The primary goal of this project is to elucidate the roles of the nuclear receptors PPAR? and FXR, and the coregulatorsSRC-1andSRC-2,intheoverallcontrolofenergybalanceintheliver.PPAR?isactivatedinthe fastedstate,promotingfattyacidoxidationandgluconeogenesis.FXRisactivatedinthefedstateandrepresses gluconeogenesis.TranscriptionalfunctionsofPPAR?andFXRaremediatedbytheSRCfamilyofcoactivators, andthemembersofthisProgramProjectteamhaveshownthatSRC-1andSRC-2arealsocentralregulators 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 PPAR? 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 PPAR? repressesit.Basedontheseresults,ouroverallhypothesisisthatPPAR?,inconcertwithSRC-1,andFXR,in concertwithSRC-2,regulatebroadpathwaysofenergyutilizationandproductioninthelivertomaintainenergy balance.Wepropose3aimstocriticallytestthishypothesisandexplorethemechanisticbasisfortheseeffects. 1. Complete the genome wide cistromic, transcriptomic, proteomic and metabolomic profiling of the roles of PPAR? and FXR in the fed and fasted liver. 2. Define the role of SRC-1, SRC-2 and NCoR in the opposing effectsofPPAR?andFXRinvivo.3.DefinethestructuralandfunctionalbasisfortheconversionofFXR/RXR heterodimersfromliganddependenttranscriptionalactivatorsonIR-1sitestoliganddependenttranscriptional repressorsonDR-1sites,anddefinethecoregulatorsassociatedwithboth.
This proposed project will provide a much more complete understanding of the therapeutic effects of two distinct approved drugs. The nuclear receptor PPAR? is the target of the fibrate drugs that are used to treat elevated serum lipids; FXR is the target of ocaliva, which was recently approved to treat cholestatic liver disease but has also shown beneficial effects in the metabolic syndrome. This project will provide important new insights into the mechanisms of action of fibrates and ocaliva, which will lead to new strategies to augment their beneficial impacts while minimizing potential deleterious effects.