Hepatic gluconeogenesis and Krebs cycle fluxes in a CCl4 model of acute liver failure.
Acute liver failure was induced in rats by CCl4 administration and its effects on the hepatic Krebs cycle and gluconeogenic fluxes were evaluated in situ by 13C NMR isotopomer analysis of hepatic glucose following infusion of [U-13C]propionate. In fed animals, CCl4 injury caused a significant increase in relative gluconeogenic flux from 0.80+/-0.10 to 1.34 +/-0.24 times the flux through citrate synthase (p<0.01). In 24-h fasted animals, CCl4-injury also significantly increased relative gluconeogenic flux from 1.36+/-0.16 to 1.80+/-0.22 times the flux through citrate synthase (p<0.01). Recycling of PEP via pyruvate and oxaloacetate was extensive under all conditions and was not significantly altered by CCl4 injury. CCl4 injury significantly reduced hepatic glucose output by 26% (42.8+/-7.3 vs 58.1+/-2.4 micromol/kg/min, p=0.005), which was attributed to a 26% decrease in absolute gluconeogenic flux from PEP (85.6+/-14.6 vs 116+/-4.8 micromol/kg/min, p<0.01). These changes were accompanied by a 47% reduction in absolute citrate synthase flux (90.6+/-8.0 to 47.6+/-8.0 micromol/kg/min, p<0.005), indicating that oxidative Krebs cycle flux was more susceptible to CCl4 injury. The reduction in absolute fluxes indicate a significant loss of hepatic metabolic capacity, while the significant increases in relative gluconeogenic fluxes suggest a reorganization of metabolic activity towards preserving hepatic glucose output.
Carvalho
Rui A
RA
Department of Biochemistry and Center of Neurosciences, University of Coimbra, Portugal. carvalho@condor.ci.ut.pt
Jones
John G
JG
McGuirk
Chris
C
Sherry
A Dean
AD
Malloy
Craig R
CR
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002247:Carbon Isotopes; D002251:Carbon Tetrachloride; D002952:Citric Acid Cycle; D005215:Fasting; D005943:Gluconeogenesis; D006706:Homeostasis; D008099:Liver / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011422:Propionates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002247:Carbon Isotopes; D011422:Propionates; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C029658:propionic acid