The AMP‐Activated Protein Kinase Is Involved in the Regulation of Ketone Body Production by Astrocytes

• Published in: Journal of neurochemistry Vol. 73; no. 4; pp. 1674 - 1682
• Main Authors: Blázquez, Cristina, Woods, Angela, De Ceballos, María L, Carling, David, Guzmán, Manuel
• Format: Journal Article
• Language: English
• Published: Oxford UK Blackwell Science Ltd 01-10-1999; Blackwell
• Subjects: Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - metabolism; Aminoimidazole Carboxamide - pharmacology; AMP-activated protein kinase; Animals; Animals, Newborn; Astrocyte; Astrocytes - cytology; Astrocytes - metabolism; Biological and medical sciences; Carnitine O-Palmitoyltransferase - metabolism; Carnitine palmitoyltransferase I; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; Cholesterol - biosynthesis; Cholesterol - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Fundamental and applied biological sciences. Psychology; Homeostasis; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA Synthase - metabolism; Hypoxia; Isolated neuron and nerve. Neuroglia; Ketone bodies; Ketone Bodies - biosynthesis; Ketone Bodies - metabolism; Male; Microdialysis; Neuroglial interactions; palmitic acid; Palmitic Acid - metabolism; Rats; Rats, Wistar; Ribonucleotides - metabolism; Ribonucleotides - pharmacology; Vertebrates: nervous system and sense organs; Ketone body; Ketogenesis; Rat; Enzyme; Neuroglia; Transferases; Rodentia; Astrocyte; Metabolism; Vertebrata; Mammalia; Enzymatic activity; Protein kinase
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.1999.731674.x

: The possible role of the AMP‐activated protein kinase (AMPK), a highly conserved stress‐activated kinase, in the regulation of ketone body production by astrocytes was studied. AMPK activity in rat cortical astrocytes was three times higher than in rat cortical neurons. AMPK in astrocytes was shown to be functionally active. Thus, incubation of astrocytes with 5‐aminoimidazole‐4‐carboxamide ribonucleoside (AICAR), a cellpermeable activator of AMPK, stimulated both ketogenesis from palmitate and carnitine palmitoyltransferase I. This was concomitant to a decrease of intracellular malonyl‐CoA levels and an inhibition of acetyl‐CoA carboxylase/fatty acid synthesis and 3‐hydroxy‐3‐methylglutaryl‐CoA reductase/cholesterol synthesis. Moreover, in 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 remarkable drop of fatty acid β‐oxidation. However, activation of AMPK during hypoxia compensated the depression of β‐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 carboxylase inhibition → decrease of malonyl‐CoA concentration → carnitine palmitoyltransferase I deinhibition → enhanced ketogenesis. Furthermore, incubation of neurons with azide blunted lactate oxidation, but not 3‐hydroxybutyrate oxidation. Results show that (a) AMPK plays an active role in the regulation of ketone body production by astrocytes, and (b) ketone bodies produced by astrocytes during hypoxia might be a substrate for neuronal oxidative metabolism.