Treatment of rats with glucagon or mannoheptulose increases mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity and decreases succinyl-CoA content in liver.
1. The activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (EC 4.1.3.5) in extracts of rapidly frozen rat livers was doubled in animals treated in various ways to increase ketogenic flux. 2. Some 90% of the activity measured was mitochondrial, and changes in mitochondrial activity dominated changes in total enzyme activity. 3. The elevated HMG-CoA synthase activities persisted throughout the isolation of liver mitochondria. 4. Intramitochondrial succinyl-CoA content was lower in whole liver homogenates and in mitochondria isolated from animals treated with glucagon or mannoheptulose. 5. HMG-CoA synthase activity in mitochondria from both ox and rat liver was negatively correlated with intramitochondrial succinyl-CoA levels when these were manipulated artificially. Under these conditions, the differences between mitochondria from control and hormone-treated rats were abolished. 6. These findings show that glucagon can decrease intramitochondrial succinyl-CoA concentration, and that this in turn can regulate mitochondrial HMG-CoA synthase. They support the hypothesis that the formation of ketone bodies from acetyl-CoA may be regulated by the extent of succinylation of mitochondrial HMG-CoA synthase.
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Department of Biochemistry, University of Cambridge, U.K.
Tubbs
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D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D005260:Female; D005934:Glucagon / Q000494:pharmacology*; D006539:Heptoses / Q000494:pharmacology*; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D008356:Mannoheptulose / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000201:enzymology*; D007652:Oxo-Acid-Lyases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D000214:Acyl Coenzyme A; D006539:Heptoses; D007656:Ketoglutaric Acids; D008356:Mannoheptulose; D005934:Glucagon; C012046:succinyl-coenzyme A; D006904:Hydroxymethylglutaryl-CoA Synthase; D007652:Oxo-Acid-Lyases