Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study.
Acute liver failure (ALF) results in alterations of energy metabolites and of glucose-derived amino acid neurotransmitters in brain. However, the dynamics of changes in glucose metabolism remain unclear. The present study was undertaken using (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopy to determine the rates of incorporation of glucose into amino acids and lactate via cell-specific pathways in relation to the severity of encephalopathy and brain edema in rats with ALF because of hepatic devascularization. Early (precoma) stages of encephalopathy were accompanied by significant 2- to 4.5-fold (P <.001) increases of total brain glutamine and lactate concentrations. More severe (coma) stages of encephalopathy and brain edema led to a further significant increase in brain lactate but no such increase in glutamine. Furthermore, (13)C isotopomer analysis showed a selective increase of de novo synthesis of lactate from [1-(13)C]glucose resulting in 2.5-fold increased fractional (13)C enrichments in lactate at coma stages. [2-(13)C]glutamine, synthesized through the astrocytic enzyme pyruvate carboxylase, increased 10-fold at precoma stages but showed no further increase at coma stages of encephalopathy. (13)C-label incorporation into [4-(13)C]glutamate, synthesized mainly through neuronal pyruvate dehydrogenase, was selectively reduced at coma stages, whereas brain GABA synthesis was unchanged at all time points. In conclusion, increased brain lactate synthesis and impaired glucose oxidative pathways rather than intracellular glutamine accumulation are the major cause of brain edema in ALF. Future NMR spectroscopic studies using stable isotopes and real-time measurements of metabolic rates could be valuable in the elucidation of the cerebral metabolic consequences of ALF in humans.
Zwingmann
Claudia
C
Neuroscience Research Unit, CHUM Hôpital Saint-Luc, Montreal, Quebec, Canada.
Chatauret
Nicolas
N
Leibfritz
Dieter
D
Butterworth
Roger F
RF
D000596:Amino Acids / Q000378:metabolism; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001769:Blood / Q000378:metabolism; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001929:Brain Edema / Q000378:metabolism; D002247:Carbon Isotopes; D005947:Glucose / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000503:physiopathology; D019344:Lactic Acid / Q000096:biosynthesis*; D017114:Liver Failure, Acute / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D011522:Protons; D011766:Pyruvate Carboxylase / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index
D000596:Amino Acids; D002247:Carbon Isotopes; D011522:Protons; D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D000641:Ammonia; D011766:Pyruvate Carboxylase; D005947:Glucose