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Title: Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPAR{gamma} agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPAR{gamma} target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPAR{gamma} ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination of RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPAR{gamma} ligands in the treatment of insulin resistance.

Authors:
; ; ; ; ; ; ; ;  [1];  [2]
  1. (Pitt)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1038618
Resource Type:
Journal Article
Journal Name:
Cell Res.
Additional Journal Information:
Journal Volume: 22; Journal Issue: (4) ; 04, 2012; Journal ID: ISSN 1001-0602
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; FUNCTIONALS; GENES; HOMEOSTASIS; INSULIN; STEROIDS; TARGETS

Citation Formats

Lin, Shengchen, Han, Ying, Shi, Yuzhe, Rong, Hui, Zheng, Songyang, Jin, Shikan, Lin, Shu-Yong, Lin, Sheng-Cai, Li, Yong, and Xiamen). Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist. United States: N. p., 2012. Web. doi:10.1038/cr.2011.162.
Lin, Shengchen, Han, Ying, Shi, Yuzhe, Rong, Hui, Zheng, Songyang, Jin, Shikan, Lin, Shu-Yong, Lin, Sheng-Cai, Li, Yong, & Xiamen). Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist. United States. doi:10.1038/cr.2011.162.
Lin, Shengchen, Han, Ying, Shi, Yuzhe, Rong, Hui, Zheng, Songyang, Jin, Shikan, Lin, Shu-Yong, Lin, Sheng-Cai, Li, Yong, and Xiamen). Thu . "Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist". United States. doi:10.1038/cr.2011.162.
@article{osti_1038618,
title = {Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist},
author = {Lin, Shengchen and Han, Ying and Shi, Yuzhe and Rong, Hui and Zheng, Songyang and Jin, Shikan and Lin, Shu-Yong and Lin, Sheng-Cai and Li, Yong and Xiamen)},
abstractNote = {Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPAR{gamma} agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPAR{gamma} target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPAR{gamma} ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination of RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPAR{gamma} ligands in the treatment of insulin resistance.},
doi = {10.1038/cr.2011.162},
journal = {Cell Res.},
issn = {1001-0602},
number = (4) ; 04, 2012,
volume = 22,
place = {United States},
year = {2012},
month = {6}
}