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Under conditions of low oxaloacetate in the liver, acetyl-CoA that cannot be oxidised in the TCA cycle is converted to ketone bodies, which can then be exported for use as fuel in non-gluconeogenetic tissues (e.g. heart, brain).

To avoid this pathway, and the additional enzymes it requires, as well as the enzymes in the receptive tissues which are needed to reverse the pathway and re-produce acetyl-CoA, why does the liver not just export acetyl-CoA directly?

One consideration is an inability to transport acetyl-CoA across membranes, but fatty acyl-CoAs deal with this using a carnitine shuttle across the mitochondrial membrane. Would developing a transport system not, evolutionarily, be a more efficient solution?

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  • $\begingroup$ Think. What are the conditions you describe as “low oxaloacetate”? What is the source of the acetylCoA and why is it being produced (rather than stored as fat, for example)? What are the needs of the organism in these circumstances? In other circumstances where acetylCoA might be useful to other tissues, how is the molecule from which it arises exported from the liver? Look at the big picture. $\endgroup$
    – David
    Commented Nov 20, 2019 at 21:59
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    $\begingroup$ "Low oxaloacetate" will presumably occur mainly when it is being taken out of the TCA cycle, for gluconeogenesis (i.e. in the fasted state). The excess acetyl-CoA in this instance is being produced from beta-oxidation of fatty acids, since lipogenesis is inhibited (high glucagon, low insulin in this state). The organism needs to produce glucose, but also maintain a supply of ATP. Acetyl-CoA can also derive from pyruvate (via pyruvate dehydrogenase). Do you refer to the Cori Cycle, where lactate is returned to the liver, oxidised to pyruvate, and then converted to glucose? $\endgroup$
    – pincushion44
    Commented Nov 21, 2019 at 2:16
  • $\begingroup$ — Ok. You’ve thought about it, but don’t see what I’m driving at. I’ll try to answer your question later today (in a different time zone). $\endgroup$
    – David
    Commented Nov 21, 2019 at 8:28

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This is simplified version of a complex situation, but in summary:

  • A key role of liver is to control the distribution of metabolic fuel for the other tissues (it always has enough for its own requirements).
  • The way it behaves differs in the fed and fasted states (because of control by hormones and the concentration of metabolites).
  • In the fed state (after storing some sugars as glycogen) the liver will synthesize triglycerides and export them as lipoproteins to the adipose tissue, which will take them up and store them. (Other tissues in the fed state will be able to obtain glucose or fatty acids from the blood.)
  • In fasting and starvation the triglycerides in the adipose tissue will be broken down to fatty acids and glycerol, much of which will be used by tissues such as muscle.
  • The priority of the liver in starvation is to provide fuel for the brain and nervous tissues in the form of glucose, by gluconeogenesis. The substrates for net gluconeogenesis under these conditions include glycerol and some amino acids derived from breakdown of protein.
  • Other amino acids, produced in protein breakdown lead to acetyl CoA, which cannot serve as a precursor for gluconeogenesis. However it can be converted to ketone bodies (acetoacetate and β-hydroxybutyrate) that the brain can use to replace some of its glucose requirement.

With this in mind, it can be seen that the reason for producing ketone bodies is not to generate a molecule that can cross the cell membrane into the blood, but to generate a molecule with special properties, lacking in fatty acids or acetyl CoA, that allows its use by the brain in life-threatening circumstances.

Of less importance, but worth mentioning, is the fact that citrate is used as an export form of acetyl CoA (when there is sufficient oxaloacetate available), a surrogate role it plays in any case in the transfer of acetyl CoA across the mitochondrial membrane for fatty acid synthesis. So it is not necessary to export acetyl CoA, and perhaps preferable to it keep intracellular.

A more detailed account of this is available at NCBI bookshelf online in Berg et al. sections 30.2 and 30.3

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