Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry
Introduction
Ketone body metabolism is highly regulated. Under some conditions, ketosis can develop and ketone bodies become a major body fuel. Ketosis is associated with protection from epilepsy, with weight reduction and with other physiological situations of medical interest, as discussed elsewhere in this issue. The circulating levels of ketone bodies are determined by their rates of production (ketogenesis) and utilization (ketolysis). In this article, we briefly review the pathways of ketogenesis and ketolysis, then examine the characteristics and control of important steps in each pathway.
Section snippets
Ketone body production, flux and utilization: general considerations
Three compounds are grouped together as “ketone bodies”: acetoacetate (AcAc), 3-hydroxybutyrate (3HB) and acetone (Fig. 1). Plasma concentrations of circulating ketone bodies range from <0.1 mM in the postprandial state to up to 6 mM during prolonged fasting [1] and 25 mM in uncontrolled diabetes [2], with considerable interindividual variation. Fasting ketosis develops over hours in children [3] and within days in adults [4], increasing gradually after postprandial nutrients and then tissue
Critical steps of ketone body metabolism
In this review, we focus on the main control points of ketogenesis and the enzymes that are directly involved in the formation and degradation of ketone bodies. The steps with the greatest regulatory power under normal physiological conditions are those determining fatty acid supply to the liver (adipocyte lipolysis), entry of fatty acids into liver mitochondria and derivation of carbon skeletons in mitochondria to ketone body synthesis. We will also discuss the process of ketolysis, which also
Adipocyte lipolysis
Under normal physiological conditions of active ketogenesis, adipose tissue-derived FAs are the principal source of circulating non-esterified fatty acids. Lipolysis is activated by β-adrenergic catecholamines, and is extremely sensitive to suppression by insulin [6] (Fig. 3). Lipolysis is active during fasting, when plasma insulin concentrations are low, and is suppressed postprandially when plasma insulin concentrations are high. While FA release from adipose tissue is clearly important
Mitochondrial entry of fatty acids
The transport of long-chain fatty acids from the cytosol to the mitochondrial matrix occurs in three sequential steps. The system is controlled at the first component, carnitine palmityl transferase I (CPT I), a protein of the outer mitochondrial membrane (Fig. 4) that catalyzes the transfer of a fatty acyl group from cytosolic acyl CoA to carnitine. The acylcarnitine is then transferred to the mitochondrial matrix by carnitine/acylcarnitine translocase. A distinct gene product, CPT II, loosely
Ketogenesis
Ketogenesis is mediated by two enzymes, mitochondrial HMG-CoA synthase (mHS) and HMG-CoA Lyase (HL).
Ketolysis
The ketolytic pathway occurs in extrahepatic tissues, via two reversible reactions that mediate the activation of free AcAc to AcAcCoA and the creation of AcCoA for energy production by terminal oxidative metabolism.
Conclusions
Consideration of the structure and properties of the ketogenic and ketolytic pathways reveals the mechanisms underlying the exquisite sensitivity of lipid energy metabolism and circulating ketone body levels to insulin, and the resulting fragility of diet-induced ketosis following dietary carbohydrate intake. It shows the rationale for the use of the ketogenic diet in some inborn errors of carbohydrate metabolism reviewed elsewhere in this issue, like pyruvate dehydrogenase deficiency and
Acknowledgements
We thank Shupei Wang for long-term collaboration and Jeannette Hernandez for help in preparing this manuscript.
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