Lipid metabolism

Question 1

1. What is the purpose of fat cells related to the fat metabolism of the whole body?
   Is it of benefit to have hormonal regulation of TAG degradation in fat cells?
   What is the name of the lipase that is found inside of fat cells? How is this enzyme finally regulated ?

Answer 1

The purpose of fat cells related to the fat metabolism of the whole body is

a.) to synthesize TAGs for storage of fatty acids after a meal (high insulin/glucagon ratio) and b.) to degrade the stored TAGs and release free fatty acids and free glycerol into the blood at low blood glucose levels or during fasting or flight and fight situations (low insulin/glucagon ratio and high serum epinephrine levels).

Hormonal regulation connects the fat metabolism in fat cells to the need of the whole body. It is beneficial to degrade the stored TAGs in fat cells only when needed for energy metabolism of other cells.

Inside of fat cells, hormone-sensitive lipase (HSL) is used to cleave TAGs.
This enzyme is only activate after phosphorylation at low insulin/glucagon ratio and also after action of epinephrine (flight or fight situation).

Hormone-sensitive lipase is finally always regulated by phosphorylation/dephosphorylation.

Question 2

2. Is hormone-sensitive lipase (HSL) active in its dephosphorylated form or is it active in its phosphorylated form? Please do not guess but think it through: epinephrine activates protein kinase A which phosphorylates HSL.
   What should be the outcome in fat cells after epinephrine action (flight and fight situation)?

Answer 2

Epinephrine action leads to phosphorylation of the enzyme, that means that HSL should be activated as this results in the release of fatty acids and glycerol into the blood from fat cells.

On the other hand, at high blood glucose levels and at insulin ruling, the TAGs shall remain stored in fat cells. Insulin leads to the inactive, dephosphorylated form of hormone-sensitive lipase.

[the TAG amount in fat cells will eventually determine the survival time of severe starvation.]

Question 3

3. How are free fatty acids transported in blood? Which cells use mainly fatty acids for energy metabolism? Are fatty acids used for energy metabolism in the brain? Explain.

Answer 3

Free fatty acids are bound non-covalently to albumin which acts as transport protein to other cells via the blood stream.

Fatty acids are used for -oxidation and energy metabolism especially in heart, skeletal muscle and liver. [The liver takes up also the glycerol released from fat cells and uses the carbons for gluconeogenesis. ]

Brain metabolism is different and only fatty acids of the 3 and 6 families pass the blood-brain barrier. Fatty acids do not contribute significantly to the energy metabolism of the brain. The dietary essential fatty acids are used to form arachidonic acid or DHA. These fatty acids render the phospholipid membrane more fluid. DHA is especially needed for brain metabolism and the visual cycle.

Question 4

4. Free fatty acids have detergent character inside of cells. They need to be activated to fatty acyl CoA and used for synthesis of TAGs or membrane lipids.
   Where in the cell is the location of the enzyme that activates fatty acids?
   What is the name of this enzyme, what are the substrates and products?
   Is this reaction reversible or irreversible? Explain.

Answer 4

Free fatty acids are activated to fatty acyl CoA at the outer mitochondrial membrane.
This is catalyzed by (fatty) acyl CoA synthetase (also known as thiokinase).
The enzyme uses free fatty acids, free CoA and ATP and synthesizes fatty acyl CoA. In this reaction ATP is cleaved to AMP and PPi. The formed PPi is immediately cleaved to 2 Pi in the cytosol and this renders the reaction irreversible.

Question 5

5. What is the purpose of the carnitine shuttle and what is transported into mitochondria via the carnitine shuttle?
   What kind of molecule is carnitine, is it derived from amino acids, lipids or carbohydrates? Can it be synthesized in the human body? Explain!

Answer 5

The carnitine shuttle has the purpose to transport long-chain fatty acyl-groups into mitochondria for -oxidation. The fatty acyl-groups are temporarily bound to carnitine.

