Regulation Of Ketogenesis And Cell Organization

Insofar as the liver is considered to be the prototype organ responsible for ketone body production, hepatocyte cells provide the paradigm for the molecular regulation of ketogenesis (3). Thus, because it contains the complete enzyme complement necessary for the FAOK pathway, an individual hepatocyte performs the complete FAOK pathway. Moreover, as noted earlier, the proposed HMGCS2-mediated dialog between the nucleus and the mitochondrion that regulates cellular acetyl-CoA concentrations can occur in individual hepatocytes.

The structural and metabolic organization of brain cells provides an intriguing contrast to that of hepatocytes (Fig. 4A). The functional cell unit of electrical impulse transmission in brain is the neuron (Fig. 4A), and it can be seen that in contrast to hepa-tocytes, the locations of the neuronal cell body nucleus and, for example, the mitochondria of the neuronal presynaptic knob may be separated by the considerable length of the neuronal axon. This potentially rules out an intracellular HMGCS2-mediated dialog between the nucleus and the mitochondria of an individual neuron, as described for individual hepatocytes. Moreover, the studies of our group and others suggest that neurons may not express the PPARa and HMGCS2 genes to any significant degree, thus potentially ruling out their capacity to perform ketogenesis (24-27). In contrast, astrocytes may be similar to hepatocytes insofar as they actively express the PPARa and HMGCS2 genes (23-25). Furthermore, astrocytes are juxtaposed between neurons and the blood environment (Fig. 4A) and are therefore ideally situated to integrate detection of diet-induced changes in blood metabolites with a response that results in appropriate

Ketogenesis Hmgcs2

Fig. 4. (A) Interrelationship between astrocytes and neurons in the central nervous system. Shaded rectangles depict the locations of mitochondria, the site of action of HMGCS2 (M) in its role as an enzyme. Shaded circles depict the location of the cell nucleus, the site of action of PPARa (P) and HMGCS2 (M), in its role as a cotranscription factor for PPARa. (B) How dietary genetic programming of gene expression in the astrocyte nucleus may influence levels, and neuron-astrocyte cycles, of metabolites in the nucleus-free neuronal synapse. Abbreviations: KBs, ketone bodies; FAs, fatty acids; Ac-CoA, acetyl-CoA; a-KG, a-ketoglutarate; GLU, glutamate; GLN, glutamine; LEU, leucine; a-KIC, a-ketoisocaproate; LAC, lacate; GLY, glycogen. Changes in acetyl-CoA level can alter the ratio of unacetylated to acetylated (-Ac) HMGCS2 (M), influencing the level of expression of the PPARa (P)-regulated HMGCS2 gene.

Fig. 4. (A) Interrelationship between astrocytes and neurons in the central nervous system. Shaded rectangles depict the locations of mitochondria, the site of action of HMGCS2 (M) in its role as an enzyme. Shaded circles depict the location of the cell nucleus, the site of action of PPARa (P) and HMGCS2 (M), in its role as a cotranscription factor for PPARa. (B) How dietary genetic programming of gene expression in the astrocyte nucleus may influence levels, and neuron-astrocyte cycles, of metabolites in the nucleus-free neuronal synapse. Abbreviations: KBs, ketone bodies; FAs, fatty acids; Ac-CoA, acetyl-CoA; a-KG, a-ketoglutarate; GLU, glutamate; GLN, glutamine; LEU, leucine; a-KIC, a-ketoisocaproate; LAC, lacate; GLY, glycogen. Changes in acetyl-CoA level can alter the ratio of unacetylated to acetylated (-Ac) HMGCS2 (M), influencing the level of expression of the PPARa (P)-regulated HMGCS2 gene.

changes in synaptic neurotransmission. Indeed, the astrocyte may be regarded as a cellular "diode" whose "output," i.e., metabolic response, is determined by its capacity to integrate the "input" of blood fuel/hormone signals with that of synaptic neurotransmit-ter signals.

On the foregoing basis, it has been proposed that neurons and astrocytes engage in an ongoing "metabolic dialog." Thus, for example, the excitatory neurotransmitter glutamate participates in both a glutamate-glutamine cycle (35) and a leucine-glutamate cycle (36) (Fig. 4B), to form a continuous and dynamic means by which the astrocyte responds to changes in synaptic activity. Moreover, astrocytes have a role in the provision of fuel to the neuronal synapse. Thus, similar to hepatocytes, astrocytes store blood glucose in the form of glycogen (37). According to need, such astrocytic glycogen stores can be broken down and fed to the neuron in the form of lactate (37) (Fig. 4B). Furthermore, our work together with that of the groups of John Edmond and Manuel Guzman indicates a similar role for ketone bodies, whereby fatty acids from the blood or from within brain can be broken down by astrocyte FAOK pathways to generate ketone bodies that are likewise fed to neurons (38-40) (Fig. 4B). Thus, many research groups are currently establishing the existence of a network of dialogs between astrocytes and neurons.

Future research in this area will expand to examine the exciting possibility of astrocytic genetic programming of synaptic acetyl-CoA/neurotransmitter/fuel concentrations, via intercellular synaptic mitochondria-astrocytic nucleus dialogs (Fig. 4B).

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