Hepatic Encephalopathy Is A Disorder Of Astrocyte Function Resulting In A N E U R O P S Y C H I At R I C Syndrome

Hepatic encephalopathy is observed in patients with severe liver failure. The disease can be in one of two forms: an acute form, called fulminant hepatic failure, and (2) a chronic form, portosystemic encephalopathy (Plum and Hindfeld, 1976). The neuropsychiatric symptoms of fulminant hepatic failure are delirium, coma, and seizures associated with acute toxic or viral hepatic failure. Patients having portosystemic encephalopathy may present personality changes, episodic confusion, or stupor, and, in the most severe cases, coma. The current view on the pathophysiology of hepatic encephalopathy is that, owing to liver failure, "toxic" substances that affect brain function accumulate in the circulation (Norenberg et al., 1992). One of the substances thought to be responsible for the neuropsychiatric "toxicity" is ammonia. The neuropathological findings are rather striking: astrocytes are the brain cells that appear principally affected. In the acute form, astrocyte swelling is prominent and likely to be the cause of the observed acute brain edema. In portosystemic encephalopathy, astrocytes adopt morphological features characteristic of what is defined as an Alzheimer type II astrocyte: in these cells, the nucleus is pale and enlarged, chromatin is mar-

ginated, and a prominent nucleolus is often observed. Lipofuscin deposits may be present, and the amount of the astrocyte-specific protein glial fibrillary acidic protein (see Chapter 2) is decreased. Neurons appear structurally normal. All the foregoing histopathological changes have been reproduced in vitro by acutely or chronically applying ammonium chloride to primary astrocyte cultures. As mentioned earlier, detoxification of ammonium is an ATP-requiring, astrocyte-specific reaction catalyzed by glutamine synthase (see Fig. 3.12). It is therefore not surprising that excess ammonia perturbs energy metabolism; indeed, ammonia stimulates glycolysis (McKhann and Tower, 1961) whereas it inhibits TCA cycle activity (Muntz and Hurwitz, 1951). In addition, ammonia markedly decreases the glycogen content of astrocytes.

In summary, although the precise pathophysiological mechanisms of the neuropsychiatric syndrome in hepatic encephalopathy are still unknown, this clinical condition provides a striking illustration of the fundamental importance of neuron-astrocyte metabolic interactions, because structural and functional alterations apparently restricted to astrocytes result in severe behavioral perturbations.

Neuron Astrocyte Capillary

Neuron Astrocyte Capillary

Brain Leucine Glutamate Flux Astrocyte

FIGURE 3.13 Metabolic intermediates are released by astrocytes to regenerate the glutamate neurotrans-mitter pool in neurons. Glutamine, formed from glutamate in a reaction catalyzed by glutamine synthase (GS), is released by astrocytes and taken up by neurons, which convert it into glutamate under the action of glutaminase. GS is an enzyme selectively localized in astrocytes. This metabolic cycle is referred to as the glutamate-glutamine shuttle. Other, quantitatively less important sources of neuronal glutamate are lactate, alanine, and a-ketoglutarate (a-KG). In astrocytes, glutamate is synthesized de novo from a-KG in a reaction catalyzed by glutamate dehydrogenase (GDH). The carbon backbone of glutamate is exported by astrocytes after conversion into glutamine under the action of GS; the conversion of leucine into a-ketoisocaproate (a-KIC), catalyzed by leucine transaminase (LT), provides the amino group for the synthesis of glutamine from glutamate. The carbons "lost" from the TCA cycle as a-KG is converted into glutamate are replenished by oxaloacetate (OxA) formed from pyruvate in a reaction catalyzed by pyruvate carboxylase (PC), another astrocyte-specific enzyme.

