GUIDELINES ON SIMILAR BIOLOGICS Regulatory Requirements for Marketing Authori...
Ketone bodies, ketosis & it’s pathogenesis
1. Dr. Ifat Ara Begum
Assistant Professor
Dept of Biochemistry
Dhaka Medical College,
Dhaka
2. Water-soluble derived lipid
Metabolic products that are produced in
excess during excessive breakdown of
fatty acid
Freely transportable form of acetyl
units (don’t need to be with LP/albumin
for transportation in blood).
Acetoacetate, Beta hydroxy butyrate,
and acetone are often referred to as
”Ketone bodies”. “Acetoacetate” is the
primary ketone body.
3.
4. Liver is the only ketogenic organ in
human body (185 gm/ D)
Normal plasma concentration of ketone
body is 1 mg/dl
During high rates of fatty acid oxidation,
primarily in the liver, large amounts of
acetyl-Co A are generated. These
exceed the capacity of the TCA cycle
and one result is the synthesis of
ketone bodies.
5.
6.
7. Ketogenesis takes place in
mitochondria of liver using Acetyl co
A as a substrate or a precursor
molecule.
Enzymes responsible for ketone
body formation are associated
mainly with the mitochondria
HMG co A synthase is the rate
limiting enzyme
8.
9.
10. This enzyme is exclusively present in
liver mitochondria.
There are two isoforms of this enzyme-cytosolic
and mitochondrial.
The mitochondrial enzyme is needed
for ketogenesis while the cytosolic form
is associated with cholesterol
biosynthesis.
11.
12. Liver continues to produce
acetoacetate & beta-hydroxybutyrate
but beta-hydroxybutyrate
predominates over acetoacetate.
Normally beta-hydroxybutyrate to
acetoacetate ratio is about 3:1.
Acetone is produced only when the
concentration of acetoacetate is very
high.
14. Ketogenesis is regulated at three crucial
steps:
(1) control of free fatty acid mobilization
from adipose tissue;
(2) the activity of carnitine acyl
transferase-I in liver, which determines
the proportion of the fatty acid flux that is
oxidized rather than esterified; and
(3) partition of acetyl-CoA between the
pathway of ketogenesis and the citric
acid cycle.
15.
16. Produced by nonenzymatic
irreversible & spontaneous
decarboxylation of acetoacetate
Not used as metabolic fuel
Don’t cause acidosis
Lost via expired air rather than
urine
Produce a characteristic odor
(acetone breath)
17. Ketone bodies are not oxidized in the liver.
Ketone bodies are not oxidized in the liver.
Utilized in extra hepatic tissues such as brain, heart,
Utilized in extra hepatic tissues such as brain, heart,
skeletal muscle and kidney
skeletal muscle and kidney
20. Ketone bodies (acetoacetate & BHB
only) serve as a fuel for extra hepatic
tissues (neuron, skeletal muscles, heart,
kidney).
They are water soluble and may be
transported across the inner
mitochondrial membrane as well as
across the blood-brain barrier and cell
membranes, so, they can be used as a
fuel source by a variety of tissues
including the CNS (exception to FA).
21. They are preferred substrates for
aerobic muscle and heart, thus
sparing glucose when they are
available.
Tissues that can use fatty acids can
generally use ketone bodies in
addition to other energy sources.
The exceptions are the liver and the
brain.
22. BHB & acetoacetate are converted
to acetyl CoA with the help of
thiophorase enzyme.
Acetyl CoA is finally oxidized in
TCA cycle to produce energy.
Liver doesn’t have thiophorase
enzyme, so, fails to use ketone
bodies as metabolic fuel.
23. Succinyl co A Acetoacetate co A
transferase, also known as
Thiophorase, is present at high levels
in most tissues except the liver. This
ensures that extra hepatic tissues
have access to ketone bodies as a
fuel source during prolonged fasting
and starvation.
24. And very low level of enzyme
expression in the liver allows the
liver to produce ketone bodies but
not to utilize them. Also, lack of this
enzyme in the liver prevents the
futile cycle of synthesis and
breakdown of acetoacetate
25. The liver has acetoacetate available
to supply to other organs because it
lacks the particular CoA transferase
and that is the reason that “Ketone
bodies are synthesized in the liver
but utilized in the peripheral
tissues”.
26. Brain is metabolically active and
metabolically privileged. It generally uses
60-70% of total body glucose requirements,
and always requires some glucose for
normal functioning. Under most
conditions, glucose is essentially the sole
energy source of the brain.
