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

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

Vinh Q Lam, Jie Zheng, Patrick R Griffin

Mol Cell Proteomics. 2017 Dec;16(12):2098-2110.

PMID: 28972081

Abstract:

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 (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 PPARγ 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 PPARγ. 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 PPARγ, suggesting cellular compartment-specific roles for this receptor.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1415252617	SR2595		1415252-61-7	Price
IAR4246435	PPARγ Modulator, SR1664			Price

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