Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone.
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- H S Camp
- Department of Cell Biology, Warner-Lambert Company, Ann Arbor, Michigan, USA.
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- O Li
- Department of Cell Biology, Warner-Lambert Company, Ann Arbor, Michigan, USA.
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- S C Wise
- Department of Cell Biology, Warner-Lambert Company, Ann Arbor, Michigan, USA.
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- Y H Hong
- Department of Cell Biology, Warner-Lambert Company, Ann Arbor, Michigan, USA.
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- C L Frankowski
- Department of Cell Biology, Warner-Lambert Company, Ann Arbor, Michigan, USA.
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- X Shen
- Department of Cell Biology, Warner-Lambert Company, Ann Arbor, Michigan, USA.
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- R Vanbogelen
- Department of Cell Biology, Warner-Lambert Company, Ann Arbor, Michigan, USA.
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- T Leff
- Department of Cell Biology, Warner-Lambert Company, Ann Arbor, Michigan, USA.
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<jats:p>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.</jats:p>
収録刊行物
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- Diabetes
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Diabetes 49 (4), 539-547, 2000-04-01
American Diabetes Association
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詳細情報 詳細情報について
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- CRID
- 1362262945163111808
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- NII論文ID
- 30026274120
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- NII書誌ID
- AA00628057
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- ISSN
- 1939327X
- 00121797
- http://id.crossref.org/issn/00121797
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