Pathways of Ketone Body Utilization

Mitochondrial pathway The major site of ketone body utilization in peripheral tissues is the mitochondria (Figure 6). Although transporters for ketone bodies have been described on the plasma and inner mitochondrial membranes of some tissues, these do not appear to limit the flux. The initiating enzyme for acetoacetate metabolism is 3-oxoacid-CoA transferase:

Acetoacetate + succinyl-CoA ^ acetoacetyl-CoA

+ succinate

The resulting acetoacetyl-CoA is cleaved to two molecules of acetyl-CoA by acetoacetyl-CoA thio-lase; they are then oxidized in the tricarboxylate cycle.

3-Hydroxybutyrate is converted to acetoacetate by 3-hydroxybutyrate dehydrogenase:

3-Hydroxybutyrate

Acetoacetate

BLOOD

Cholesterol

Hydroxymethyl glutaryl-CoA

Lipids

Acetoacetate

Acetoacetyl-CoA (3)

Acetyl-CoA

Citrate-

CYTOSOL

3-Hydroxybutyrate (1)«

Acetoacetate (2)

Succinyl-CoA Succinate

Acetoacetyl-CoA (3)

Acetyl-CoA

Acetoacetyl-CoA (3)

Acetyl-CoA

Oxaloacetate

Tricarboxylic acid cycle

MITOCHONDRIA

Oxaloacetate

Tricarboxylic acid cycle

MITOCHONDRIA

Figure 6 Pathways of ketone body utilization in peripheral tissues. (1) Hydroxybutyrate dehydrogenase, (2) 3-oxoacid-CoAtransferase; (3) acetoacetyl-CoA thiolase; (4) acetoacetyl-CoA synthetase.

3-Hydroxybutyrate + NAD+ ^ acetoacetate

The ready reversibility of the three enzymes of the mitochondrial pathway (Figure 6) means that if the overall system is near equilibrium within the cell in vivo, the utilization of the ketone bodies will be dependent on their respective concentrations and on the rate of removal of the products. Thus acet-oacetate utilization will be promoted when mito-chondrial acetyl-CoA is decreased, whereas an increase in the latter will have the opposite effect. Similarly, oxidation of hydroxybutyrate will increase if the concentrations of NADH2 and acetoacetate fall. Unlike the hepatic hydroxymethyl-glutaryl-CoA pathway for ketogenesis, which is essentially irreversible, the free reversibility of this pathway in peripheral tissues can be viewed as means of buffering the mitochondrial acetyl-CoA pool and hence energy production. Some of the acetyl-CoA can be transported to the cytosol in the form of citrate to act as a precursor for lipogenesis (Figure 6).

Cytosolic pathway The cytosol of tissues where active lipogenesis occurs (adipose tissue, developing brain, lactating mammary gland, and liver) contains an enzyme, acetoacetyl-CoA synthetase, which converts acetoacetate to acetoacetyl-CoA (Figure 6):

Acetoacetate + ATP + CoA

! acetoacetyl-CoA + AMP + pyrophosphate

Its activity is at least an order of magnitude lower than that of the mitochondrial 3-oxoacid-CoA trans-ferase, whereas its affinity for acetoacetate is appreciably higher. The presence of acetoacetyl-CoA thiolase in the cytosol allows the conversion of acet-oacetate to acetyl-CoA and then to lipids without the involvement of the mitochondria.

Brain cytosol also contains 3-hydroxy-3-methyl-glutaryl-CoA synthase, allowing acetoacetate to act as a direct precursor for sterol synthesis. Evidence from in vivo experiments with 14C-labelled acetoa-cetate has confirmed the existence of this pathway in developing brain and liver. The cytosolic route for acetoacetate utilization can be seen as a mechanism for directing this substrate to lipid or sterol synthesis rather than to oxidation.

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