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

Cytokines play an important role in the lipid disturbances commonly associa ted with sepsis. Ketogenesis is inhibited during sepsis, and tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) have been suggested to m ediate 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 in duction of nitric oxide (NO) synthesis, using rat hepatocyte monolayers. He patocytes were incubated for 6 h, with either alpha -ketoisocaproate (KIC) (1 mM) or oleic acid (0.5 mM) in the presence or absence of TNF alpha (25 m ug/L) and IL-6 (15 mug/L). In some experiments, cells were incubated with N O synthase (NOS) inhibitors. The ketone body (beta -hydroxybutyrate and ace toacetate) production and nitrite production were measured in the incubatio n medium. Our results indicated no involvement of nitric oxide in the inhib itory action of cytokines on ketogenesis. Secondly, we showed that cyclohex imide (10(-4) M) did not counteract the cytokine-mediated ketogenesis decre ase; hence, the effects of cytokines on ketogenesis are not protein synthes is-dependent. The cytokine-mediated inhibition of ketogenesis is therefore unrelated to either NO production or protein synthesis. (C) 2001 Harcourt P ublishers Ltd.