The effects of inflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α) on energy metabolism were studied in primary cultured rat hepatocytes. Adenine nucleotide (ATP, ADP, and AMP) content, lactate production, the ketone body ratio (acetoacetate/β-hydroxybutyrate) reflecting the liver mitochondrial redox state (NAD + /NADH), and nitric oxide formation were measured. Insulin increased ATP content in hepatocytes and had a maximal effect after 8-12 h of culture. Both interleukin-1β and interleukin-6, but not tumor necrosis factor-α, significantly inhibited the ATP increase time-and dose-dependently. Interleukin-1β and interleukin-6 also stimulated lactate production. During the same period, interleukin-1β but not interleukin-6 decreased the ketone body ratio. Furthermore, interleukin-1β markedly stimulated nitric oxide formation in hepatocytes, and this increase was blocked by N G -monomethyl-L-arginine (a nitric oxide synthase inhibitor) and by interleukin-1 receptor antagonist. N G -monomethyl-L-arginine reversed inhibition of the ATP increase, decrease in the ketone body ratio, and increase in lactate production, which were induced by interleukin-1β. Interleukin-1 receptor antagonist completely abolished all of the effects induced by interleukin-1β. These results demonstrated that interleukin-1β and interleukin-6 affect the insulin-induced energy metabolism in rat hepatocytes by different mechanisms. Specifically, interleukin-1β inhibits ATP synthesis by causing the mitochondrial dysfunction, a process which may be mediated by nitric oxide.
Kitade, H., Kanemaki, T., Sakitani, K., Inoue, K., Matsui, Y., Kamiya, T., … Okumura, T. (1996). Regulation of energy metabolism by interleukin-1β, but not by interleukin-6, is mediated by nitric oxide in primary cultured rat hepatocytes. Biochimica et Biophysica Acta - Molecular Cell Research, 1311(1), 20–26. https://doi.org/10.1016/0167-4889(95)00188-3