Fatty acyl CoA itself cannot transfer the inner mitochondrial membrane.

The carnitine shuttle is needed for long-chain fatty acyl-CoA (mainly 16-20 carbons), whereas medium-chain fatty acids do not need the carnitine shuttle.
Medium-chain fatty acids enter directly the mitochondrial matrix where they are activated to medium-chain fatty acyl CoA for -oxidation.

Carnitine is a molecule derived from amino acids (lysyl residue and methylation using S-adenosylmethionine, SAM). It can be taken up from the diet but also be synthesized in humans with the final step in liver.

Carnitine is not synthesized in skeletal or heart muscle and these cells are dependent on uptake of carnitine from the blood via a specific transporter.

Question 6

6. What are the functions of carnitine palmitoyl transferase I (CPT I), carnitine-acylcarnitine translocase and carnitine palmitoyl transferase II (CPT II)? Where in the cell are they located?

Answer 6

CPT I is bound in the outer mitochondrial membrane and uses fatty acyl CoA and free carnitine as substrates. It forms fatty acyl carnitine.

[Both, fatty acyl CoA and fatty acyl-carnitine can pass through the outer mitochondrial membrane, and graphs sometimes show the reaction taking place to the cytosolic side or to the inter-membrane space, which is correct as well.]

The translocase allows the transfer of fatty acyl-carnitine through the inner mitochondrial membrane into the matrix, and at the same time it transfers free carnitine from the matrix back into the inter-membrane space.

CPT II is bound in the inner mitochondrial membrane and uses fatty acyl-carnitine and free CoA as substrates and forms fatty acyl CoA in the mitochondrial matrix which is then subjected to oxidation.

Question 7

7. How is the carnitine shuttle regulated in the liver? Under which metabolic situation should it be inhibited?

Answer 7

The carnitine shuttle is meant to transport long-chain fatty acyl-groups into mitochondria for -oxidation. This is activated by increased availability of cytosolic fatty acids during fasting.

This should not happen to newly synthesized fatty acids which are meant in the liver to be used for TAG synthesis and released inside of lipoproteins (VLDL) into the blood.

Question 8

8. Where in the cell are palmitoyl CoAs formed and how is it prevented that the newly formed fatty acyl CoAs are degraded by -oxidation in liver mitochondria?

Answer 8

Acyl CoA synthetase is bound in the outer mitochondrial membrane. The newly formed palmitate leaves the FAsynthase and will be activated to palmitoyl CoA at the outer mitochondrial membrane.

When fatty acid synthesis takes place, the carnitine shuttle shall be inhibited. Malonyl-CoA inhibits the enzyme carnitine palmitoyl transferase I (CPT I). Malonyl CoA is formed in liver cytosol only during fatty acid synthesis.

Question 9

9. What is needed for -oxidation, under which conditions is -oxidation inhibited?

Answer 9

In order to perform -oxidation, the cell needs mitochondria and an active ETC and oxidative phosphorylation which reforms NAD+ and FAD needed as coenzymes for -oxidation.

Oxygen deficiency inhibits -oxidation ( and also the PDH and TCA cycle).

Question 10

10. How is mitochondrial -oxidation regulated?

Answer 10

The amount of serum free fatty acids will primarily regulate the rate of -oxidation.
During fasting free fatty acids are released from the fat cells and transported to tissues via the blood bound to albumin. They enter cells and participate in the carnitine shuttle.
Secondly it is regulated at CPT I, which can be inhibited by malonyl-CoA .

Question 11

11. Which group of enzymes acts on fatty acyl CoA in -oxidation in mitochondria?
    Which coenzyme is needed? Does the formed FADH2 participate directly in the ETC at the level of CoQ (like succinase dehydrogenase reaction in complexII)?

Answer 11

The enzymes are (fatty) acyl CoA dehydrogenases.
These enzymes needs FAD as prosthetic group and form FADH2.

