Estrogen-Related Receptor α Directs Peroxisome Proliferator-Activated Receptor α Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle

Abstract

Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERR␣ have not been well defined. To identify ERR␣-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERR␣. ERR␣ upregulated a subset of PGC-1␣ target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C 2 C 12 myotubes, and cardiac and skeletal muscle of ERR␣ ؊/؊ mice. Consistent with the gene expression results, ERR␣ increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERR␣ are known targets for the nuclear receptor PPAR␣, and therefore, the interaction between these regulatory pathways was explored. ERR␣ activated PPAR␣ gene expression via direct binding of ERR␣ to the PPAR␣ gene promoter. Furthermore, in fibroblasts null for PPAR␣ and ERR␣, the ability of ERR␣ to activate several PPAR␣ targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1␣ was also shown to activate ERR␣ gene expression. We conclude that ERR␣ serves as a critical nodal point in the regulatory circuitry downstream of PGC-1␣ to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.The essential role of nuclear receptors in regulating various cellular metabolic pathways is becoming increasingly evident. In recent years, various nuclear receptors that do not respond to classical endocrine ligands, including peroxisome proliferator-activated receptors (PPARs), liver X receptors, farnesoid X receptors, and retinoid X receptors, have been shown to be activated by low-affinity diet-derived ligands (6,11,26,44). Activation of these receptors by metabolite ligands such as fatty acids, oxysterols, and bile acids elicits downstream transcriptional regulation of pathways involved in synthesis and catabolism of these ligands. The remaining receptors, designated orphan receptors because endogenous ligands have not been identified, comprise the largest subcategory of nuclear receptors. It is likely that orphan receptors serve additional roles in regulating intermediary metabolism. Linking orphan receptors to target genes is an important goal in the field of nuclear receptor biology. Target gene profiling will also provide insights for determining what metabolites serve as endogenous ligands for these receptors and, in turn, for developing pharmacologic interventions designed to regulate cellular metabolism.One group of orphan receptors recently identified as candidate regulators of cellular metabolism are the estrogen-related recepto...

Orphan nuclear receptor estrogen-related receptor-β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer

“…Cumulative evidences indicate that another ERR subtype, ERRa, plays significant roles in energy metabolism and mitochondrial biogenesis in certain target cells and tissues via direct regulation of genes involved in fatty acid oxidation, ERRb suppresses prostate cancer cell growth S Yu et al glucose metabolism, oxidative phosphorylation and mitochondrial fusion Huss et al, 2004;Schreiber et al, 2004;Wende et al, 2005;Soriano et al, 2006;Villena et al, 2007). Moreover, ectopic ERRa expression can promote lipid accumulation in primary cardiac myocytes (Huss et al, 2004), whereas its loss of function reduces body fat in ERRa-knockout mouse (Luo et al, 2003). In a recent expression profiling study of all 49 NRs in mouse tissues, ERRb is shown to be widely and rhythmically expressed in many organ systems, suggesting that ERRb together with other NRs are important in maintaining global basal metabolism under circadian control Yang et al, 2006).…”

A Role for the Transcriptional Coactivator PGC-1α in Muscle Refueling

“…Northern blot hybridizations with random-primed 32 P-labeled cDNA probes were performed using QuikHyb (Stratagene). Real-time quantitative reverse transcription-PCR (RT-PCR) was performed as previously described (37) and results were normalized to the expression of 36B4. Mouse-specific primers used for RNA analysis may be found in supplemental materials Table S1.…”

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

“…ERR␣ is ubiquitous among tissues of the developing embryo and adult (20 -22) and regulates an assortment of genes and physiological processes (23)(24)(25)(26). Like the ERs, ERR␣ binds to EREs but is capable of also binding an estrogen-related response element (ERRE) unique to the ERRs (27)(28)(29) in monomer or dimer form (30).…”