A yeast two-hybrid screen using the conserved carboxyl terminus of the nuclear receptor corepressor SMRT as a bait led to the isolation of a novel human gene termed SHARP (SMRT/HDAC1 Associated Repressor Protein). SHARP is a potent transcriptional repressor whose repression domain (RD) interacts directly with SMRT and at least five members of the NuRD complex including HDAC1 and HDAC2. In addition, SHARP binds to the steroid receptor RNA coactivator SRA via an intrinsic RNA binding domain and suppresses SRA-potentiated steroid receptor transcription activity. Accordingly, SHARP has the capacity to modulate both liganded and nonliganded nuclear receptors. Surprisingly, the expression of SHARP is itself steroid inducible, suggesting a simple feedback mechanism for attenuation of the hormonal response. The transcription action of steroids, retinoids, and thyroid hormone and their cognate receptors (NRs) (Mangelsdorf and Evans 1995; are modulated by an extensive set of nuclear receptor cofactors Glass and Rosenfeld 2000;Westin et al. 2000). A great deal of effort has focused on the identification and characterization of the constituents of these complexes to understand the mechanistic basis of the regulated events. The recruitment of coactivator complexes is a critical step in hormone induction, whereas the recruitment of corepressor complexes mediates active repression of unliganded nuclear receptors. SMRT and N-CoR have been identified as nuclear receptor corepressors (Chen and Evans 1995;Horlein et al. 1995;Ordentlich et al. 1999). Various lines of evidence suggest that at least one mechanism underlying the repression activity of SMRT and N-CoR is through their recruitment of a histone deacetylase complex containing mSin3A and HDAC1 (Alland et al. 1997;Hassig et al. 1997;Heinzel et al. 1997;Laherty et al. 1997;Nagy et al. 1997;Zhang et al. 1997). Direct interaction of SMRT with the class II histone deacetylase (HDAC 4-7) independent of Sin3A provides yet another mechanism for SMRT-mediated transcriptional repression (Huang et al. 2000;Kao et al. 2000). Recruitment of histone deacetylase complexes by corepressors has been proposed to cause a local change in the chromatin structure, therefore resulting in transcriptional repression (Knoepfler and Eisenman 1999).A search for cofactors that mediate ligand-dependent transactivation by nuclear receptors led to the identification of coactivators such as CBP/p300, PCAF, and the p160 family members including SRC-1, GRIP1/TIF2, and ACTR/RAC3/p/CIP (Onate et al. 1995;Hong et al. 1996; Kamei et al. 1996;Yao et al. 1996;Chen et al. 1997;Torchia et al. 1997;Blanco et al. 1998). Among these factors, CBP, PCAF, SRC-1, and ACTR have been shown to possess intrinsic histone acetyltransferase activity, consistent with a role for induced histone acetylation in transcriptional activation (Bannister and Kouzarides 1996;Ogryzko et al. 1996;Yang et al. 1996;Chen et al. 1997;Spencer et al. 1997). Targeted deletion of SRC-1 or p/CIP causes partial hormone insensitivity, suggesting a criti...

The three PPAR (peroxisome proliferator-activated receptor) isoforms are critical regulators of lipid homeostasis by controlling the balance between the burning and storage of long chain fatty acids. Whereas PPAR␣ and PPAR␥ have been studied extensively, the function of PPAR␦ remains the most elusive. Intriguingly, in cotransfection experiments, PPAR␦ is a potent inhibitor of ligandinduced transcriptional activity of PPAR␣ and PPAR␥. This inhibition is achieved, in part, by binding of PPAR␦ to a peroxisome proliferator response element and the association of nonliganded PPAR␦ with corepressors SMRT (silencing mediator for retinoid and thyroid hormone receptors), SHARP (SMRT and histone deacetylase-associated repressor protein), and class I histone deacetylases. Stable expression of PPAR␦ inhibits the expression of endogenous PPAR␣ target gene expression in 3T3-PPAR␣ cells, whereas a PPAR␦ mutant that does not interact with the corepressor SMRT loses its ability to repress the induction of PPAR␣ target gene. Similarly, stable expression of PPAR␦ in 3T3-PPAR␥ cells leads to inhibition of PPAR␥ target gene expression and PPAR␥-mediated adipogenesis. Given the widespread expression of PPAR␦ and the restricted pattern for PPAR␣ and PPAR␥, these results suggest a role for PPAR␦ as a gateway receptor whose relative levels of expression can be used to modulate PPAR␣ and PPAR␥ activity.T he PPAR subfamily includes three isoforms (␣, ␥, and ␦) that all bind to the peroxisome proliferator response elements (PPRE) as a heterodimer with retinoid X receptor (RXR), yet exhibit distinct tissue distribution and physiological function. PPAR␣ is highly expressed in the liver and was originally identified as a molecule that mediates the transcriptional effects of drugs that induce peroxisome proliferation in rodents (1). In addition to its activation in response to peroxisome proliferators such as Wy14,643, PPAR␣ is also activated by a variety of medium-and long-chain fatty acids (2) and has been shown to stimulate lipid metabolism by the induction of peroxisomal ␤-oxidation and fatty acid -hydroxylation (3). Mice lacking functional PPAR␣ are incapable of responding to peroxisome proliferators and fail to induce expression of a variety of genes required for the metabolism of fatty acids, including acyl-CoA oxidase (AOX) (4).PPAR␥ is highly enriched in adipose tissue and has been shown to play a central role in activating adipogenesis both in vitro and in vivo (5, 6). It is also expressed at high levels in lipid-accumulating macrophages and plays a role in the development of the atherogenic lesion (7). PPAR␥ has been shown to be activated by 15-deoxy-(12,14)-prostaglandin J2 (15d-PGJ2) or its synthetic analog thiazolidinedione, a novel class of antidiabetic drugs (8, 9). The PPAR␥-null mice are embryonic lethal due in part to disrupted placental function (6). Rescue of the placental defect results in lipid dystrophy and neonatal death (10,11).PPAR␦ (also known as PPAR␤) is widely expressed with relatively higher levels in brain, col...

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