Succinate dehydrogenase (complex II of the ETC) , which also contains FAD as prosthetic group, acts directly with CoQ of the ETC after FADH2 formation.

Acyl CoA dehydrogenases are mainly found in the mitochondrial matrix and will interact with other flavoproteins which then eventually will enter the ETC at CoQ with their FADH2.

Question 12

12. What is special about the preference for specific fatty acyl chain lengths of different fatty acyl CoA dehydrogenases?

Answer 12

Long-chain fatty acyl-groups are oxidized by long-chain acyl CoA dehydrogenase.

Once the fatty acyl-group gets smaller to ~12 carbons (medium-chain) then the long-chain acyl CoA dehydrogenase acts less on it. Instead, -oxidation is continued using medium-chain acyl CoA dehydrogenase.

Finally medium-chain acyl CoA dehydrogenases act less on shorter acyl-groups and short-chain acyl CoA dehydrogenase finishes the total degradation.

Question 13

13. Which clinical outcome would be expected in patients with medium-chain fatty acyl CoA dehydrogenase deficiency?

Answer 13

These patients cannot totally degrade long-chain fatty acyl CoAs and they can also not use medium-chain fatty acids for -oxidation. This leads to severe hypoglycemia and hypoketonemia.

In the liver, -oxidation is needed to provide the energy for gluconeogenesis and also provides acetyl CoA for activation of pyruvate carboxylase and inhibition of PDH.

The liver needs also acetyl CoA from -oxidation for ketone body synthesis.

In addition to already less gluconeogenesis by the liver, the tissues that rely during fasting normally mainly on -oxidation and usage of ketone bodies for their energy metabolism, use now more glucose than normal, which reduces blood glucose levels even more.

Question 14

14. Is MCAD deficiency always a hereditary defect or can it result from food intake?

Answer 14

MCAD deficiency is a common hereditary defect of metabolism but it can also result from food intake of unripe ackee fruit, especially during a vacation in the Caribbean.

Ripe ackee fruit is a staple food in Jamaica, and please note, it is only the unripe ackee fruit that leads to inhibition of MCAD by hypoglycin A. This inhibition leads to Jamaican Vomiting sickness. It is a severe sickness with similar clinical outcome like hereditary MCAD deficiency.

Question 15

15. Which compounds are found in MCAD deficiency in blood and urine? Explain!

Answer 15

Blood and urine contain medium-chain fatty acyl-carnitine and dicarboxylic acids.
This is characteristic for MCAD deficiency.

Medium-chain acylcarnitine is normally not as medium-chain fatty acids do not use the carnitine shuttle and enter directly the mitochondrial matrix.

(the formation of medium-chain acylcarnitine is not clear, but they may be formed in patients inside of the mitochondrial matrix at the very high levels of accumulated medium-chain acyl CoA by reaction with free carnitine . Carnitine translocase may transport them together with free carnitine out of mitochondria)

[The formation of medium-chain fatty acyl-carnitine in the liver can overwhelm the normal re-uptake of carnitine in the kidney, and they are released into the urine. MCAD deficiency can lead this way to secondary systemic carnitine deficiency due to loss in urine.]

Dicarboxylic acids are formed by -oxidation at the methyl end in the ER. This is normally a minor microsomal pathway but is up-regulated in MCAD deficiency.

Question 16

16. Which food contains TAGs with medium-chain fatty acids ?

Answer 16

Milk contains TAGs with medium-chain fatty acids. These TAGs are mainly cleaved by lingual and gastric lipase in the stomach lumen and do not need pancreatic lipase and bile salts. It is also special that free medium-chain fatty acids can reach directly the liver via the portal vein (and are not esterified in TAGs and put it chylomicrons, like long-chain fatty acids.)

Question 17

17. Name the sequence of one cycle of -oxidation and the coenzymes needed!

Answer 17

One cycle of the -oxidation spiral has the sequence of oxidation, hydration, the second oxidation and thiolysis.

