated Receptor Gamma (PPAR?) Modulation by Functional Selective Ligands.

ABSTRACT: The nuclear receptor PPAR? regulates adipogenesis and plays a central role in lipid and glucose homeostasis, and is the molecular target of the glitazones (TZDs), therapeutics used to treat insulin resistance and type-2 diabetes (T2D). Although the TZDs, which are PPAR? agonists, demonstrated robust clinical efficacy in T2D, their use has been hampered by an array of untoward side effects. Paradoxically, partial agonists (e.g. MRL24), antagonists (e.g. SR1664), and inverse agonists (e.g. SR10171 and SR2595), possess similar insulin-sensitizing efficacy as the TZDs in obese diabetic mice. Given the unique pharmacology of these modulators, we sought to identify the components of the PPAR? transcriptional complex that is regulated by these ligands. To achieve this, we employed subcellular fractionation of adipocytes combined with either trapping of the receptor complex on biotinylated DNA oligonucleotide, or classical immunoprecipitation. Tandem mass spectrometry analysis revealed unique, partially overlapping, compound- and subcellular compartment-specific complexes. Components of these interactomes are putative coregulators of PPAR?. Interestingly, complexes isolated in the cytosol contain sets of proteins involve in cellular assembly and extracellular matrix. Furthermore, the interactome observed for cytosolic non-DNA bound receptor was distinct from that observed from nuclear chromatin associated PPAR?, suggesting cellular compartment-specific roles for this receptor.

SUBMITTER: Lam VQ

PROVIDER: S-EPMC5724174 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Unique Interactome Network Signatures for Peroxisome Proliferator-activated Receptor Gamma (PPARγ) Modulation by Functional Selective Ligands.

Lam Vinh Q VQ Zheng Jie J Griffin Patrick R PR

Molecular & cellular proteomics : MCP 20170929 12

The nuclear receptor PPARγ regulates adipogenesis and plays a central role in lipid and glucose homeostasis, and is the molecular target of the glitazones (TZDs), therapeutics used to treat insulin resistance and type-2 diabetes (T2D). Although the TZDs, which are PPARγ agonists, demonstrated robust clinical efficacy in T2D, their use has been hampered by an array of untoward side effects. Paradoxically, partial agonists (<i>e.g.</i> MRL24), antagonists (<i>e.g.</i> SR1664), and inverse agonists ...[more]

PMID: 28972081

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Project description:Ascites (serous fluid accumulation in the abdominal cavity) has been observed worldwide in fast growing broilers. Pulmonary vascular remodeling is an important pathological feature of broiler ascites syndrome. Peroxisome proliferators-activated receptor gamma (PPARγ) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) are expressed in pulmonary vascular endothelial cells and vascular smooth muscle cells (VSMC) where they participate in the regulation of normal pulmonary vascular function. The objective of the present study was to investigate the effects of omega-3 fatty acids (found in fish oil) and pioglitazone (PIO) as natural and synthetic PPARγ ligands supplementation on PPARγ and PGC-1α expression in the prevention of pulmonary arterial hypertension (PAH) syndrome in broiler chickens. The experiment was conducted with 4 treatment groups: 1) negative control, normal temperature conditions with basal diet; 2) positive control, low-temperature conditions with basal diet; 3) positive control + 10 mg PIO/kg of weight/d and 4) positive control + 1% FO. Each treatment had 5 replicates. Ascites heart index (RV/TV) was significantly (P < 0.05) reduced in chickens receiving FO (0.20) and PIO (0.21) compared to the positive control group (0.26). The addition of PIO in broilers under cold-induced ascites significantly increased the expression of PPARγ (9.44) and PGC-1α (5.81) genes in lung tissue compared to the negative control group (1.03, P < 0.05). Proliferative indexes of VSMC in pulmonary arteries such as PMT, PIT, and percentage wall thickness were significantly elevated in positive control group, indicating that pulmonary vascular remodeling occurred following VSMC proliferation in ascites. The vessel internal diameter was increased in FO and PIO groups. Based on these results, activation and expression of PPARγ and PGC-1α genes as a critical regulator of pulmonary artery smooth muscle cell using ligands, especially PIO, can be effective in reducing the incidence of PAH in broiler chickens.

Dataset Information

Unique Interactome Network Signatures for Peroxisome Proliferator-activated Receptor Gamma (PPAR?) Modulation by Functional Selective Ligands.

Publications

Unique Interactome Network Signatures for Peroxisome Proliferator-activated Receptor Gamma (PPARγ) Modulation by Functional Selective Ligands.

Similar Datasets

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