Evidence for a role of insulin in hepatocytic differentiation of human hepatoma BC1 cells.

To examine the effect of insulin on hepatocytic differentiation, we took advantage of the properties of the newly established human hepatoma BC1 cell line to maintain quiescence after confluency and to progressively acquire in culture (3 weeks after confluency) an hepatocytic phenotype, as assessed by expression of specific hepatic genes (Le Jossicet al., 1995). In BC1 cells cultured in the presence of insulin (1 μM: ), expression of albumin and transferrin mRNA and protein occurs earlier than in cells cultured in its absence (1 weekvs 2 weeks). Moreover, at any time considered, the level of the two hepatic markers was higher (2- to 3-fold) in the former than in untreated cells. The beneficial effect of insulin on hepatocytic differentiation of BC1 cells was paralleled by: i) modest increases in insulin receptor (IR) mRNA level and IR binding activity, and ii) a 6-fold increase in sensitivity to insulin for stimulation of glycogenesis. These results provide the first evidence for insulin's ability to exert a positive effect on hepatocytic differentiation. The beneficial effect of insulin probably results both from increased IR expression and binding activity and from alteration at post-receptor levels.