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The anaplerotic flux and ammonia detoxification in hepatic encephalopathy

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Abstract

Metabolic alterations in the brain underly many of the mechanisms leading to acute and chronic Hepatic Encephalopathy (HE). Controversy exists about the role of glutamine accumulation as a causal factor in HE. Glutamine formation contributes to detoxify ammonia, whereby anaplerotic mechanisms in the astrocytes have to be sufficient to replenish Krebs cycle intermediates. The application of ex vivo high-resolution nuclear magnetic resonance (NMR) spectroscopy permits direct measurements of metabolites and different metabolic pathways. Ex vivo 13C-NMR studies in experimental animal models of acute and chronic HE have provided new insights. In an experimental rat model of ALF, 13C isotopomer analysis of glucose metabolism showed that alterations of glucose flux through astrocytic pyruvate carboxylase might be linked to the pathogenesis of ALF as a limited anaplerotic flux in the brain, but not in the muscle, correlates with the development of brain edema. Moreover, 13C-NMR data from a rat model of mild HE demonstrated relative differences in the pathway of glucose through pyruvate carboxylase in thalamus compared to frontal cortex, which might explain the vulnerability of this brain region compared to thalamus. These findings further support that glutamine accumulation might be not the primary cause of neurological symptoms in HE, and show that anaplerotic mechanisms could be essential for ammonia detoxification in HE.

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Acknowledgements

This work was supported by the Canadian Instituts for Health Research (CIHR). C. Zwingmann has received fellowships from the Quebec Ministry of Education and the Deutsche Forschungsgemeinschaft (DFG).

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  1. Neuroscience Research Unit, CHUM Hôpital Saint-Luc, Montreal, Quebec, Canada

    Claudia Zwingmann

  2. Département de médicine, Centre de Recherche, Hôpital Saint-Luc, Université de Montréal, 264, René Lévesque Est, Montréal, Quebec, H2X 1P1, Canada

    Claudia Zwingmann

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Correspondence to Claudia Zwingmann.

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Zwingmann, C. The anaplerotic flux and ammonia detoxification in hepatic encephalopathy. Metab Brain Dis 22, 235–249 (2007). https://doi.org/10.1007/s11011-007-9069-y

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