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A novel non-agonist peroxisome proliferator-activated receptor ? (PPAR?) ligand UHC1 blocks PPAR? phosphorylation by cyclin-dependent kinase 5 (CDK5) and improves insulin sensitivity.

ABSTRACT: Thiazolidinedione class of anti-diabetic drugs which are known as peroxisome proliferator-activated receptor ? (PPAR?) ligands have been used to treat metabolic disorders, but thiazolidinediones can also cause several severe side effects, including congestive heart failure, fluid retention, and weight gain. In this study, we describe a novel synthetic PPAR? ligand UNIST HYUNDAI Compound 1 (UHC1) that binds tightly to PPAR? without the classical agonism and which blocks cyclin-dependent kinase 5 (CDK5)-mediated PPAR? phosphorylation. We modified the non-agonist PPAR? ligand SR1664 chemically to improve its solubility and then developed a novel PPAR? ligand, UHC1. According to our docking simulation, UHC1 occupied the ligand-binding site of PPAR? with a higher docking score than SR1664. In addition, UHC1 more potently blocked CDK5-mediated PPAR? phosphorylation at Ser-273. Surprisingly, UHC1 treatment effectively ameliorated the inflammatory response both in vitro and in high-fat diet-fed mice. Furthermore, UHC1 treatment dramatically improved insulin sensitivity in high-fat diet-fed mice without causing fluid retention and weight gain. Taken together, compared with SR1664, UHC1 exhibited greater beneficial effects on glucose and lipid metabolism by blocking CDK5-mediated PPAR? phosphorylation, and these data indicate that UHC1 could be a novel therapeutic agent for use in type 2 diabetes and related metabolic disorders.

SUBMITTER: Choi SS

PROVIDER: S-EPMC4176243 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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A novel non-agonist peroxisome proliferator-activated receptor γ (PPARγ) ligand UHC1 blocks PPARγ phosphorylation by cyclin-dependent kinase 5 (CDK5) and improves insulin sensitivity.

Choi Sun-Sil SS Kim Eun Sun ES Koh Minseob M Lee Soo-Jin SJ Lim Donghyun D Yang Yong Ryoul YR Jang Hyun-Jun HJ Seo Kyung-Ah KA Min Sang-Hyun SH Lee In Hee IH Park Seung Bum SB Suh Pann-Ghill PG Choi Jang Hyun JH

The Journal of biological chemistry 20140806 38

Thiazolidinedione class of anti-diabetic drugs which are known as peroxisome proliferator-activated receptor γ (PPARγ) ligands have been used to treat metabolic disorders, but thiazolidinediones can also cause several severe side effects, including congestive heart failure, fluid retention, and weight gain. In this study, we describe a novel synthetic PPARγ ligand UNIST HYUNDAI Compound 1 (UHC1) that binds tightly to PPARγ without the classical agonism and which blocks cyclin-dependent kinase 5 ...[more]

PMID: 25100724

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Project description:BackgroundHumans are exposed to a complex mixture of environmental chemicals that impact bone and metabolic health, and traditional exposure assessments struggle to capture these exposure scenarios. Peroxisome proliferator activated receptor-gamma (PPARγ) is an essential regulator of metabolic and bone homeostasis, and its inappropriate activation by environmental chemicals can set the stage for adverse health effects. Here, we present the development of the Serum PPARγ Activity Assay (SPAA), a simple and cost-effective method to measure total ligand activity in small volumes of serum.MethodsFirst, we determined essential components of the bioassay. Cos-7 cells were transfected with combinations of expression vectors for human PPARγ and RXRα, the obligate DNA-binding partner of PPARγ, along with PPRE (DR1)-driven luciferase and control eGFP reporter constructs. Transfected cells were treated with rosiglitazone, a synthetic PPARγ ligand and/or LG100268, a synthetic RXR ligand, to characterize the dose response and determine the simplest and most efficacious format. Following optimization of the bioassay, we assessed the cumulative activation of PPARγ by ligands in serum from mice treated with a PPARγ ligand and commercial human serum samples.ResultsCos-7 cells endogenously express sufficient RXR to support efficacious activation of transfected PPARγ. Co-transfection of an RXR expression vector with the PPARγ expression vector did not increase PPRE transcriptional activity induced by rosiglitazone. Treatment with an RXR ligand marginally increased PPRE transcriptional activity in the presence of transfected PPARγ, and co-treatment with an RXR ligand reduced rosiglitazone-induced PPRE transcriptional activity. Therefore, the final bioassay protocol consists of transfecting Cos-7 cells with a PPARγ expression vector along with the reporter vectors, applying rosiglitazone standards and/or 10 μL of serum, and measuring luminescence and fluorescence after a 24 h incubation. Sera from mice dosed with rosiglitazone induced PPRE transcriptional activity in the SPAA in a dose-dependent and PPARγ-dependent manner. Additionally, human serum from commercial sources induced a range of PPRE transcriptional activities in a PPARγ-dependent manner, demonstrating the ability of the bioassay to detect potentially low levels of ligands.ConclusionsThe SPAA can reliably measure total PPRE transcriptional activity in small volumes of serum. This system provides a sensitive, straightforward assay that can be reproduced in any cell culture laboratory.

Dataset Information

A novel non-agonist peroxisome proliferator-activated receptor ? (PPAR?) ligand UHC1 blocks PPAR? phosphorylation by cyclin-dependent kinase 5 (CDK5) and improves insulin sensitivity.

Publications

A novel non-agonist peroxisome proliferator-activated receptor γ (PPARγ) ligand UHC1 blocks PPARγ phosphorylation by cyclin-dependent kinase 5 (CDK5) and improves insulin sensitivity.

Similar Datasets

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