Transcript Lipids (lect,7)).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
Notes on ketogenesis:
1- HMG-CoA is also a precursor of cholesterol (see latter)
2- 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
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 (the last reversible step in ketogenesis)
Acetoacetate + CoA
→ acetoacetyl CoA → 2 Acetyl CoA → Kreb’s
The conversion of Acetoacetate into Acetoacetyl CoA is catalyzed by the enzyme
Thiophorase which 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.
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.
Causes of ketonemia and ketosis:
1- Severe (uncontrolled) diabetes mellitus: due to i- There is insulin deficiency,
which leads to decrease in glucose oxidation, thus the body is forced to use depot
fat as the main source of energy. ii- Lipolysis is stimulated, so acetyl CoA is
produced in large amounts. Excess acetyl CoA condenses to give more ketone
bodies.
2- Starvation, low CHO and protein diet:
Ketogenesis is stimulated during fast (starvation), low carbohydrate or protein diet,
where the body is forced to use depot fat and ketone bodies as source of energy. So
excess acetyl CoA is produced and enter in ketone bodies synthesis