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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.

Hepatic steatosis is a consequence of both obesity and ethanol use. Nonalcoholic steatosis (NASH) resemble alcoholic steatosis and steatohepatitis. Both exhibit increased hepatocellular triglycerides(TG), reflecting an increase in long chain fatty acids (LCFA). LCFA enter cells by both facilitated transport and passive diffusion. A driving force for both is the plasma unbound LCFA concentration ([LCFAu]). In both obese rodents and obese patients, adipocyte LCFA uptake via both facilitated transport and diffusion is increased. However, the LCFA uptake Vmax in hepatocytes is not increased in obese animals. Nevertheless, total LCFA uptake in obese rodents is increased ~3-fold, reflecting increased plasma LCFA concentrations. With advancing obesity, resistance to the antilipolytic effects of insulin results in increased lipolysis within the omental fat depot, a consequent further rise in portal venous LCFA, and an even greater rise in portal [LCFAu]. This causes a further increase in hepatocellular LCFA uptake, increased intracellular generation of reactive oxygen species (ROS), and transition from simple steatosis to NASH. By contrast, in rodent hepatocytes and in human hepatoma cell lines, ethanol up-regulates the LCFA uptake Vmax. Consequently, although plasma LCFA are unaltered, hepatocellular LCFA uptake in ethanol-fed rats is also increased~3-fold, leading to increased ROS generation and evolution of alcoholic hepatitis. Thus, while increased hepatic LCFA uptake contributes to the pathogenesis of both NASH and alcoholic hepatitis,the underlying mechanisms differ. Recognizing these mechanistic differences is important in developing strategies for both prevention and treatment of these conditions.

Leptin treatment of ob/ob mice leads to weight loss appreciably greater than that in pair-fed mice. To test whether this "extra" weight loss is mediated by leptin-induced alterations in nutrient partitioning, the effects in ob/ob mice of subcutaneous leptin infusion (500 ng/h for 0.5 vs. normal C57BL/6J controls). Adipocyte mRNA levels for plasma membrane fatty acid binding protein and fatty acid translocase, putative fatty acid transporters that are up-regulated three- to fourfold in adipocytes from ob/ob mice, had also normalized by d 21. The initial changes in V(max) preceded decreases in food intake and body weight by at least 24 h. In pair-fed mice, insulin levels, V(max) and body weight all declined more slowly than in leptin-treated mice, and all remained significantly elevated compared with normal values at d 21. The data suggest that insulin up-regulates and leptin down-regulates adipocyte fatty acid uptake, leading to alterations in fatty acid partitioning that affect adiposity.