ERRalpha: a metabolic function for the oldest orphan

Abstract

Estrogen receptor related receptor (ERR)alpha was one of the first identified (1988) orphan nuclear receptors. Many of the orphan receptors identified after ERRalpha were deorphanized in a timely manner and appreciated as key transcriptional regulators of metabolic pathways. ERRalpha, however, remains an orphan. Nevertheless, recent studies have defined regulatory mechanisms and transcriptional targets of ERRalpha, allowing this receptor to join ranks with other nuclear receptors that control metabolism. Notably, mice lacking ERRalpha show defects when challenged with stressors that require a 'shift of gears' in energy metabolism, such as exposure to cold, cardiac overload or infection. These findings establish the importance of ERRalpha for adaptive energy metabolism, and suggest that strategies targeting ERRalpha may be useful in fighting metabolic diseases.

Figure 1

ERRα is regulated by protein-protein interactions with coregulators. The ability of ERRα to affect gene expression is controlled by its association with specific coregulators, such as the coactivators PGC-1α and PGC-1β and the corepressor RIP140. Consequently, ERRα activity is regulated by the tissue- and physiologic state-specific signals that regulate levels and activity of PGC-1α/β and RIP140. For example, ERRα is a positive regulator of the TCA cycle gene IDH3A in brown adipose tissue, which expresses high levels of PGC-1α/β, but a negative regulator of the OxPhos gene SDHB in white adipocytes, which express high levels of RIP140 [44,54]. Gene-specific factors, such as the type of ERRE sequence and the proteins binding in the vicinity of the ERRE, may also contribute to the ability of ERRα to interact with PGC-1α/β versus RIP140.

Figure 2

ERRα regulates genes important for mitochondrial biogenesis and oxidative metabolism. ERRα acts as a downstream effector of PGC-1α and PGC-1β in the regulation of expression of genes with roles in fatty acid oxidation, the TCA cycle, oxidative stress responses, mitochondrial biogenesis and dynamics, and oxidative phosphorylation (OxPhos). It acts both directly on genes encoding mitochondrial structural components and enzymes, as well as indirectly by enhancing expression of other transcriptional factors, such as PPARD, NRF1 and NRF2/GABP, that regulate these pathways.

Figure 3

ERRα function in vivo is important for adaptive metabolic responses under conditions of increased energetic demand. Mice lacking ERRα show compromised responses to stresses imposed by exposure to cold, cardiac overload, and bacterial infection. In all three cases, a decreased capacity for oxidative metabolism leads to reduced fitness [44,46,52]. A role for ERRα in skeletal muscle is supported by findings that ERRα null mice have a reduced capacity for exercise (Villena and Kralli, unpublished data). ERRα may have additional roles in other states, as indicated by the increased expression of the gluconeogenic/glyceroneogenic enzyme PEPCK in livers of fed mice [56].