Primary fetal hepatocytes derived from Zucker rats with expected fa gene frequencies of 0.0 and 0.75 have been established and can be used to detect early effects of the fa gene on hepatocellular metabolism. Paired incubation experiments demonstrate that protein synthesis in 0.75 fa gene cultures is significantly less than in 0.0 fa gene cultures under basal conditions. Insulin stimulates protein synthesis in 0.0 fa gene cultures but has no effect on 0.75 fa gene cultures. Cycloheximide inhibits protein synthesis in both types of culture. NH4Cl inhibits protein synthesis in 0.0 but not in 0.75 fa gene cultures. These data suggest that fetal hepatocytes bearing the fa gene have in vitro a generally sluggish anabolic capacity and a blunted capacity to respond to insulin compared to fetal hepatocytes without the fa gene. These diminished capacities may be expression of a genetic error in lysosomal function.