Mechanisms by which tumor necrosis factor stimulates hepatic fatty acid synthesis in vivo.
We have previously shown that bolus intravenous administration of tumor necrosis factor (TNF) to normal rats results in a rapid (within 90 min) stimulation of hepatic fatty acid synthesis, which is sustained for 17 hr. We now demonstrate that TNF stimulates fatty acid synthesis by several mechanisms. Fatty acid synthetase and acetyl-CoA carboxylase (measured after maximal stimulation by citrate) were not higher in livers from animals that had been treated with TNF 90 min before study compared to controls. In contrast, 16 hr after treatment with TNF, fatty acid synthetase was slightly elevated (35%) while acetyl-CoA carboxylase was increased by 58%. To explain the early rise in the hepatic synthesis of fatty acids, we examined the regulation of acetyl-CoA carboxylase. The acute increase in fatty acid synthesis was not due to activation of acetyl-CoA carboxylase by change in its phosphorylation state (as calculated by the ratio of activity in the absence and presence of 2 mM citrate). However, hepatic levels of citrate, an allosteric activator of acetyl-CoA carboxylase, were significantly elevated (51%) within 90 min of TNF treatment. TNF also induces an acute increase (within 90 min) in the plasma levels of free fatty acids. However, hepatic levels of fatty acyl-CoA, which can inhibit acetyl-CoA carboxylase, did not rise 90 min following TNF treatment and were 35% lower than in control livers by 16 hr after TNF. These data suggest that TNF acutely regulates hepatic fatty acid synthesis in vivo by raising hepatic levels of citrate.(ABSTRACT TRUNCATED AT 250 WORDS)
Grunfeld
C
C
Metabolism Section, University of California, San Francisco.
Verdier
J A
JA
Neese
R
R
Moser
A H
AH
Feingold
K R
KR
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002951:Citrates / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000214:Acyl Coenzyme A; D002951:Citrates; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D014409:Tumor Necrosis Factor-alpha; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase