The speed of the TCA in the liver

In previous writings I have looked at the liver and also ketone production from different angles but now I want to zoom in a bit on the TCA cycle itself.

Previous related writings:

In order to accumulate sufficient substrate for ketogenesis, acetyl-coa has to accumulate. The TCA cycle depends on the supply of acetyl-coa which makes them compete for the same resource. So how can this accumulation take place?

Below is a picture of the TCA cycle from wikipedia so that you can find back some of the elements mentioned further down.

Malonyl-coa interferes with long-chain fatty acid import into the mitochondria so with a reduction more fatty acids can get into those mitochondria. This is the location where fatty acids are processed to generate those acetyl-coa’s. On the other hand, increased malonyl-coa stimulates fatty acid synthesis. We want breakdown not buildup.

Malonyl-coa formation is dependent on glucose availability. On a ketogenic diet, in the liver cells we have a reduction in glucose. That allows for more AMPK activity which blocks the cytosolic conversion of acetyl-coa to malonyl-coa.

Regulation of malonyl CoA content via enzymatic control and... | Download  Scientific Diagram

There are other aspects to take into account than just a reduction in malonyl-coa. This is where we need to have a look at the effects on the TCA cycle.

Oxaloacetate or oxaloacetic acid is reduced in supply. This is important because it forms a source for citrate production. Once transported out of the mitochondria, it pushes the conversion of cytosolic oxaloacetate to malonyl. This reaction consumes NADH. So under low glucose availability, we get an accumulation of NADH.

The production of ketone bodies is stimulated by the overproduction of acetyl-CoA (increased lipolysis and beta-oxidation) without concomitant production of an adequate amount of oxaloacetic acid (Paoli et al., 2015a). It is thus worthy to underline that the reduction of glucose flux, due to the nutritional carbohydrate restriction, leads to a lower level of oxaloacetate.

“Ketogenic Diet and Skeletal Muscle Hypertrophy: A Frenemy Relationship?”

What is important about NADH?

What we can learn from ethanol (alcohol) in the liver is that it also accumulates NADH. NADH reduces the activity of the enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase that take care of converting isocitrate to α-ketoglutarate and α-ketoglutarate to succinyl-coa in the TCA cycle. What we care about though is that both these enzymes produce NADH in the reaction. By NADH accumulation inhibiting these enzymes, it acts as a negative feedback-loop.

“Ethanol Alters Energy Metabolism in the Liver”

Interestingly the accumulation of NADH also prevents oxidation of lactate and AA’s to pyruvate (part of gluconeogenesis (GNG)). Details are not provided here on how this mechanism works so consider that a little gap in proofing but I come back on this further down.

“Ethanol Alters Energy Metabolism in the Liver”

However, malonyl in the cytosol is imported in the mitochondria where it undergoes conversion to oxaloacetate. This step generates NADH. Also pyruvate conversion to acetyl-coa produces NADH.

So on one side we see a reduction in production while on the other side we see a reduction in consumption. The question then remains, if and how does a KD increase NADH availability in the liver?

The answer may purely come from the beta-oxidation step. Shifting the balance to enhanced fatty acid import and breakdown in acetyl-coa we get increased NADH production with every cleavage.

This causes an accumulation, impacting the TCA cycle so that acetyl-coa are processed at a reduced rate. This causes the piling up of acetyl-coa so that ketone bodies can be formed.

Normally acetyl-coa accumulation stimulates fatty acid synthesis but because we are in a state of low insulin and high glucagon, in the liver this results in ketones.

In skeletal muscle cells this works out differently because they don’t produce ketones. There we see the increase of intracellular lipid droplets leading to local insulin resistance.

Knowing this, circulating BHB can be somewhat seen as a proxy for the speed of the TCA in your liver. Circulating levels are impacted by various other conditions but in general when you are at rest it will probably be a good reflection.

This is all driven by the availability of glucose in the liver cells. What does this mean for the liver though? If the TCA cycle is reduced, doesn’t that mean that ATP production is lowered in liver cells?

Each cycle of the TCA produces 1 ATP molecule and the whole mechanism also relies on AMPK activation. This indicates that the cells are in maintenance mode rather than growth which should be beneficial for liver health.

However, the beta-oxidation step itself produces 5 ATP for each acetyl-coa produced so producing ketones in the liver does not completely dry out the cell from its ATP.

Related to this beta-oxidation and NADH..

The formation of acetyl-coa also processes 4-HNE, a toxic lipid peroxide. This likely happens throughout the body where fatty acids are used, essentially working as a detoxification.

“Dietary-regulation of catabolic disposal of 4-hydroxynonenal analogs in rat liver” in the pathogenesis and progression of human diseases”

Coming back on the NADH accumulation and lactate as a source for GNG.. As we understand, under low glycogen levels shouldn’t that mean that the liver is also a source of lactate production?

The only study I could find that looked at liver lactate production in humans was one where they looked at NAFLD patients and put them on a 6-day KD diet. The lactate production from the liver was higher before than on the KD diet.

“Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease”

However, in NAFLD we have an insulin resistant liver skewing the results. Insulin drives glycogen formation in the liver so NAFLD may have glycogen levels that are even lower than on a KD diet. This actually supports the case even more for lactate production rather than consuming it for GNG purposes.

“Insulin Resistance and NAFLD: A Dangerous Liaison beyond the Genetics” “Lack of liver glycogen causes hepatic insulin resistance and steatosis in mice”

NAFLD is closely linked with hepatic insulin resistance. Accumulation of hepatic diacylglycerol activates PKC-ε, impairing insulin receptor activation and insulin-stimulated glycogen synthesis.

“Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases”

Although it is a study in mice, the authors of the following study came to the same conclusions as to what I expect.

In parallel, it was observed that blood lactate level was enhanced whereas liver glycogen levels were reduced in mice perfused with BHB. Because G6Pase is common to gluconeogenesis and glycogenolysis, which classically leads to glucose release, it appears in our case that the observed glycogen breakdown would not lead to glucose release but rather to a glycolytic processing of glucose residues arising from glycogen. In other words, the observed glycogen degradation would lead to a hepatic lactate production, thus explaining the increased lactate level, reinforced by the decreased gluconeogenesis that would prevent hepatic lactate utilization and rather promote circulating lactate accumulation.

“Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice”


We can learn a lot from studying the liver but we have to keep in mind that results are liver-specific. Nevertheless, it has a key role in the energy metabolism regulation throughout our body. It is essentially an intersection point where a lot of decisions are taken.

—- T H E – E N D —-

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