Endogenous HNF4 Ligands in Physiology and Disease

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DESCRIPTION (provided by applicant): Hepatocyte nuclear factor 4 (HNF4) is an essential liver-enriched transcription factor that plays a central role in liver development and differentiation. HNF4 is mutated in an inherited form of type Il diabetes, Maturity Onset Diabetes of the Young 1 (MODY1), and regulates the expression of many genes responsible for liver function, including those in intermediary metabolism - i.e., glucose, lipid, amino acid, xenobiotic and drug metabolism - and blood maintenance as well as other transcription factors. Through its role in the liver and other tissues where it is also expressed - pancreas, kidney, intestine and colon - HNF4 is linked to several human diseases in addition to diabetes, including atherosclerosis, hemophilia, hepatitis and possibly cancer. HNF4 is also one of the most highly conserved members of the nuclear receptor superfamily and yet a ligand for h has not yet been identified. In this proposal, we use a novel method to identify an endogenous dietary compound that binds in the ligand binding pocket of HNF4 expressed in mammalian cells and mouse liver. In the two specific aims of this R21 we propose to: 1) determine whether the binding of the compound affects HNF4 function; 2) determine the physiological and pathological conditions under which HNF4 binds the compound. Results from these studies will not only enhance significantly our understanding of how HNF4 regulates transcription in the liver, kidney and the GI track but could also impact the use of HNF4 as a drug target for diabetes and possibly other diseases.