The Orphan Nuclear Receptor Estrogen-Related Receptor α Is a Transcriptional Regulator of the Human Medium-Chain Acyl Coenzyme A Dehydrogenase Gene

Abstract

Estrogen-related receptor ␣ (ERR␣) is an orphan member of the superfamily of nuclear hormone receptors. ERR␣ 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 ERR␣ cDNA and used it to characterize the expression of ERR␣ transcripts and to identify potential ERR␣ target genes. RNA in situ hybridization studies detect ERR␣ 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, ERR␣ is most highly expressed in kidney, heart, and brown adipocytes, tissues which preferentially metabolize fatty acids. Binding site selection experiments show that ERR␣ preferentially binds to an ERR␣ response element ( The orphan nuclear receptor estrogen-related receptor ␣ (ERR␣) 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 ERR␣ 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). ERR␣ 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 ERR␣ displays significant homology to the estrogen receptor, it does not bind estrogens in vitro, nor is its transcriptional activity modulated by estrogens (12, 39). Like many other members of the nuclear receptor superfamily, ERR␣ has no known ligand and is therefore considered an orphan receptor. In the absence of an associated ligand, one approach to uncovering potential physiologic roles for ERR␣ is to identify possible target genes.

Estrogen-Related Receptor α1 Transcriptional Activities Are Regulated in Part via the ErbB2/HER2 Signaling Pathway

“…The lower amount of phospo-labeled ERRa1 observed in the 4D5-treated cells was due to this treatment being inhibitory to cell growth (data not shown). Thus, we confirmed prior reports that ERRa1 is a phosphoprotein (9,38). We also conclude that ERRa1 was phosphorylated in vivo at several sites, with the extent of phosphorylation being cell type dependent and reduced by disruption of the ErbB2 signaling pathway.…”

Estrogen Induces Estrogen-related Receptor α Gene Expression and Chromatin Structural Changes in Estrogen Receptor (ER)-positive and ER-negative Breast Cancer Cells

“…We have demonstrated that E 2 induction of ERR␣ relies on the MAPK signaling pathway as it is susceptible to a MAPK inhibitor. Stimulation of the MAPK pathway by estrogen can lead to the activation of ERR␣ via phosphorylation (22,78). Phosphorylated ERR␣ binds DNA and interacts with co-activators more efficiently.…”

Genetic analysis of the estrogen-related receptor α and studies of association with obesity and type 2 diabetes

“…7 ESRRA is expressed in several tissues, but most abundantly in tissues with a high capacity for b-oxidation, such as skeletal muscle, heart, kidney, liver and adipose tissue. 1,8 The esrra knockout (KO) mouse has reduced body weight, diminished lipogenesis in adipose cells and exhibits resistance to dietinduced obesity, indicating that ERRa may be a potent regulator of energy metabolism in vivo. 9 Specifically, through interaction with the peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a) and the peroxisome proliferator-activated receptor a (PPARa), ERRa has been reported to regulate the medium-chain acyl-CoA dehydrogenase (MCAD), an enzyme involved in the oxidation of fatty acids.…”