Ketone bodies

 Liver mitochondria have the capacity to convert acetyl CoA derived from fatty acid oxidation into ketone bodies which are: 1- Acetoacetic acid 2- β-hydroxy butyric acid 3- Acetone

Functions of ketone bodies:

 1-Used as source of energy. They are reconverted into acetyl CoA which is oxidized in Kreb's cycle to give energy.

2- In prolonged fasting and starvation, ketone bodies can be used as source of energy by most tissues except liver.N.B. In fasting, most tissues get energy from oxidation of both ketone bodies and fatty acids, but the brain gets its energy from oxidation of ketone bodies. Brain never oxidizes fatty acids.

Synthesis of ketone bodies by the liver (Ketogenesis) Site of ketogenesis: Mitochondria of liver cells due to high activity of HMG-CoA synthase, HMG- CoA- lyase. Steps of ketogenesis: See Figure (not required) 1- 3 molecules of acetyl CoA are condensed to give 3-hydroxy 3-glutaryl CoA (HMG CoA). This step is catalyzed by HMG CoA synthase (the key enzyme)

2- HMG CoA is then broken by HMG CoA lyase enzyme to acetoacetate.

3- Part of acetoacetate is converted into acetone and part is converted into β-hydroxy butyric acid

Notes on ketogenesis:

1- HMG- CoA synthase is the rate limiting enzyme in the synthesis of ketone bodies and is present in significant amounts only in the liver.

3- Acetone is a volatile, nonmetabolized product that can be released in the breath.

Regulation of ketogenesis: Regulation of HMG-CoA synthase

A- Inhibited after CHO diet (after meal): CHO diet inhibits HMG-CoA synthase. In addition, after meal, insulin is released and inhibits HMG-CoA synthase B- Simulated in fasting & starvation, low CHO diet, and in severe (uncontrolled) DM (insulin decrease): all these factors stimulate HMG-CoA synthase

HMG CoA

→ to extrahepatic tissues

For illustration

Ketolysis (Use of Ketone bodies by peripheral tissues) 

Def. It is the complete oxidation (breakdown) of ketone bodies (β- hydroxybutyrate)

into energy + CO2 + H2O

Site: Mitochondria of the extrahepatic tissues. Oxidation not occurs in liver due to

the absence of thiophorase in the liver. Ketolysis also not occur in RBCs due to lack

of mitochondria.

Briefly, ketolysis occur as follow:

β- hydroxybutyrate ↔ Acetoacetate

Acetoacetate + succinyl CoA → acetoacetyl CoA

acetoacetyl CoA + CoASH (Thiolysis reaction) → 2 Acetyl CoA → Kreb’s

  

1- The first step in ketolysis is the conversion of β- hydroxybutyrate into acetoacetate.

2- The second step is the activation of acetoacetate into acetoacetyl CoA. The source

of CoA is succinyl CoA. This reaction needs enzyme called Thiophorase or called also

Succinyl CoA-Acetoacetate CoA Transferase (meaning the enzyme that transfer

CoA from succinyl CoA to acetoacetate). Thiophorase is present sufficiently in extra-

hepatic tissues including brain. In contrast, the liver does not contain thiophorase, and

therefore can’t oxidize ketone bodies or use them as a fuel.

3-The third step is thiolysis reaction involving the breakdown of acetoacetyl CoA into

2 acetyl CoA in the presence of CoASH and ketothiolase enzyme

Ketolysis (oxidation of ketonbodies) in extrahepatic tissues

ThiophoraseThis enzyme is absent in liver

Ketosis 

Ketone bodies formed in the liver must be passed to blood to be oxidized.

Normal blood ketone bodies must not exceed 1.5-2 mg%.

Ketosis: is the increase of blood ketone bodies above normal levels.

It occurs if the rate of ketogenesis increases and exceeds the rate of ketolysis.

The excess ketone bodies pass to urine (ketonuria).

Both acetoacetate and beta-hydroxybutyrate are acidic, and, if levels of these

ketone bodies are too high, the pH of the blood drops, resulting in ketoacidosis.

In severe cases of ketosis as in uncontrolled D.M. coma may be developed and

the condition may be fatal.