Albumin AFP Gene Family Regulation in Fetal and Adult Liver

The liver is a complex organ that must coordinately express numerous proteins to facilitate proper development and maintain normal physiological homeostasis. In the adult liver, appropriate gene expression, including zonal gene expression, must be maintained during normal conditions, when hepatocytes are generally quiescent, and during disease, when some hepatocytes may be damaged and others may be proliferating. Zonal gene expression is a particularly unique phenomenon in which certain liver enzymes are expressed in pericentral hepatocytes whereas other enzymes are expressed in periportal hepatocytes. . This compartmentalization of function, or “liver zonation”, enables the liver to perform multiple, and sometimes opposing, metabolic pathways in distinct hepatocyte subpopulations. Our ongoing studies zonal control of gene expression, based on our work with the alpha-fetoprotein (AFP) gene will help elucidate aspects of liver gene expression during development and disease. In particular, we will use AFP enhancer 3 (E3) as a model of zonal regulation. Two aims are proposed. In the first aim, we will analyze the TCF site in AFP E3 to determine how the â-catenin signaling pathway controls genes in pericentral hepatocytes. In the second aim, we will analyze the Nuclear Receptor (NR) site in E3 to understand how NRs control genes in pericentral hepatocytes. Many genes important for cholesterol control, glucose homeostasis, and detoxification of ammonia and environmental toxins are expressed in pericentral hepatocytes. Our studies will provide a better understanding of zonal control and lead to insight into diseases in which this mode of regulation is altered.