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FK614, a novel peroxisome proliferator-activated receptor gamma modulator, induces differential transactivation through a unique ligand-specific interaction with transcriptional coactivators.

Abstract：

:Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcriptional factor implicated in regulating adipogenesis, glucose homeostasis, and in mediating the action of the insulin sensitizing anti-diabetic thiazolidinedione (TZD) compounds. [3-(2,4-Dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3-H-benzimidazole-5-carboxamide] (FK614) is a structurally novel PPARgamma agonist that demonstrates potent anti-diabetic activity in vivo. Herein, we describe that FK614 is a selective PPARgamma ligand with specific transactivation properties that are dependent upon the context of coactivators. FK614 dissociates the corepressors NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors) from PPARgamma as effectively as rosiglitazone and pioglitazone, but can also differentially induce a ligand specific interaction of PPARgamma with coactivators. The amount of CBP (CREB-binding protein) and SRC-1 (steroid receptor coactivator-1) recruited by FK614 was less than that induced by rosiglitazone and pioglitazone, but FK614 caused similar PGC-1alpha (PPARgamma coactivator-1alpha) recruitment as these compounds. As a consequence of these ligand-specific differences in the strength of ligand-type specific interactions of PPARgamma and coactivators, FK614 functions as a partial or full agonist for transcriptional activation depending upon the amount of specific coactivators in cells following overexpression. In conclusion, FK614 is a novel, non-TZD type, and selective PPARgamma modulator whose pharmacological properties are distinct from rosiglitazone and pioglitazone.

journal_name

J Pharmacol Sci

journal_title

Journal of pharmacological sciences

authors

Fujimura T,Sakuma H,Konishi S,Oe T,Hosogai N,Kimura C,Aramori I,Mutoh S

doi

10.1254/jphs.fp0050578

subject

Has Abstract

pub_date

2005-12-01 00:00:00

pages

342-52

issue

eissn

1347-8613

issn

1347-8648

pii

JST.JSTAGE/jphs/FP0050578

journal_volume

pub_type

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FK614, a novel peroxisome proliferator-activated receptor gamma modulator, induces differential transactivation through a unique ligand-specific interaction with transcriptional coactivators.