The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes

The possible role of the AMP-activated protein kinase (AMPK), a highly cons erved stress-activated kinase, in the regulation of ketone body production by astrocytes was studied, AMPK activity in rat cortical astrocytes was thr ee times higher than in rat cortical neurons. AMPK in astrocytes was shown to be functionally active. Thus, incubation of astrocytes with 5-aminoimida zole-4-carboxamide ribonucleoside (AICAR), a cell-permeable activator of AM PK, stimulated both ketogenesis from palmitate and carnitine palmitoyltrans ferase I. This was concomitant to a decrease of intracellular malonyl-CoA l evels and an inhibition of acetyl-CoA carboxylase/fatty acid synthesis and 3-hydroxy-3-methylglutaryl-CoA reductase/cholesterol synthesis. Moreover, i n microdialysis experiments AICAR was shown to stimulate brain ketogenesis markedly. The effect of chemical hypoxia on AMPK and the ketogenic pathway was studied subsequently. Incubation of astrocytes with azide led to a rema rkable drop of fatty acid beta-oxidation. However, activation of AMPK durin g hypoxia compensated the depression of beta-oxidation, thereby sustaining ketone body production. This effect seemed to rely on the cascade hypoxia - -> increase of the AMP/ATP ratio --> AMPK stimulation --> acetyl-CoA carbox ylase inhibition --> decrease of malonyl-CoA concentration --> carnitine pa lmitoyltransferase I deinhibition --> enhanced ketogenesis. Furthermore, in cubation of neurons with azide blunted lactate oxidation, but not 3-hydroxy butyrate oxidation. Results show that (a) AMPK plays an active role in the regulation of ketone body production by astrocytes, and (b) ketone bodies p roduced by astrocytes during hypoxia might be a substrate for neuronal oxid ative metabolism.