The first oxidation step needs FAD for acyl CoA dehydrogenase, the second oxidation step needs NAD+ as coenzyme for hydroxyacyl CoA dehydrogenase.

Question 18

18. What is the difference between thiolysis and hydrolysis? What is the advantage of thiolysis as last step in one round of the -oxidation spiral?

Answer 18

Thiolysis is special as it uses free CoA (which has a sulfhydryl group) for cleavage instead of using water.
Thiolysis in -oxidation is a tool to generate a fatty acyl CoA and acetyl CoA instead of a free fatty acid and acetyl CoA. The free fatty acid would have detergent character. The generation of fatty acyl CoA allows another round of -oxidation in the mitochondrial matrix.

[just to remember, the special case of phosphorolytical cleavage is used by glycogen phosphorylase and which uses Pi instead of water]

Question 19

19. Outline the energy obtained in total degradation of one palmitate. Compare it to the ATP obtained from aerobic glucose degradation.

Answer 19

The activation of palmitate to palmitoyl CoA uses ATP and sometimes it is counted as 2 ATP, as AMP and PPi are formed and PPi is also cleaved.

Each spiral of -oxidation generates one FADH2, one NADH and one acety CoA and also a fatty acyl CoA that is two carbons shorter. The following outline for energy obtained for simplicity refers to FADH2 leading to 2 ATP and NADH leading to 3 ATP.

[newer counting often uses 1.5 and 2.5 ATP, respectively]

One cycle of the -oxidation spiral forms one FADH2 which leads to 2 ATP, one NADH which leads to 3 ATP and the formed acetyl CoA can be used in the TCA cycle.

One round of the TCA cycle using acetyl CoA generates 3 NADH, one FADH, and one GTP, which is commonly counted as total 12 ATP equivalents formed in the TCA cycle.

In addition, one cycle of -oxidation only cleaves 2 carbons from the fatty acyl CoA. This leaves a shorter fatty acyl CoA that can continue in more -oxidation spirals.

Overall, the total degradation of palmitate generates 129 ATP.
Glucose subjected to aerobic glycolysis, PDH and TCA cycle leads to about 38 ATP (when the malate-aspartate shuttle is used).

Question 20

20. Mitochondrial -oxidation is mostly outlined for saturated fatty acids.
    Are unsaturated fatty acids common components of phospholipids in membranes?
    How are unsaturated fatty acids in general degraded?

Answer 20

Unsaturated fatty acids are common components of membrane phospholipids and represent half of their fatty acids.

The degradation of unsaturated fatty acids is performed by -oxidation in mitochondria and needs one or two additional enzymes to -oxidation (an isomerase and a specific reductase).

Question 21

21. Most fatty acids in humans are even-numbered.
    In which food group do we find odd-numbered fatty acids?
    Where in the cell are odd-numbered fatty acids degraded?
    What is formed during -oxidation of odd-numbered fatty acids? What is special?

Answer 21

Odd-numbered fatty acids are found in plants. They are degraded by -oxidation in mitochondria. Acetyl CoAs are formed, but the last acyl CoA is propionyl CoA.

Propionyl CoA is the only part of the fatty acid that can provide carbons for gluconeogenesis. Propionyl CoA degradation leads (via methylmalonyl CoA) to an additional molecule of succinyl CoA that can be used for gluconeogenesis.

[The formation of this succinyl CoA needs vitamin B12.]

[Propionyl CoA is also formed in the degradation of specific amino acids ( valine, isoleucine, methionine and threonine)]

Question 22

22. Which type of fatty acids is degraded in peroxisomes? What is special?

Answer 22

Very-long-chain fatty acids (VLCF) and branched-chain fatty acids are degraded in peroxisomes.

VLCF (larger than 20 carbons) are degraded by peroxisomal -oxidation.
The degradation of branched-chain fatty acids uses in the first step -oxidation and continues then with peroxisomal -oxidation.

