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 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 show...

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Bibliographic Details
Published in:Journal of neurochemistry 1999-10, Vol.73 (4), p.1674-1682
Main Authors: Blázquez, Cristina, Woods, Angela, De Ceballos, María L, Carling, David, Guzmán, Manuel
Format: Article
Language:English
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
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Summary:: 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.
ISSN:0022-3042
1471-4159
DOI:10.1046/j.1471-4159.1999.731674.x