TNF-α and IL-6 synergistically inhibit ketogenesis from fatty acids and α-ketoisocaproate in isolated rat hepatocytes
1998
Background: During sepsis, lipid metabolism is shunted toward triacylglycerol synthesis and hepatic
lipogenesis. A decrease in
ketogenesisfrom free fatty acids also is observed, probably mediated by cytokines involved in host response to infection. Whether such an inhibition of
ketogenesisoccurs with other
ketone bodyprecursors such as ketoacids is not known. The aim of this study was to determine the effects of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) on hepatic
ketone bodyproduction from octanoic acid, a
medium-chain fatty acid, and from α-ketoisocaproate (KIC), the ketoanalogue of leucine. Methods: The experiments were conducted in cultured hepatocytes isolated from 24-hour-fasted Sprague-Dawley rats. Hepatocyte monolayers were incubated for 6 hours, with either KIC or octanoic acid (1 mmol/L), in the presence of glucagon and TNF-α (25 μg/L) IL-6 (15 μg/L) and/or IL-6.
Acetoacetate, β-hydroxybutyrate, and free fatty acids were determined in culture medium by enzymatic methods and KIC was measured by high-performance liquid chromatography. Results: KIC and octanoic acid uptake by hepatocytes was 79% and 92%, respectively, over 6 hours, and cytokines had no influence. However, TNF-α and IL-6 caused inhibition of
ketogenesisfrom α-ketoisocaproate (5.6% ± 2.3% and 4.4% ± 3.0%, respectively), and from octanoic acid (7.9% ± 2.9%, 5.7% ± 3.2%, respectively). In addition, when the two cytokines were present together in the culture medium, the inhibition was enhanced (inhibition of
ketogenesisfrom KIC: 14.0% ± 4.8%; from octanoic acid: 11.6% ± 3.4%). Conclusions: In our experimental conditions, cytokines mediate an inhibition of
ketogenesis; this process could be explained by a direct effect of cytokines on metabolic pathways of octanoic acid and KIC aran indirect effect by modification of the mitochondrial redox state.
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