Endogenous HNF4 Ligands in Physiology and Disease

描述（由申请人提供）：肝细胞核因子4 （HNF4）是一种必需的肝脏富集转录因子，在肝脏发育和分化中起核心作用。HNF4在Il型糖尿病的一种遗传形式中发生突变，即成熟型糖尿病1 (MODY1)，并调节许多负责肝功能的基因的表达，包括中间代谢-即葡萄糖，脂质，氨基酸，外源和药物代谢-和血液维持以及其他转录因子。通过其在肝脏和其他表达它的组织（胰腺、肾脏、肠道和结肠）中的作用，HNF4除了与糖尿病有关，还与几种人类疾病有关，包括动脉粥样硬化、血友病、肝炎和可能的癌症。HNF4也是核受体超家族中最保守的成员之一，但h的配体尚未确定。在本研究中，我们采用了一种新的方法来鉴定一种内源性膳食化合物，该化合物结合在哺乳动物细胞和小鼠肝脏中表达的HNF4的配体结合口袋中。在本次R21的两个具体目标中，我们提出：

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.