Long chain fatty acids (LCFA) enter cells by both facilitated transport and diffusion, the former accounting for > or = 90%. Facilitated LCFA transport is up-regulated in adipocytes from obese rats, mice, and humans. To clarify the role of hepatocellular LCFA uptake in hepatic steatosis (fatty liver), [3H]-oleic acid (OA) uptake was studied in hepatocytes isolated from Zucker fatty(Z) and control(C) and ethanol-fed(E) Wistar rats, and demonstrated both saturable and non-saturable components, each a function of the unbound OA concentration ([OAu]). The uptake Vmax was identical in C and Z animals, but was increased 2.4-fold in E animals (p < 0.01). The non-saturable uptake rate constant did not differ between groups. Plasma LCFAs averaged 600 microM in C and E and 1,200 microM in Z animals. Total LCFA uptake averaged 1.35, 2.78 and 3.54 pmol/sec/50,000 cells in C, Z, and E animals, respectively. A 2-fold uptake increase in Z animals, in which Vmax was unaltered, entirely reflected the increased plasma LCFA concentration, whereas the 2.6-fold increase in E animals, in which plasma LCFA were not increased, resulted from up-regulation of facilitated transport. Thus, while increased hepatic LCFA uptake contributes to pathogenesis of hepatic steatosis in both obesity and excessive ethanol consumption, the mechanisms differ.