Fetal survival depends upon continued organ function and growth in a relatively low glucose environment. Adaptation to low fetal circulating glucose levels is of particular importance for the liver. Because the fetal liver is not exposed intermittently to glucose-enriched portal blood during cycles of feeding and fasting as in postnatal life, glucose must be transported into the fetal hepatocyte in the presence of relatively low concentrations of both glucose and insulin. Glucose is the major energy source for cellular metabolism and protein production by the hepatocyte in utero. Glucose availability permits appropriate synthesis of structural and regulatory glycoproteins and glycolipids. In addition, neonatal survival in the interval between loss of the umbilical energy supply at delivery and commencement of feeding depends upon efficient glucose transport as the first component of the glycogen storage cascade by the fetal hepatocyte. We hypothesize that the remarkable glucose transport capacity of the fetal hepatocyte is both intrinsic and enhanced by availability of specific hormones and substrates. We will study the cultured human fetal hepatocyte and compare it with the rat fetal hepatocyte and human and rat adult hepatocyte in culture in order to understand one aspect of the energy storage capacity of human fetal liver, that of glucose transport. The special characteristics of the fetal hepatocyte and its milieu include intrinsic or induced upregulation of glucose transport and phosphorylation, limited circulating glucose supply, high levels of substrates such as lactate and glutamine and a specialized endocrine/paracrine milieu. We have demonstrated increased glucose transport and glucose transporters (GLUT1, GLUT2) in rat fetal hepatocytes, and evidence for transcriptional and post-transcriptional regulation of these transporters. Moreover, we cave described medium glucose-induced down-regulation of GLUT1 mRNA in adult rat and human hepatocytes, lesser regulation of GLUT1 in fetal rat hepatocytes, and no medium glucose regulation of GLUT1 in human fetal hepatocytes. We hypothesize that this metabolic control mechanism is missing or diminished in fetal hepatocytes because of increased intracellular glucose even at low ambient glucose. We will use immunohistochemistry to confirm the ontogeny of the hepatic glucose transporters in fetal human liver. We will quantitate glucose transport/transporters in isolated cultured fetal human hepatocytes and compare with cultured human adult and rat fetal and adult hepatocytes in order to develop information of direct relevance to human fetal physiology. We will determine the metabolic/hormonal controls and signal transduction pathways for glucose transport/'glucose transporters in fetal adult human hepatocytes. Increased understanding of the energy needs and energy storage mechanisms of the human fetus will contribute to our ability to sustain the immature fetus in utero and ex utero. Moreover, an understanding of the metabolism/metabolic maturation of human fetal liver will enhance our ability to take advantage of the potential of the human fetal liver as a source of hepatocytes for treatment of human disease.
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