FIGURE 3.13 Metabolic intermediates are released by astrocytes to regenerate the glutamate neurotrans-mitter pool in neurons. Glutamine, formed from glutamate in a reaction catalyzed by glutamine synthase (GS), is released by astrocytes and taken up by neurons, which convert it into glutamate under the action of glutaminase. GS is an enzyme selectively localized in astrocytes. This metabolic cycle is referred to as the glutamate-glutamine shuttle. Other, quantitatively less important sources of neuronal glutamate are lactate, alanine, and a-ketoglutarate (a-KG). In astrocytes, glutamate is synthesized de novo from a-KG in a reaction catalyzed by glutamate dehydrogenase (GDH). The carbon backbone of glutamate is exported by astrocytes after conversion into glutamine under the action of GS; the conversion of leucine into a-ketoisocaproate (a-KIC), catalyzed by leucine transaminase (LT), provides the amino group for the synthesis of glutamine from glutamate. The carbons "lost" from the TCA cycle as a-KG is converted into glutamate are replenished by oxaloacetate (OxA) formed from pyruvate in a reaction catalyzed by pyruvate carboxylase (PC), another astrocyte-specific enzyme.

through the TCA cycle, whereas an exogenous source of nitrogen is necessary (see Fig. 3.13). Convincing evidence, obtained by using 15N-labeled amino acids whose metabolic fate was determined by gas chro-matography and mass spectrometry, indicates that plasma leucine provides the nitrogen required for net glutamate synthesis from a-KG (Yudkoff et al., 1994). Thus, leucine taken up from the circulation at astro-cytic end feet provides the amino group to a-KG in a reaction catalyzed by leucine transaminase (LT), resulting in the formation of glutamate and a-ketoiso-caproate (a-KIC) (see Fig. 3.13). Because this reaction takes place in astrocytes, to replenish the neuronal glutamate pool, the astrocytes export glutamate as glutamine. As noted earlier, the neuronal glutamate pool could also be replenished by lactate released by astrocytes (Hassel and Brathe, 2000).

Finally, another potential pathway described by Arne Schousboe and colleagues exists for the de novo synthesis of glutamate in neurons from substrates provided by astrocytes. With the use of uniformly13C-

labeled compounds in combination with magnetic resonance spectroscopy, astrocytes have been shown to release significant amounts of alanine and a-KG (Westergaard et al., 1995). Both metabolic intermediates are taken up by neurons and can be converted into glutamate and pyruvate in a transamination reaction catalyzed by ALAT (see Fig. 3.12). In this case, as for the glutamate-glutamine shuttle (Fig. 3.13), astro-cytes provide the substrate(s) necessary for glutamate synthesis in neurons.

Note that because a-KG is used for glutamate synthesis, metabolic intermediates downstream of a-KG must be available to maintain a sustained flux through the TCA cycle in astrocytes (see Fig. 3.13). This need is met by the activity of the enzyme pyru-vate carboxylase (PC), which fixes CO2 on pyruvate to generate oxaloacetate, which, by condensing with acetyl-CoA, maintains the flux through the TCA cycle. The carboxylation of pyruvate to oxaloacetate is referred to as an anaplerotic (Greek for "fill up") reaction. Interestingly, like glutamine synthase, PC is selectively localized in astrocytes (Shank et al., 1985). The fact that these two enzymes are localized in astro-cytes in conjunction with the existence of a gluta-mate-glutamine shuttle stresses that astrocytes are essential for maintaining the neuronal glutamate pool used for neurotransmission (see Fig. 3.13).

As noted earlier, the metabolic intermediate a-KG lies at the branching point of glucose and glutamate metabolism (see Fig. 3.12). Any change in the activities of the enzymes that convert a-KG into glutamate or into succinyl-CoA, the next intermediate in the TCA cycle, may affect the efficacy of the TCA cycle or glutamate levels. Interestingly, a marked decrease in the activity of a-ketoglutarate dehydrogenase (a-KGDH), the enzyme catalyzing the conversion of a-KG into succinyl-CoA, was observed in a very large proportion of postmortem brains from patients with Alzheimer's disease (Sheu et al., 1994); in addition, a similar decrease in a-ketoglutarate dehydrogenase activity has been demonstrated in the fibroblasts of patients affected by the familial form of Alzheimer's disease (Sheu et al., 1994).

Summary

A key function of astrocytes is to remove synapti-cally released glutamate. A large proportion of glutamate is transformed to glutamine through an energy-requiring process that also allows for the detoxification of ammonium. Glutamine released by astrocytes regenerates the neuronal glutamate pool. Some of the glutamate is also regenerated from lactate and through the fixation of the amino group of leucine onto the TCA intermediate a-KG, providing another indication of the tight link existing between glutamate and nitrogen metabolism and of the crucial function that astrocytes play in maintaining the neuronal glutamate pool at levels that ensure the maintenance of synaptic transmission.

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