We have developed an in vitro rat hepatocyte model in which cytokines inhibit fatty acid oxidation. Cytokine administration resulted in decreased fatty acid oxidation, ketone body production and acetyl CoA/CoA ratios. The inhibitory effects of TNF on fatty acid oxidation were enhanced by either IL-1 or IL-6. TNF (20 U/ml) + IL-6 (30 ng/ml) produced maximal inhibition, whereas IL-1 enhanced inhibition at submaximal TNF concentrations. The key to our model is that substrate input into the tricarboxylic acid cycle in the form of either alanine or pyruvate was required for cytokine mediated inhibition of fatty acid oxidation. Alanine or pyruvate may serve as a source for increased production of malonyl CoA, a potent inhibitor of fatty acid oxidation. We hypothesize that cytokines cause an inappropriate switch from fatty acid oxidation to fatty acid synthesis which has serious consequences for energy levels in the liver and can lead to end organ failure.