Effects of recombinant monokines on hepatic pyruvate dehydrogenase, pyruvate dehydrogenase kinase, lipogenesis de novo and plasma triacylglycerols. Abolition by prior fasting.
1. The effects of recombinant human tumour necrosis factor alpha (TNF) and murine interleukin-1 alpha (IL-1) on the activation state of the hepatic pyruvate dehydrogenase complex (PDHa), the activity of mitochondrial PDH kinase, hepatic lipogenesis de novo and plasma triacylglycerol (TG) concentrations were studied. 2. Monokine effects depended upon prior nutritional state. In rats fasted for 20 h or 45 h before monokine administration and refeeding (orally or with intravenous glucose), PDHa, TG and hepatic lipogenesis were not increased. In rats fed ad libitum, treatment with TNF plus IL-1 increased the contribution of hepatic lipogenesis to circulating TG to 550% of control values (P = 0.03) and plasma TG concentrations to 159% (P = 0.02), whereas PDHa increased slightly to 120% (P = 0.02) and liver glycogen content fell to 45.8% (P = 0.05) of control values. 3. Intrinsic hepatic PDH kinase activity was not changed by monokine treatment in rats fed ad libitum. 4. The increased lipogenesis de novo showed no correlation (r2 = 0.05, not significant) with hepatic PDHa in individual animals fed ad libitum. 5. In conclusion, these results suggest that monokines increase pyruvate flux through hepatic PDH in vivo in rats fed ad libitum primarily by mechanisms other than covalent modification of PDH. Prior nutritional status exerts a permissive effect for monokine stimulation of PDHa and lipogenesis, consistent with a substrate-mediated action, but the mechanism of this permissive effect remains uncertain.
Blackham
M
M
Department of Nutritional Sciences, University of California, Berkeley 94720.
Cesar
D
D
Park
O J
OJ
Vary
T C
TC
Wu
K
K
Kaempfer
S
S
Shackleton
C H
CH
Hellerstein
M K
MK
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004789:Enzyme Activation; D005215:Fasting / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D015846:Monokines / Q000494:pharmacology*; D009752:Nutritional Status / Q000502:physiology*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects* / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D013395:Sucrose / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D007375:Interleukin-1; D008055:Lipids; D008112:Liver Glycogen; D015846:Monokines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; D011994:Recombinant Proteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D013395:Sucrose; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases