Estrogen-related receptor ␣ (ERR␣) is one of the first orphan nuclear receptors to be identified, yet its physiological functions are still unclear. We show here that ERR␣ is an effector of the transcriptional coactivator PGC-1␣ [peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣], and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERR␣ compromises the ability of PGC-1␣ to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content. A constitutively active form of ERR␣ is sufficient to elicit both responses. ERR␣ binding sites are present in the transcriptional control regions of ERR␣͞PGC-1␣-induced genes and contribute to the transcriptional response to PGC-1␣. The ERR␣-regulated genes described here have been reported to be expressed at reduced levels in humans that are insulin-resistant. Thus, changes in ERR␣ activity could be linked to pathological changes in metabolic disease, such as diabetes. E strogen-related receptor ␣ (ERR␣, NR3B1) was identified on the basis of its sequence similarity to classical, hormoneregulated steroid receptors (1). Based on its ability to recognize similar DNA sequences as the estrogen receptors, ERR␣ has been proposed to modulate estrogen signaling (2-5). ERR␣ may also regulate bone formation, given that it is highly expressed at ossification sites, promotes osteoblast differentiation in vitro, and activates the promoter of the bone matrix protein osteopontin (6, 7). Finally, ERR␣ may regulate fatty acid oxidation. Consistent with this function, ERR␣ is prominently expressed in tissues with high capacity for ␤-oxidation of fatty acids, such as brown fat, heart, muscle, and kidney, and induces the expression of the medium-chain acyl-CoA dehydrogenase gene (8,9).A better understanding of the transcriptional programs and cellular pathways that depend on ERR␣ has been hampered by the lack of tools to regulate the activity of this receptor. Despite the high similarity between ERR␣ and other ligand-dependent nuclear receptors, it is not clear whether ERR␣ activity is regulated by small lipophilic ligands. Compounds that inhibit ERR␣-dependent transcription, such as toxaphene, chlordane, and diethylstilbestrol, have been described (10, 11). However, these compounds are not specific enough for ERR␣ to facilitate studies of its cellular function. Recently, we demonstrated that the transcriptional coactivator peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) regulates ERR␣ function (12). PGC-1␣ induces the expression of ERR␣ and interacts physically with ERR␣, enabling it to activate transcription (12, 13). These findings suggest that PGC-1␣ can be used as a protein ''ligand'' to regulate ERR␣-dependent transcription and study ERR␣ function.PGC-1␣ has been identified as a tissue-specific coactivator of nuclear receptors (14-16). The expression of PGC-1␣ is most prominent in tissues with high energy demands, similar to the ex...

Nuclear receptors constitute a large family of ligand-modulated transcription factors that mediate cellular responses to small lipophilic molecules, including steroids, retinoids, fatty acids, and exogenous ligands. Orphan nuclear receptors with no known endogenous ligands have been discovered to regulate drugmediated induction of cytochromes P450 (CYP), the major drugmetabolizing enzymes. Here, we report the cloning of an orphan nuclear receptor from chicken, termed chicken xenobiotic receptor (CXR), that is closely related to two mammalian xenobioticactivated receptors, the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Expression of CXR is restricted to tissues where drug induction of CYPs predominantly occurs, namely liver, kidney, small intestine, and colon. Furthermore, CXR binds to a previously identified phenobarbital-responsive enhancer unit (PBRU) in the 5-flanking region of the chicken CYP2H1 gene. A variety of drugs, steroids, and chemicals activate CXR in CV-1 monkey cell transactivation assays. The same agents induce PBRU-dependent reporter gene expression and CYP2H1 transcription in a chicken hepatoma cell line. These results provide convincing evidence for a major role of CXR in the regulation of CYP2H1 and add a member to the family of xenobiotic-activated orphan nuclear receptors.

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