Cytokine-mediated inhibition of ketogenesis is unrelated to nitric oxide or protein synthesis

Cytokines play an important role in the lipid disturbances commonly associated with sepsis. Ketogenesis is inhibited during sepsis, and tumor necrosis factor α (TNF α) and interleukin-6 (IL-6) have been suggested to mediate this impairment, irrespective of the ketogenic substrate (fatty acid or branched chain ketoacid). However, the underlying mechanism of cytokine action is still unknown. First we investigated the possible role of the induction of nitric oxide (NO) synthesis, using rat hepatocyte monolayers. Hepatocytes were incubated for 6 h, with either α -ketoisocaproate (KIC) (1 mM) or oleic acid (0.5 mM) in the presence or absence of TNF α (25 μg/L) and IL-6 (15 μg/L). In some experiments, cells were incubated with NO synthase (NOS) inhibitors. The ketone body (β -hydroxybutyrate and acetoacetate) production and nitrite production were measured in the incubation medium. Our results indicated no involvement of nitric oxide in the inhibitory action of cytokines on ketogenesis. Secondly, we showed that cycloheximide (10−4M) did not counteract the cytokine-mediated ketogenesis decrease; hence, the effects of cytokines on ketogenesis are not protein synthesis-dependent. The cytokine-mediated inhibition of ketogenesis is therefore unrelated to either NO production or protein synthesis.