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 alpha (ERR alpha) is an orphan member of the superfamily of nuclear hormone receptors. ERR alpha was initially iso lated based on its sequence homology to the estrogen receptor hut is n ot activated br classic estrogens. To identify possible physiologic fu nctions for this orphan receptor, we cloned the mouse ERR alpha cDNA a nd used It to characterize the expression of ERR alpha transcripts and to identify potential ERR alpha target genes. RNA in situ hybridizati on studies detect ERR alpha transcripts in am organ-specific manner th rough mid- to late embryonic development, with persistent high-level e xpression in brown adipose tissue and intestinal mucosa, In the adult mouse, ERR alpha is most highly expressed in kidney, heart, and brown adipocytes, tissues which preferentially metabolize fatty acids, Bindi ng site selection experiments show that ERR alpha preferentially binds to an ERR alpha response element (ERRE) containing a single consensus half-site, TNAAGGTCA. An ERRE is present in the 5'-flanking region or the gene encoding medium-chain acyl coenzyme A dehydrogenase (MCAD), a key enzyme involved in the mitochondrial beta-oxidation of fat. The MCAD nuclear receptor response element 1 (NRRE-1) interacts in vitro w ith ERR alpha expressed in COS-7 cells, Supershift experiments show th at endogenous ERR alpha present in nuclear extracts obtained from a br own fat tumor cell line (HIB) interacts with NRRE-1. In the absence of its putative ligand, ERR alpha does not activate the MCAD promoter in transient transfection studies; however, a VP16-ERR alpha chimera act ivates natural and synthetic promoters containing NRRE-1. Hn addition, ERR alpha efficiently represses retinoic acid induction mediated by N RRE-1. These results demonstrate that ERR alpha fan control the expres sion of MCAD through the! NRRE-1 and thus may play an important role i n regulating cellular energy balance in vivo.