Transcript Ketonbodies (224).ppt

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
For
illustration
HMG CoA
→ to
extrahepatic
tissues
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 extrahepatic 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
This enzyme
is absent in
liver
Thiophorase
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.