Albumin AFP Gene Family Regulation in Fetal and Adult Liver

说明(申请人提供)：肝脏在体内执行多种代谢和稳态功能，包括异物代谢、能量储存/生产、尿素形成、谷氨酰胺合成和胆固醇稳态。虽然有些肝功能(如白蛋白分泌)可以由所有肝细胞执行，但其他功能仅限于部分肝细胞，并由细胞在小叶中的位置决定。具体地说，某些酶只在中央静脉周围的细胞中表达，而其他酶只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)异质性或代谢分带。这种功能划分使肝脏能够在不同的肝细胞亚群中执行多个代谢途径，有时是相反的代谢途径。带状基因调控对正常肝功能是必不可少的。地带性的破坏 调节代谢过程可以改变碳水化合物和脂肪代谢、氨排毒和胆汁功能。许多药物(酒精、药物和毒素)优先损害中央静脉周围的肝细胞，因为这些细胞中P450酶的表达受到限制。因此，基因表达的分区控制具有重要的临床意义。这项建议的总体目标是更好地理解带状基因调控。在我们对小鼠甲胎蛋白(AFP)基因调控研究的基础上，我们建立了一个带状调控模型。具体地说，我们发现AFP增强子元件E3在成人肝脏中央静脉周围的肝细胞中表现出高度受限的活性。在我们实验室和其他实验室进行的研究的基础上，我们将调查 孤儿核受体亚家族与Wnt/b-catenin/Tcf信号通路在E3调控中的作用这些研究利用了我们实验室开发的一套独特的试剂和转基因小鼠品系。这些研究的长期目标是了解控制许多肝脏基因区带调节的基本机制，这将导致更好地治疗人类肝病。

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.