Question 23

23. What is the major difference between -oxidation in mitochondria and -oxidation in peroxisomes?

Answer 23

In contrast to -oxidation found in mitochondria, FADH2 formed in the first peroxisomal -oxidation step leads to hydrogen peroxide inside of peroxisomes (instead of eventually joining the ETC via other flavoproteins.)

This leads to less ATP generation, but hydrogen peroxide is important for the functions of peroxisomes.

[Peroxisomes contain other enzymes that form hydrogen peroxide, like xanthine oxidase. Catalase in peroxisomes needs hydrogen peroxide when this enzyme is used to detoxify other molecules. In addition, catalase can also detoxify hydrogen peroxide itself]

Question 24

24. What is defective in Zellweger syndrome?

Answer 24

Zellweger syndrome is a hereditary defect related to a peroxisomal biogenesis disorder which leads to the absence of recognizable amounts of hepatic peroxisomes.

Very-long-chain fatty acids cannot be degraded due to the lack of peroxisomes and they accumulate in the blood and tissues in these patients.

Question 25

25. Describe patients with Zellweger syndrome!

Answer 25

Patients with Zellwerger syndrome show commonly neuronal disorders, mental retardation and hepatomegaly. Sometimes severe hypotonia and weakness are seen in infants. Zellweger syndrome is usually fatal in infancy.

Question 26

26. Which food group contains branched-chain fatty acids?

Name a branched-chain fatty acid that is commonly formed in ruminant animals! Describe shortly the degradation.

Answer 26

Phytanic acid is a common branched-chain fatty acid formed in ruminant animals during chlorophyll digestion and is stored in their fat tissue and also found in dairy products.

Degradation takes place after phytanoyl CoA is formed.
The methyl-group on the -carbon does not allow -oxidation and that is why one time -oxidation is performed which needs a specific enzyme.

The degradation is then continued by peroxisomal -oxidation and leads to propionyl CoAs due to the methyl branches.

Question 27

27. Describe Refsums’ disease!
    What are the symptoms of a patient with Refsums’ disease? Why is it possible to treat this disease via the diet, which is not possible in Zellweger syndrome?

Answer 27

Refsums’disease is a rare hereditary disease and leads to deficient degradation of branched-chain fatty acids. It is the step of -oxidation in peroxisomes that cannot be performed as normal.

Patients show primarily neurologic symptoms due to accumulation of mostly phytanic acid in blood and tissues. This can lead to visual defects (retinitis pigmentosa) , cerebrellar ataxia and can include also skeletal malformations and hearing loss.

Branched-chain fatty acids are not synthesized in humans, and Refsums disease is treated by dietary exclusion of branched-chain fatty acids.

On the other hand, very-long-chain fatty acids are synthesized in humans with important functions in the brain and the exclusion via the diet is not possible. Zellweger syndrome cannot be treated via the diet.

Question 28

28. After we have discussed degradation of different kinds of fatty acids, let’s go back to the carnitine shuttle: what happens in an individual with a deficiency of the carnitine shuttle?

Answer 28

An individual with a deficiency of the carnitine shuttle cannot perform -oxidation in mitochondria as usual and this leads mainly to hypoglycemia and hypoketonemia (liver) and to muscle weakness.

Question 29

29. Outline the deficiency of the carnitine shuttle related to deficiency of the molecule carnitine itself and compare it to the deficiency of the enzymes of the carnitine shuttle, CPT I and CPT II.

Answer 29

Systemic primary carnitine deficiency is often related to a hereditary defect of the plasma-membrane carnitine transporter protein. This would lead to reduced uptake of dietary carnitine, reduced uptake into cells from the blood and also reduced re-uptake by the kidney.

