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Anne-M Krogsdam

Publications and source records attributed to Anne-M Krogsdam.

5 recordsLinked to original sources
PubMed2002

Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation.

The nuclear receptor corepressor (NCoR) was isolated as a peroxisome-proliferator-activated receptor (PPAR) delta interacting protein using the yeast two-hybrid system. NCoR interacted strongly with the ligand-binding domain of PPAR delta, whereas interactions with the ligand-binding domains of PPAR gamma and PPAR alpha were significantly weaker. PPAR-NCoR interactions were antagonized by ligands in the two-hybrid system, but were ligand-insensitive in in vitro pull-down assays. Interaction between PPAR delta and NCoR was unaffected by coexpression of retinoid X receptor (RXR) alpha. The PPAR delta-RXR alpha heterodimer bound to an acyl-CoA oxidase (ACO)-type peroxisome-proliferator response element recruited a glutathione S-transferase-NCoR fusion protein in a ligand-independent manner. Contrasting with most other nuclear receptors, PPAR delta was found to interact equally well with interaction domains I and II of NCoR. In transient transfection experiments, NCoR and the related silencing mediator for retinoid and thyroid hormone receptor (SMRT) were shown to exert a marked dose-dependent repression of ligand-induced PPAR delta-mediated transactivation; in addition, transactivation induced by the cAMP-elevating agent forskolin was efficiently reduced to basal levels by NCoR as well as SMRT coexpression. Our results suggest that the transactivation potential of liganded PPAR delta can be fine-tuned by interaction with NCoR and SMRT in a manner determined by the expression levels of corepressors and coactivators.

Animals↗
PubMed2002

Opposing effects of fatty acids and acyl-CoA esters on conformation and cofactor recruitment of peroxisome proliferator-activated receptors.

The peroxisome proliferator-activated receptors (PPARs) bind and are activated by a variety of fatty acids and derivatives thereof. Agonist binding enhances PPAR-mediated transactivation via release of corepressors and recruitment of coactivator complexes. Recently, we and others have reported that acyl-CoA esters act as PPAR antagonists in vitro. Here, we show that the binding of the nonhydrolyzable acyl-CoA analogue, S-hexadecyl-CoA, differentially affected conformation and coactivator recruitment of the individual PPAR subtypes. In protease protection assays, S-hexadecyl CoA increased the sensitivity of PPARalpha and PPARdelta towards chymotrypsin, whereas the action of chymotrypsin on PPARgamma was only marginally affected, suggesting distinct subtype-dependent differences in the effects of S-hexadecyl-CoA on conformation of the PPARs. In keeping with these findings, S-hexadecyl-CoA abrogated ligand-induced recruitment of coactivators to PPARalpha and PPARdelta, whereas coactivator recruitment to PPARgamma was unaffected by S-hexadecyl-CoA.

Acyl Coenzyme A↗