The brain cannot use fatty acids as
they cannot cross the blood-brain barrier.
As glucose availability decreases, the brain
is forced to use either amino acids or
ketone bodies for fuel.
27. Heart muscle and the renal cortex
use acetoacetate in preference to
glucose.
In contrast, the brain adapts to the
utilization of acetoacetate during
starvation and diabetes.
In prolonged starvation,75% of the
fuel needs of the brain are met by
ketone bodies.
28. Individuals eating diets extremely
high in fat and low in carbohydrate,
or starving, or suffering from a
severe lack of insulin (Type I
diabetes mellitus) therefore
increase the synthesis and
utilization of ketone bodies
29. 1. Excretion from body,
acetoacetate & BHB via urine and
acetone via expired air
2. Utilization as metabolic fuel by
neuron, skeletal muscles, heart &
kidney.
30.
31. There is simultaneous occurrence
of ketonemia (ketone body
concentration in blood more than
normal) with ketonuria (urinary loss
of ketone body which occurs when
blood ketone body concentration is
more than their renal threshold) .
32.
33. Chronic alcoholism
Heavy exercise
Low carbohydrate diet- For weight
loss
Toxemia of pregnancy
Nonpathologic forms of ketosis are
found under conditions of high-fat
feeding
After severe exercise in the post
absorptive state.
34.
35. Both β-hydroxybutyrate and
acetoacetate are organic acids and
are released in the protonated form
to lower the pH of the blood.
In normal individuals, other
mechanisms compensate for the
increased proton release.
36. But when ketone bodies are
released in large quantities the
normal pH-buffering mechanisms
are overloaded ; the reduced pH, in
combination with a number of other
metabolic abnormalities results in
ketoacidosis. In severe
ketoacidosis, cells begin to lose
ability to use ketone bodies also.
37. Acidosis due to excess ketone bodies
in blood.
Acid-base homeostasis in the blood is
normally maintained
through bicarbonate
buffering, respiratory compensation to
vary the amount of CO2 in the
bloodstream, hydrogen ion absorption
by tissue proteins and bone, and renal
compensation through increased
excretion of dihydrogen
phosphate and ammonium ions.
38. As Ketone bodies are acidic ,
prolonged excess of ketone bodies
can overwhelm normal compensatory
mechanisms, leading to acidosis
(blood pH falls below 7.35).
Two major causes of ketoacidosis:
1. Diabetic ketoacidosis (DKA)
2. Alcoholic ketoacidosis (AKA)
A mild acidosis may result from
prolonged fasting or when following
a ketogenic diet or a very low calorie
diet
39. • Diabetic Ketoacidosis (DKA) is a
state of inadequate insulin levels
resulting in high blood sugar and
accumulation of organic acids and
ketones in the blood.
• It is a potentially life-threatening
complication.
• It happens predominantly in type 1
diabetes mellitus, but can also occur
in type 2 diabetes mellitus under
certain circumstances.
40. DKA results from relative or absolute
insulin deficiency combined
with counter regulatory hormone
excess (Glucagon, Catecholamine,
cortisol, and growth hormone).
Diabetic Ketoacidosis may be
diagnosed when the combination
of hyperglycemia (high blood
sugars), ketones on urinalysis and
acidosis are demonstrated.
41. DM -> Lack of insulin -> Decreased
glucose entry in to cell ->
Decreased OAA -> Suppression of
TCA cycle -> Decreased oxidation
of acetyl CoA -> Accumulation of
acetyl CoA -> Accelerated
ketogenesis -> Ketosis &
ketoacidosis.
42. DM -> Lack of insulin -> Stimulation
of HSL & lipolysis in adipose tissue
-> Excess FFA -> Increased beta
oxidation of FA -> Excess acetyl
CoA production -> Accumulation of
acetyl CoA -> Accelerated
ketogenesis -> ketosis &
ketoacidosis
43. Starvation, vomiting ->
Hypoglycemia -> Lack of insulin ->
same as before
Alcoholism -> suppression of
gluconeogenesis -> Hypoglycemia
-> Lack of insulin -> Same as before
44. Substances that promote ketogenesis
FFA, ketogenic AA
ANTI-KETOGENIC SUBSTANCE:
Substances which prevent ketogenesis.
Carbohydrates, Glucogenic AA,
Glycerol derived from fat, Insulin.