Cytokines inhibit fatty acid oxidation in isolated rat hepatocytes: synergy among TNF, IL-6, and IL-1.
We have developed an in vitro rat hepatocyte model in which cytokines inhibit fatty acid oxidation. Cytokine administration resulted in decreased fatty acid oxidation, ketone body production and acetyl CoA/CoA ratios. The inhibitory effects of TNF on fatty acid oxidation were enhanced by either IL-1 or IL-6. TNF (20 U/ml) + IL-6 (30 ng/ml) produced maximal inhibition, whereas IL-1 enhanced inhibition at submaximal TNF concentrations. The key to our model is that substrate input into the tricarboxylic acid cycle in the form of either alanine or pyruvate was required for cytokine mediated inhibition of fatty acid oxidation. Alanine or pyruvate may serve as a source for increased production of malonyl CoA, a potent inhibitor of fatty acid oxidation. We hypothesize that cytokines cause an inappropriate switch from fatty acid oxidation to fatty acid synthesis which has serious consequences for energy levels in the liver and can lead to end organ failure.
Nachiappan
V
V
Department of Pediatrics, University of Pennsylvania Medical School, Philadelphia 19104, USA.
Curtiss
D
D
Corkey
B E
BE
Kilpatrick
L
L
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000409:Alanine / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002952:Citric Acid Cycle / Q000187:drug effects*; D003864:Depression, Chemical; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D007657:Ketone Bodies / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000378:metabolism; D008954:Models, Biological; D010084:Oxidation-Reduction / Q000187:drug effects; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D005227:Fatty Acids; D007375:Interleukin-1; D015850:Interleukin-6; D007657:Ketone Bodies; D011773:Pyruvates; D014409:Tumor Necrosis Factor-alpha; D008316:Malonyl Coenzyme A; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D000409:Alanine