The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene.

Estrogen-related receptor a (ERRa) is an orphan member of the superfamily of nuclear hormone receptors. ERRa was initially isolated based on its sequence homology to the estrogen receptor but is not activated by classic estrogens. To identify possible physiologic functions for this orphan receptor, we cloned the mouse ERRa cDNA and used it to characterize the expression of ERRa transcripts and to identify potential ERRa target genes. RNA in situ hybridization studies detect ERRa transcripts in an organ-specific manner through mid- to late embryonic development, with persistent high-level expression in brown adipose tissue and intestinal mucosa. In the adult mouse, ERRa is most highly expressed in kidney, heart, and brown adipocytes, tissues which preferentially metabolize fatty acids. Binding site selection experiments show that ERRa preferentially binds to an ERRa response element (ERRE) containing a single consensus half-site, TNAAGGTCA. An ERRE is present in the 5*-flanking region of the gene encoding medium-chain acyl coenzyme A dehydrogenase (MCAD), a key enzyme involved in the mitochondrial b-oxidation of fat. The MCAD nuclear receptor response element 1 (NRRE-1) interacts in vitro with ERRa expressed in COS-7 cells. Supershift experiments show that endogenous ERRa present in nuclear extracts obtained from a brown fat tumor cell line (HIB) interacts with NRRE-1. In the absence of its putative ligand, ERRa does not activate the MCAD promoter in transient transfection studies; however, a VP16-ERRa chimera activates natural and synthetic promoters containing NRRE-1. In addition, ERRa efficiently represses retinoic acid induction mediated by NRRE-1. These results demonstrate that ERRa can control the expression of MCAD through the NRRE-1 and thus may play an important role in regulating cellular energy balance in vivo. The orphan nuclear receptor estrogen-related receptor a (ERRa) was initially cloned by low-stringency screening of a human kidney library with an estrogen receptor DNA binding domain probe (12). Subsequently, protein micropurification and microsequencing techniques identified ERRa as a repressor of the simian virus 40 major late promoter and implicated the receptor as a key regulator of the early-to-late switch of simian virus 40 gene expression (35). ERRa has also been shown to accentuate estrogen-dependent induction of the complex lactoferrin estrogen response element (ERE), possibly by forming heterodimers with the estrogen receptor (39). While