Differential activation of peroxisome proliferator-activated receptor-γ by troglitazone and rosiglitazone

被引:193
|
作者
Camp, HS
Li, O
Wise, SC
Hong, YH
Frankowski, CL
Shen, XQ
Vanbogelen, R
Leff, T
机构
[1] Warner Lambert Parke Davis, Parke Davis Pharmaceut Res Div, Dept Cell Biol, Ann Arbor, MI 48105 USA
[2] Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI 48109 USA
关键词
D O I
10.2337/diabetes.49.4.539
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The antidiabetic thiazolidinediones, which include troglitazone and rosiglitazone, are ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma and exert their antihyperglycemic effects by regulation of PPAR-gamma-responsive genes. We report here that PPAR-gamma activation by troglitazone depends on the experimental setting. Troglitazone acts as a partial agonist for PPAR-gamma in transfected muscle (C2C12) and kidney (HEK 293T) cells, producing a submaximal transcriptional response (1.8- to 2.5-fold activation) compared with rosiglitazone (7.4- to 13-fold activation). Additionally troglitazone antagonizes rosiglitazone-stimulated PPAR-gamma transcriptional activity. Limited protease digestion of PPAR-gamma suggests conformational differences in the receptor bound to troglitazone versus rosiglitazone. Consistent with this finding, an in vitro coactivator association assay demonstrated that troglitazone-bound PPAR-gamma recruited the transcriptional coactivators p300 and steroid receptor coactivator 1 less efficiently than rosiglitazone-bound receptor. In contrast to these observations, troglitazone behaves as a full agonist of PPAR-gamma in 3T3L1 adipocytes. Two-dimensional protein gel electrophoresis demonstrated that troglitazone and rosiglitazone regulated distinct but overlapping sets of genes in several cell types. Thus, troglitazone may behave as a partial agonist under certain physiological circumstances and as a full agonist in others. These differences could be caused by variations in the amount of specific cofactors, differences in PPAR response elements, or the presence of different isoforms of PPAR-gamma.
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收藏
页码:539 / 547
页数:9
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