This results in low levels of carnitine in blood and all tissues. As a result we find hypoglycemia and hypoketonemia (liver) and muscle weakness.
A secondary systemic carnitine deficiency is often due to
**chronic renal failure leading to less renal re-absorption of carnitine or due to
**liver disease leading to less synthesis of carnitine.
Treatment with specific antibiotics can also result in carnitine deficiency.
MCAD deficiency also leads to loss of carnitine in form of medium-chain acyl-carnitine in urine.
In contrary to systemic carnitine deficiency, myopathic carnitine deficiency is limited to a defect of the plasma-membrane isoform transporter found in the skeletal and in the cardiac muscle.

Muscle cells do not synthesize carnitine and are dependent on the uptake of carnitine from the blood which was provided by the liver. With the deficiency of the transporter, these cells lack carnitine and we find muscle weakness. Blood carnitine levels are mostly normal. There is no hypoglycemia or hypoketonemia as the liver is functioning normally.

Question 30

30. Describe deficiency of CPT I and compare it to deficiency of CPT II. Which tissues are mainly affected?

Answer 30

Deficiency of CPT I is very rare and it is mostly due to the deficiency of the isozyme found in the liver. This leads to severe hypoglycemia and hypoketonemia.

[the CPT IA gene is found in liver, the CPTIB gene is found in skeletal muscle]

Deficiency of CPT II is mostly affecting the isozyme of the muscle and leads to cardiomyopathy and muscle weakness. TAGs accumulate in skeletal muscle and prolonged exercise leads to myoglobinuria and elevated levels of CK-MM in blood.

[in comparison to McArdle syndrome, these patients show increase of blood lactate following anaerobic muscle contraction.]

Question 31

31. Compare blood data in patients with systemic carnitine shuttle deficiency to blood data in patients with MCAD deficiency! What is characteristic for MCAD deficiency that is not found in patients with a deficiency of the carnitine shuttle?

Answer 31

Patients with systemic carnitine shuttle deficiency or with MCAD deficiency have in common that they show low blood glucose and low ketone bodies during fasting due to reduced -oxidation in liver mitochondria.

Patients with carnitine shuttle deficiency show elevated blood levels of free fatty acids.

Patients with MCAD deficiency show loss of carnitine in form of medium-chain fatty acyl carnitines that accumulate in blood and are released in urine. Also, they show characteristic dicarboxylic acids formed by microsomal -oxidation which accumulate in blood and urine.

Question 32

32. An easy question related to the “big picture”: Does ketone body synthesis take place in liver and kidney, or does it take place only in the liver or only in the kidney? Compare this pathway to the pathway of gluconeogenesis.

Answer 32

Only the liver synthesizes ketone bodies as only the liver contains remarkable amounts of mitochondrial HMG CoA synthase.

Gluconeogenesis can be performed by both liver and kidney as both tissues contain glucose 6-phosphatase.

Question 33

33. Describe ketone bodies! Under which metabolic condition would they be synthesized and released into the blood by the liver?

Answer 33

Acetoacetate and 3-hydroxybutyrate are ketone bodies found in the blood during fasting or starvation. Ketone bodies are soluble in aqueous solutions like the blood.

Acetoacetate can be spontaneously decarboxylated to acetone which is exhaled and can be smelled in the breath of Type I diabetic patients.

The liver synthesizes ketone bodies during fasting or flight and fight situations, when hormone-sensitive lipase in fat cells is active and generates many free fatty acids that are released into the blood and taken up by the liver.

Insulin levels are low and CPT I is not inhibited by malonyl CoA in the liver cytosol.

With that the liver is subjected to a large influx of fatty acyl-groups and performs a highly active -oxidation which generates many reductive equivalents.

[At the same time, the liver performs gluconeogenesis and the high levels of NADH inhibit PDH and the TCA cycle]
This results in liver mitochondria in high levels of acetoacetyl CoA and acetyl CoA which are then used for ketone body synthesis.

