Albumin AFP Gene Family Regulation in Fetal and Adult Liver

描述（由申请人提供）：肝脏在体内执行许多代谢和稳态功能，包括异种代谢，能量储存/生产，尿素形成，谷氨酰胺合成和胆固醇稳态。虽然某些肝功能（如白蛋白分泌）可以由所有肝细胞完成，但其他功能仅限于一小部分肝细胞，并由细胞在小叶中的位置决定。具体来说，某些酶仅在中心静脉周围的细胞中表达，而其他酶仅在门静脉三联体周围的肝细胞中表达。这种现象被称为位置（或地带性）异质性或代谢地带性。这种功能的区隔化使肝脏能够在不同的肝细胞亚群中执行多种，有时是相反的代谢途径。区域基因调控对正常肝功能至关重要。纬向破坏

DESCRIPTION (provided by applicant): The liver performs numerous metabolic and homeostatic functions in the body, including xenobiotic metabolism, energy storage/production, urea formation, glutamine synthesis and cholesterol homeostasis. While some liver functions (such as albumin secretion) can be carried out by all hepatocytes, other functions are limited to a subset of hepatocytes and determined by cell position within the lobule. Specifically, certain enzymes are expressed only in cells surrounding the central vein whereas others are expressed only in hepatocytes surrounding the portal triads. This phenomenon is called positional (or zonal) heterogeneity or metabolic zonation. This compartmentalization of function enables the liver to perform multiple, and sometimes opposing, metabolic pathways in distinct hepatocyte subpopulations. Zonal gene regulation is essential for normal liver function. Disruption of zonally regulated metabolic processes can alter carbohydrate and lipid metabolism, ammonia detoxification and biliary function. A number of agents (alcohol, drugs and toxins) preferentially damage hepatocytes surrounding the central veins due to restricted expression of P450 enzymes in these cells. Thus, zonal control of gene expression has significant clinical implications. The overall objective of this proposal is to develop a better understanding of zonal gene regulation. Based on our studies on mouse alpha-fetoprotein (AFP) gene regulation, we have developed a model of zonal regulation. Specifically, we have found that AFP enhancer element E3 exhibits highly restricted activity in hepatocytes surrounding the central vein in the adult liver. Building on studies performed by our lab and others, we will investigate the role of a subfamily of orphan nuclear receptors and the Wnt/b-catenin/TCF signaling pathway in the control of E3. These studies utilize a unique set of reagents and transgenic mouse lines developed in our lab. The long-term goal of these studies is to understand the basic mechanisms that govern the zonal regulation of many liver genes which will lead to better treatment of liver disease in humans.