Ketone bodies and PET

Ketone bodies include acetoacetate (AcAc), D-β-hydroxybutyrate (β-HB, BHB), and acetone. L-β-hydroxybutyrate is not used in energy metabolism but excreted in the urine.

Acetone
Acetone
Acetoacetate
Acetoacetate (AcAc)
beta-hydroxybutyrate
β-hydroxybutyrate (β-HB)

Ketone bodies, mainly AcAc and β-HB are important alternative fuels to glucose for the brain, the heart, kidneys, skeletal muscle, and tumours. Cerebral metabolic rate of glucose increases almost in proportion to the rise in plasma ketones, independent on the concentration of glucose in plasma (Hasselbalch et al., 1996; Blomqvist et al., 2002; Courchesne-Loyer et al., 2017). Increased plasma concentration of ketone bodies also decreases myocardial glucose uptake (Gormsen et al., 2017), but acute hyperketonemia does not affect glucose or palmitate uptake in abdominal organs or skeletal muscle (Lauritsen et al., 2020).

In normal conditions small quantities of the ketone bodies (including also acetone) are produced in the liver as the break-down product of fatty acids in mitochondrial β-oxidation, but during fasting the production of ketones increases. Hepatocytes do not metabolize acetoacetate but release it into the circulation. In other tissues, acetoacetate can be converted to acetoacetyl-CoA and acetyl-CoA in cytosol and mitochondria, and used in energy production or synthesis of several products including amino acids, fatty acids, and sterols (Bentourkia et al., 2009; Croteau et al., 2014).

Blood ketone concentration in the range of 3-5 mM can be reached with ketogenic diet (very low carbohydrate intake), but levels >0.5 mM can already be considered a ketosis state, and can be reached with intermittent fasting and caloric restriction. Ingested ketone precursors (medium chain triglycerides and ketone esters) lead to mild ketosis. Oral D-BHB is rapidly absorbed and metabolized, and it can increase blood ketones to millimolar levels (Cuenoud et al., 2020).

Acetoacetate, β-hydroxybutyrate, pyruvate, lactate, and α-keto acids are transported across the BBB by passive and active diffusion. From Monocarboxylate transporters, MCT1 is a common carrier for these molecules in endothelial cells and pericytes, MCT2 in neurons and astrocytes (Bentourkia et al., 2009), and MCT4 in astrocytes.

Ketone bodies labelled with positron emitting radionuclides allows in vivo PET studies of ketone metabolism (Bouteldja et al., 2014). Acetoacetate has been labelled with 11C, giving [1-11C]Acetoacetate ([11C]AcAc), and β-hydroxybutyrate with 11C and 18F, giving R-β-[1-11C]hydroxybutyrate ([11C]β-HB) and (3S)-4-[18F]fluoro-3-hydroxybutyric acid ([18F]FBHB). Ketones have also been labelled with 13C for NMR studies.

[1-11C]acetoacetate
[11C]AcAc
beta-[1-11C]-hydroxybutyrate
[11C]β-HB
4-[18F]-3-hydroxybutyrate
[18F]FBHB

[11C]AcAc, [11C]β-HB, and [11C]acetate follow the same transport and metabolism pathway through acetyl-CoA, enabling the use of the same models as are used to analyse [11C]acetate PET studies (Bentourkia et al., 2009; Croteau et al., 2014). [11C]AcAc and [11C]β-HB equilibrate rapidly in vivo, and both of these radiopharmaceuticals, but mostly [11C]β-HB, will be present in blood after administration of either of those (Blomqvist et al., 2002; Bentourkia et al., 2009).

[18F]FBHB has been used in mice studies (Mattingly et al., 2020). Dynamic 60-min PET scans with [18F]FBHB showed uptake that was consistent with that of the structurally related ketone body D-BHB, including moderate heart and brain uptake, and renal clearance. Uptake in breast cancer xenografts was higher than in muscle. Fasting caused small increases in [18F]FBHB uptake in the heart and brain, but not in tumour (Mattingly et al., 2020).


See also:


Literature

Bouteldja N, Andersen LT, Møller N, Gormsen LC. Using positron emission tomography to study human ketone body metabolism: A review. Metabolism 2014; 63(11): 1375-1384. doi: 10.1016/j.metabol.2014.08.001.

Courchesne-Loyer A, Croteau E, Castellano C-A, St-Pierre V, Hennebelle M, Cunnane SC. Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study. J Cereb Blood Flow Metab. 2017; 37(7): 2485-2493. doi: 10.1177/0271678x16669366.

Hasselbalch SG, Madsen PL, Hageman LP, Olsen KS, Justesen N, Holm S, Paulson OB. Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia. Am J Physiol. 1996; 270(5 Pt 1): E746-E751. doi: 10.1152/ajpendo.1996.270.5.e746.

Roy M, Nugent S, Tremblay-Mercier J, Tremblay S, Courchesne-Loyer A, Beaudoin JF, Tremblay L, Descoteaux M, Lecomte R, Cunnane SC. The ketogenic diet increases brain glucose and ketone uptake in aged rats: a dual tracer PET and volumetric MRI study. Brain Res. 2012; 1488: 14-23. doi: 10.1016/j.brainres.2012.10.008.



Tags:

Updated at: 2023-08-24
Created at: 2017-06-28
Written by: Vesa Oikonen