EXPERIMENTAL-EVIDENCE THAT THE PHYSIOLOGICAL POSITION OF THE LIVER WITHIN THE CIRCULATION IS NOT A MAJOR DETERMINANT OF ZONATION OF GENE-EXPRESSION

Many enzymes are distributed heterogeneously within the liver lobule. The factors that play a determining role in the establishment and main tenance of these heterogeneous expression patterns have not yet been i dentified. To investigate whether the composition of the afferent hepa tic blood plays a crucial role in the maintenance of the heterogeneity of gene expression of the parenchymal cells within the liver lobule, we changed the source of the afferent hepatic blood by microsurgical t echniques. Three different groups of experimental animals were studied : rats with livers that are perfused with portal blood only (ligation of the hepatic artery), with caval blood only (portocaval transpositio n and ligation of the hepatic artery) and arterial blood only (portoca val shunt, arterialization of the distal end of the portal vein and li gation of the hepatic artery). To study differences in gene expression patterns, we chose enzymes that have a heterogeneous expression patte rn within the liver lobule: the periportally located enzymes carbamoyl phosphate synthase, succinate dehydrogenase, phosphoenolpyruvate carbo xykinase and the pericentrally located enzymes glutamine synthase, glu tamate dehydrogenase and NADPH-cytochrome P-450 reductase. To eliminat e the potential interference of the long half-lives of some of these p roteins on the interpretation of the results, we also studied the dist ribution of the mRNAs of carbamoylphosphate synthase, glutamine syntha se, glutamate dehydrogenase and phosphoenolpyruvate carboxykinase. The animals were studied 2 wk after the operations. On the basis of their changes in body weight the animals were in steady state for at least a week. The patterns of gene expression of the enzymes studied did not change, regardless of the source of the altered afferent hepatic bloo d. The changes in gene expression that were observed in animals that d id not regain their preoperative weight were shown to be caused by a l imited intake of food. This study demonstrates that the physiological position of the liver within the circulation (i.e., between the gastro intestinal tract and the systemic circulation) is not as critical as i s often stated and is certainly not essential for the maintenance of l iver cell heterogeneity. The data suggest that the direction of the bl oodstream (i.e., the existence of an upstream and a downstream compart ment) is a major determinant of zonation of gene expression.