PROJECT SUMMARYThe interrelation between liver disease and kidney function is becoming increasingly researched as hepatic-derived systemic inflammation can have a profound effect on the physiology of the kidney. This is a vital factorto consider with respect to precision medicine as these changes can disrupt the proper metabolism andelimination of the 32% of marketed therapeutics that rely upon renal function for excretion. Among the liverdiseases that affect renal physiology is nonalcoholic fatty liver disease (NAFLD) characterized by a series ofmechanistic events that mediate the transition from simple steatosis to nonalcoholic steatohepatitis (NASH)which include inflammatory events. Our lab has identified NASH-induced phenotypic conversions of several drugmetabolizing enzyme and transport proteins that significantly alter the pharmacokinetic profiles of certain drugsand xenobiotics. Interestingly in a profiling study of various rodent models of NASH we have also identifiedNASH-induced phenoconversion of renal transport proteins a phenomenon that also contributes to alteredpharmacokinetics of xenobiotic substrates in vivo. To date no studies have been published examining humanNASH-related phenoconversion of renal drug transporters and that will be the first item we address in thisapplication. Our central hypothesis is that NASH alters the expression and function of major renal drugtransporters thereby increasing the risk of adverse drug reactions and environmental toxicities inpatients with NASH. Our study design seeks not only to identify phenoconversion of specific renal transportersin NASH but also to pinpoint the associated secretory pathways to better narrow down mechanisms of alteredpharmacokinetics for certain therapeutics and environmental contaminants. Our aims are to: 1) Determine thechanges in expression and localization of renal transporters in human NASH patients 2) Determine thefunctional changes in individual secretion pathways and resulting potential for environmental toxicity in a rodentmodel of NASH and 3) Determine the impact of NASH on GFR and select secretion pathways in human patients.By completing these aims we will be able to identify classes of drugs that present a greater risk of adverse drugevents for NASH patients.