NMR study of 13C‐glucose and 13C‐acetate metabolism in the brain of rats with acute liver failure

Abstract

Acute liver failure (ALF) is characterized by hepatic encephalopathy (HE) with brain edema as the main cause of death. The role of brain energy failure in ALF is still controversial. In the present study we investigated the association of encephalopathy with brain energy metabolism in rats with ALF induced by liver devascularization. Using [1–13]glucose and [2–13C]acetate combined with [1H, 13C]NMR spectroscopy anaerobic and aerobic carbon fluxes were studied in brain extracts from ALF rats. The anaplerotic flux of 13C‐label from glucose was found to be stimulated resulting in a 10‐fold increase of [13C]glutamine (Gln) starting at precoma stages of encephalopathy. In contrast, de novo synthesis of alanine and lactate increased to 320 and 210% in precoma, followed by a further elevation at coma stages to 615 and 425% of sham‐operated control values. Using [2–13C]acetate, the higher 13C‐enrichment of C‐2 in Gln, glutamate (Glu) and the corresponding C‐4 in GABA compared to C‐3 of either compound suggests cleavage of [2–13C]citrate and formation of [3–13C]oxaloacetate, which enters the glial TCA cycle. On the other hand, decreased synthesis of [4–13C]Glu and [2–13C]GABA was observed. This may result from decreased neuronal oxidative metabolism, since the ratio of [4–13C]Glu/[2–13C]GABA is unchanged and increased [2–13C]Glu and corresponding [4–13C]GABA suggests a stimulated flux of astrocytic label to neurons. Impaired neuronal energy metabolism and selective stimulation of lactate synthesis may contribute to the pathogenesis of HE in ALF.Acknowledgements: Funded by CIHR Canada.