*Transcriptional Regulation by ERR and Its Role in NAFLD Pathogenesis DOI: http://dx.doi.org/10.5772/intechopen.109089*

PGCs are originally identified as transcriptional coactivators of PPARγ for adaptive thermogenesis in response to cold induction [58]. All three members of the PGC family (PGC-1α, PGC-1β and PRC) of coactivators play roles in mitochondrial biogenesis by regulating the expression of overlapping genes. Unlike the p160 family of coactivators, PGC-1 family of coactivators does not possess histone acetyltransferase activities. Instead, they provide docking sites for histone acetyltransferases including SRC-1 as well as CBP/p300 [63]. PGC-1α responds to different stimuli to induce mitochondrial biogenesis via binding to ERRs as well as others nuclear receptors such as PPARγ and nuclear respiratory factors (NRF). PGC-1 s also have the capacity to bind other transcriptional factor including the forkhead and the yin-yang transcriptional factors among others [6]. Thus, the activity of these transcription factors including ERRs are coordinately coregulated through their competition and coordination in binding to PGC-1. In addition, the binding of PGC-1α to ERRs and other nuclear factors is regulated by Prox1, a homeobox protein that is tethered with ERRs and other nuclear factors to participate in their transcriptional activity [44].

PGC-1 s are subject themselves to post-translational regulation, and these regulations play important roles in their response to different stimuli. In general, PGC-1α responds to the different stimuli and is regulated by cell signaling pathways to control mitochondrial biogenesis and function. Notably, AMP activated kinase (AMPK) phosphorylates PGC-1α on Thr177 and Ser 538 and increases its transcriptional activity [64]. On the other hand, PGC-1α phosphorylation by AKT or S6K integrates nutrient signals to suppress its gluconeogenesis and activity towards fatty acid oxidation [65, 66]. PGC-1α also cross-talks with the sirtuin family of protein deacetylases to regulate metabolism. PGC-1α is activated by SIRT1-mediated deacetylation when cells sense changes of NAD+/NADH ratios [67]. In addition, PGC-1α is also methylated and ubiquitinated to meet different cellular energy demands [68].
