Disease relevance of Esrra

• However, ERRalpha knockout mice have reduced fat mass and are resistant to diet-induced obesity [1].
• Here we show that ERRalpha-/- mice are viable, fertile and display no gross anatomical alterations, with the exception of reduced body weight and peripheral fat deposits [2].
• Detection of estrogen receptor-like high affinity components by exposure of cytosols from mouse Leydig cell tumor or male rat liver to chaotropic salts [3].
• These results demonstrate that the nuclear receptor ERRalpha is required for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure [4].

High impact information on Esrra

• Mechanistically, RIP140 was found to require the nuclear receptor ERRalpha to regulate hexose uptake and mitochondrial proteins SDHB and CoxVb, although it likely acts through other nuclear receptors as well [5].
• Our findings demonstrate that ERRalpha is a key regulator of mitochondrial biogenesis and oxidative metabolism, and essential for adaptive thermogenesis [6].
• Rather, we show that ERRalpha is needed for the high levels of mitochondrial biogenesis and oxidative capacity characteristic of brown adipose tissue (BAT), and thus for providing the energy necessary for thermogenesis [6].
• Here, we show that mice lacking ERRalpha are unable to maintain body temperature when exposed to cold [6].
• The discovery of potent and selective ERRalpha modulators and their effect on PGC-1alpha signaling provides mechanistic insight into gene regulation by PGC-1alpha [7].

Biological context of Esrra

• Consistent with the gene expression results, ERRalpha increased myocyte lipid accumulation and fatty acid oxidation rates [8].
• We have used interspecific backcross analysis to map the murine Estrra locus to chromosome 19 and Estrrb to mouse chromosome 12 [9].
• PGC-1beta down-regulation is associated with reduced ERRalpha activity and MCAD expression in skeletal muscle of senescence-accelerated mice [10].
• In particular, ERRalpha induces a high energy expenditure in the presence of the coactivator PGC-1alpha [1].
• Our findings suggest that ERRalpha has opposing effects on genes important for mitochondrial oxidative capacity and gluconeogenesis [11].

Anatomical context of Esrra

• These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRalpha-/- mice [8].
• To identify ERRalpha-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRalpha [8].
• In support of the physiological role of ERRalpha in this pathway, isolated enterocytes from ERRalpha knockout mice display lower capacity for beta-oxidation [1].
• ERRalpha is expressed in epithelial cells of the small intestine, and because the intestine is the first step in the energy chain, we investigated whether ERRalpha plays a function in dietary energy handling [1].
• At the cellular level, transcriptional activation driven by the PPARalpha/RXRalpha complex was counteracted by the expression of ERRalpha in HeLa cells [12].

Associations of Esrra with chemical compounds

• The different functions of ERRalpha in the regulation of these pathways suggest that enhancing ERRalpha activity could have beneficial effects on glucose metabolism in diabetic subjects by two distinct mechanisms: increasing mitochondrial oxidative capacity in peripheral tissues and liver, and suppressing hepatic glucose production [11].
• The protein-DNA complexes formed in response to estradiol, however, exhibited a high affinity for the estrogen-responsive element, suggesting the participation of an estrogen-receptor-like molecule in the DNA binding [13].
• Importantly, DNA microarray analysis of gene expression in adipose tissue demonstrates altered regulation of several enzymes involved in lipid, eicosanoid, and steroid synthesis, suggesting that the loss of ERRalpha might interfere with other nuclear receptor signaling pathways [2].

Physical interactions of Esrra

• Gel shift assays demonstrated that the PGC-1alpha-responsive element bound the estrogen-related receptor alpha (ERRalpha), a recently identified component of the PGC-1alpha signaling pathway [14].

Regulatory relationships of Esrra

• ERRalpha upregulated a subset of PGC-1alpha target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration [8].

Other interactions of Esrra

• We conclude that ERRalpha serves as a critical nodal point in the regulatory circuitry downstream of PGC-1alpha to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle [8].
• Many of the genes regulated by ERRalpha are known targets for the nuclear receptor PPARalpha, and therefore, the interaction between these regulatory pathways was explored [8].
• We report here that the regulatory sequences of the PEPCK gene harbor a functional ERRalpha binding site [11].
• Mutations of the putative core elements have shown that these three sites are differentially involved in ERRalpha and PPARalpha/RXRalpha binding [12].
• ERRgamma distribution was clearly distinguished from that described for ERRalpha, for ERRbeta, and for estrogen receptors (ER) pointing at functional differences between ERRgamma and these receptors [15].

Analytical, diagnostic and therapeutic context of Esrra

• Chromatin immunoprecipitation assays confirmed that PGC-1alpha and ERRalpha occupied the mPDK4 promoter in C(2)C(12) myotubes [14].
• Using real-time PCR analyses we found that ERRgamma, like the ERRalpha and PGC-1alpha is induced in mouse liver during fasting [16].

References