Nitrogen metabolism in liver : structural and functional organization and physiological relevance

The liver was identified early in the fundamental work of Hans Krebs [1,2] as having a particular role in urea and glutamine metabolism. At the acinar level, these pathways are embedded into a sophisticated structural and functional organization with metabolic interactions between different hepatocyte populations. This provided a new insight into the role of the liver in maintaining ammoniat and bicarbonate homeostasis under physiological and pathological conditions. The functional units of the liver are the so-called acini [3,4], which extend from the terminal portal venule along the sinusoids to the terminal hepatic venule. Periportal hepatocytes (near the sinusoidal inflow) can be distinguished from more downstream located perivenous hepatocytes (near the sinusoidal outflow), whereas the borderline between the periportal and the perivenous compartment is not defined in general anatomical terms. The definition used here is a comparative-functional one, and thus will depend on the metabolic pathways under consideration. This is because periportal and perivenous hepatocytes differ in their complement of enzymes and their metabolic functions ('functional hepatocyte heterogeneity' or 'metabolic zonation'). The size of a periportal or perivenous 'metabolic zone' is pathway-specific. Thus, for example, a periportal compartment exhibiting a certain metabolic function can overlap with a perivenous compartment which is characterized by another pathway. Several reviews have appeared on this subject [5-11], and the subacinar localization of various metabolic pathways is summarized in Table 1. This article focuses on the functional significance of liver parenchymal cell heterogeneity in nitrogen metabolism.