Question 34

34. Acetoacetate is a ketone body. Why is it not possible to release acetoacetate out of acetoacetyl CoA ? Explain!

Answer 34

The liver does not contain an enzyme that cleaves mitochondrial acetoacetyl CoA to free acetoacetate and free CoA. Acetoacetyl CoA itself cannot leave mitochondria.

Instead, acetoacetyl CoA and acetyl CoA are used to form hydroxy-methylglutaryl CoA (HMG CoA) synthesized by mitochondrial HMG CoA synthase.
HMG CoA can now be cleaved to acetoacetate and acetyl CoA by HMG CoA lyase.

Acetoacetate can leave the mitochondria and be released into the blood by the liver.

Question 35

35. Which enzyme is the regulated enzyme of ketone body synthesis? Is this enzyme found in other tissues?

Answer 35

Mitochondrial HMG CoA synthase is the regulated enzyme of ketone body synthesis and it is present in significant amounts only in the liver.

Question 36

36. What is the advantage to use acetoacetate and form 3-hydroxybutyrate from it during ketone body synthesis in liver mitochondria? Which molecule is more stable in blood?

Answer 36

During ketone body synthesis, the NADH levels in mitochondria are high.

The formation of 3-hydroxybutyrate from acetoacetate in liver mitochondria uses NADH and regenerates NAD+ which can be used for another round of -oxidation.

3-hydroxybutyrate is more stable than acetoacetate and it is not spontaneously cleaved to acetone like acetoacetate.

Question 37

37. What is formed in extra-hepatic cells from 3-hydroxybutyrate?

Answer 37

Extra-hepatic cells take up both acetoacetate and 3-hydroxybutyrate from the blood.
They form acetoacetate from 3-hydroxybutyrate and generate in this reaction already one NADH, which can be used directly in the ETC for 3 ATP formation.

Question 38

38. As we discussed, the liver does not have an enzyme that cleaves acetoacetyl CoA to free acetoacetate and free CoA and the formation of mitochondrial HMG CoA was needed.

On the other hand, do extra-hepatic cells contain an enzyme that uses free acetoacetate and free CoA and forms acetoacetyl CoA? Explain.

Answer 38

The answer is no, there is no enzyme that links acetoacetate to free CoA.
But extra-hepatic tissue can contain an enzyme in mitochondria that uses succinyl CoA and links the CoA of this molecule to acetoacetate and forms acetoacetyl CoA.

Question 39

39. What is the name of the enzyme that forms acetoacetyl CoA from acetoacetate in mitochondria? Is this enzyme found in the liver?

Answer 39

The enzyme is named succinyl-CoA: acetoacetate CoA transferase and is also known as thiophorase.

Thiophorase is absent in liver cells and that is why the liver cannot use ketone bodies for its own energy metabolism.

Question 40

40. Which cells use ketone bodies? What is the advantage that some cells use ketone bodies for energy metabolism? Describe the reaction of thiophorase and the follow up metabolism.

Answer 40

Ketone bodies are used for energy generation mostly in the heart and muscle in addition to free fatty acids during fasting.

The brain can use ketone bodies (in addition to glucose) during prolonged starvation and uses less glucose.

The usage of ketone bodies in prolonged starvation leads to a protein sparing effect, as less gluconeogenesis is necessary to provide a normal fasting blood glucose level.

Thiophorase uses acetoacetate and succinyl CoA (of the TCA cycle) as substrates and forms acetoacetyl CoA and succinate (which continues in the TCA cycle, only the formation of GTP is missed).

The formed acetoacetyl CoA is cleaved to 2 acetyl CoAs. The loss of GTP formation due to the thiophorase reaction is made up by formation of 2 acetyl CoAs which now participate in the normal TCA cycle.

[Energy metabolism using glucose or fatty acids requires ATP input, which is needed to form glucose 6-P or fatty acyl CoA as part of the degradation pathways. Acetoacetate is activated to acetoacetyl CoA without input of ATP]