Download ketone bodies

KETONE BODIES
(KETOGENESIS)
WHERE:
LIVER, MITOCHONDRIA
FUNCTION: 1. TO SERVE AS FUEL FOR HEART, RENAL CORTEX OF
KIDNEY UNDER NORMAL CONDITIONS
2. TO SERVE AS FUEL FOR BRAIN DURING STARVATION,
INSULIN DEFICIENCY, FOR MUSCLE DURING VIGOROUS AEROBIC
ACTIVITY
HOW MUCH:
WHEN:
- SECRETED IN URINE
NORMAL 0.1 G/24 HRS
KETOSIS
100G/24 HRS
- LOW LEVELS ALWAYS PRODUCED
- HIGH LEVELS DURING INSULIN DEFFICIENCY,
STARVATION (LACK OF CHO), LOW CHO DIET, VIGOROUS
AEROBIC ACTIVITY
PATHWAY: SEE LECTURE NOTES
DISTRIBUTION:
LIVER
SERUM
FFA
TISSUE
2Ac CoA
AcAcCoA
Acetone
AcAc
Acetone
AcAc
-OH Butyrate
-OH Butyrate
AcAc
-OH Butyrate
Ketone bodies and insulin dependent diabetes (type I diabetes)
 inadequate levels of insulin secretion result in:
 reduced uptake of glucose by muscle and adipose tissue (GluT4)
 increased output of glucagon by  cells of pancreas and increased ratio of
glucagon/insulin. This leads to:
 increased gluconeogenesis, lipolysis and protein breakdown




fat and proteins yield FFA and amino acids that are further
catabolized to give AcCoA. Because OAA is been utilized for
gluconeogensis, it is less available for citrate synthase and AcCoA
accumulates. As concentration of AcCoA increases it inhibits PDH
and stimulates pyruvate carboxylase, further favoring the diversion
of pyruvate for gluconeogenesis (pyr
OAA
PEP). In addition,
as the concentration of AcCoA increases, rate of HMGCoA
synthase (which has a relatively high Km for AcCoA) increases
resulting in enhanced synthesis of ketone bodies and preventing
the further accumulation of AcCoA.
Generally similar changes occur during fasting, low carb diets and
vigorous aerobic exercise.
Note: low I/G ratio results in increased synthesis of PEPCK and
HMGCoA synthase, further favoring gluconeogenesis and KB
formation.
Question: defective fatty acid oxidation results in decreased
gluconeogensis and ketone body production. Why?
Pyruvate
PEP
Alanine (primarily
from breakdown of
muscle protein)
FA
AcCoA
AcAc
HMGCoA
(Cit syn. slow due to low
availability of OAA)
OAA
citrate
AcAc
Formation of ketone bodies in liver under conditions of insulin deficiency,
starvation, low carbohydrate diet and prolonged aerobic exercise.
Downside of KB as fuel:
 "wasteful": secreted in the urine, loss of calories
 can lead to lowering of blood pH - ketoacidosis
 generally serum concentration of KB will not exceed about 5 mM. Above
this, elevated levels of KB stimulate sufficient insulin release to reduce
production of KB and prevent concentration from becoming too high.

insulin results in decreased FA oxidation and reduced synthesis of
HMGCoA synthase