INHIBITION OF HEPATIC KETOGENESIS BY TUMOR-NECROSIS-FACTOR-ALPHA IN RATS

Tumor necrosis factor-alpha (TNF-alpha) stimulates hepatic lipogenesis. Therefore, it could play a role in the control of ketogenesis. To test this hypothesis, we measured simultaneously free fatty acids (FFA; [1-C-13]palmitate) and ketone body (KB; [3,4-C-13(2)]acetoacetate) kinetics, before and after intraperitoneal injection of saline or TNF-alpha, in postabsorptive rats or rats starved for 24 h. In both groups of rats, TNF-alpha injection did not modify insulinemia and induced a moderate increase of FFA concentrations and appearance rates (P < 0.05). Despite increased FFA availability, ketogenesis was impaired after TNF-alpha injection, as shown by lower KB concentrations and appearance rates; this effect was more important in postabsorptive than in starved rats. The percentage of FFA flux used for ketogenesis was decreased by TNF-alpha in the postabsorptive group (P < 0.05) and starved (P < 0.05) rats. In both groups, maximal liver acetyl-coenzyme A carboxylase activity and estimated phosphorylation state were not modified by TNF-alpha injection, but hepatic concentrations of citrate were increased (P < 0.05). This increased citrate level could be related to a mobilization of glucose stored as glycogen since liver glycogen was decreased by TNF-alpha injection (P < 0.05). In conclusion, TNF-alpha injection in rats decreased hepatic ketogenesis. This action could be related to an increased mobilization and utilization of carbohydrate stores.