Project 2 - Project Summary The primary goal of this project is to elucidate the roles of the nuclear receptors PPARα and FXR, and the coregulators SRC-1 and SRC-2, in the overall control of energy balance in the liver. PPARα is activated in the fasted state, promoting fatty acid oxidation and gluconeogenesis. FXR is activated in the fed state and represses gluconeogenesis. Transcriptional functions of PPARα and FXR are mediated by the SRC family of coactivators, and the members of this Program Project team have shown that SRC-1 and SRC-2 are also central regulators of liver energy balance. SRC-2 promotes hepatic fed state functions, including glucose uptake and lipid absorption, and SRC-2 activity is inhibited in the fasted state. In contrast, SRC-1 is induced by fasting and is essential for activation of gluconeogenesis in the fasted state. We have recently shown that PPARα and FXR coordinately regulate another fundamental nutrient response in the liver, autophagy, via mutually antagonistic effects of induction and repression. Our preliminary results identify the hepatic secretome as another, quite unexpected potential target for complementary control of liver energy balance. Secretion is a very energy intensive function of the liver, and we have evidence that FXR activates the hepatic secretome, while PPARα represses it. Based on these results, our overall hypothesis is that PPARα, in concert with SRC-1, and FXR, in concert with SRC-2, regulate broad pathways of energy utilization and production in the liver to maintain energy balance. We propose 3 aims to critically test this hypothesis and explore the mechanistic basis for these effects. 1. Complete the genome wide cistromic, transcriptomic, proteomic and metabolomic profiling of the roles of PPARα and FXR in the fed and fasted liver. 2. Define the role of SRC-1, SRC-2 and NCoR in the opposing effects of PPARα and FXR in vivo. 3. Define the structural and functional basis for the conversion of FXR/RXR heterodimers from ligand dependent transcriptional activators on IR-1 sites to ligand dependent transcriptional repressors on DR-1 sites, and define the coregulators associated with both.