Differential effects of interleukin-1 and tumor necrosis factor on ketogenesis.
To determine the role of cytokines in mediating the decrease in ketones associated with infection, we studied the effect of endotoxin (LPS), interleukin-1 (IL-1), and tumor necrosis factor (TNF) on serum and hepatic ketone body levels (KB), serum free fatty acids (FFA), and hepatic malonyl-CoA levels. LPS decreased serum and hepatic KB in C57Bl/6 (LPS sensitive) mice, whereas it had little effect in C3H/HeJ (LPS resistant) mice, whose macrophages lack the ability to produce IL-1 and TNF in response to LPS, suggesting that IL-1 and TNF may mediate this effect. IL-1 and TNF decreased serum KB in both strains of mice. As seen with LPS, IL-1 decreased hepatic KB, whereas TNF had no such effect. LPS, IL-1, and TNF increased hepatic malonyl-CoA levels. TNF acutely raised serum FFA, whereas LPS and IL-1 did not. Postulating that the TNF-induced increase in FFA overrides the inhibitory effect of malonyl-CoA on fatty acid oxidation and ketogenesis, we used R-2-phenylisopropyladenosine to block TNF-induced lipolysis and demonstrated that in the absence of increased fatty acid flux, TNF inhibits KB formation. As seen with LPS, IL-1, but not TNF, decreased KB in the fasting state. These data suggest that IL-1 and TNF may mediate the antiketogenic effect of infection and that IL-1 has properties closest to that of LPS.
Memon
R A
RA
Department of Medicine, University of California, San Francisco 94143.
Feingold
K R
KR
Moser
A H
AH
Doerrler
W
W
Adi
S
S
Dinarello
C A
CA
Grunfeld
C
C
D000818:Animals; D004351:Drug Resistance / Q000235:genetics; D004731:Endotoxins / Q000494:pharmacology; D004926:Escherichia coli; D005230:Fatty Acids, Nonesterified / Q000097:blood; D007375:Interleukin-1 / Q000494:pharmacology*; D007657:Ketone Bodies / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004731:Endotoxins; D005230:Fatty Acids, Nonesterified; D007375:Interleukin-1; D007657:Ketone Bodies; D014409:Tumor Necrosis Factor-alpha