The liver in general and hepatocytes in particular maintain an awesome array of function—synthesis, catabolism, intermediary metabolism, and detoxification. Recent work has enlarged our knowledge of the factors that permit this range of function to be expressed, and in particular the complex inter-relations of cellular and non-cellular elements in the liver that contribute to this. The functions expressed by the liver obviously vary over time. For example, growth and regeneration are associated with a functional repertoire that differs from that of mature adult liver, as in most tissues proliferation is associated with reduced expression of normal differentiated function and expression, generally short-lived, of cell cycle and other replication associated genes.1 Disease alters function, although there is some support for the “intact hepatocyte” hypothesis suggesting that in chronic disease the surviving hepatocytes continue to express a relatively normal functional array.2In acute disease, however, there are many changes in function such as the upregulation of acute phase protein production as well as the initiation of replication to regenerate liver mass.

Understanding the conditions necessary for a normal hepatocyte to express its full functional repertoire is important as science strives to recreate normality in a diseased liver. That understanding is also fundamental to attempts to establish fully functional cultures of liver cells, whether for experimental studies or with the aim of creating a bio-artificial liver. This article highlights three main areas relevant to maintaining expression of normal differentiated hepatic function: the multiplicity of cell types present, the relation between cells and non-cellular elements, particularly extracellular matrix (ECM), and intracellular events that modulate specific gene expression.