Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 69 Ketone Body Metabolism Notes. - biochemistry notes pdf, biochemistry mbbs 1st year notes pdf, biochemistry mbbs notes pdf, biochemistry lecture notes, paramedical biochemistry notes, medical biochemistry pdf, biochemistry lecture notes 2022 ppt, biochemistry pdf.
Incomplete Oxidation
Of Fatty Acids And There Products
Ketone Body
Metabolism
Ketogenesis And Ketolysis
OR
Formation And Breakdown
Of Ketone Bodies
Formation And Fates
Of
Ketone Bodies
In Human Body
What are Ketone Bodies ?
When ? Where? Why?
and How?
Ketone Bodies are Formed
In Human Body???
? Ketone body Metabolism Includes:
?Ketogenesis : Formation of Ketone
bodies
?Ketolysis: Breakdown and Utilization
of Ketone bodies
?Ketosis: Imbalance in Ketogenesis
and Ketolysis.
REVIEW!
?Main role of Glucose to body
cells is to serve as primary
source of energy.
?Glucose is completely
oxidized to CO2,H2O and
generate ATPs.
?When body has very excess
Glucose available it is utilized
as below:
? Required amount of Glucose
is ful y oxidized
?Further Stored as Glycogen
? Stil further transformed to
fatty acids and stored as TAG.
In Emergency Condition
? When cel ular Glucose uptake go below sub
normal
? Fatty acids secondary source of energy undergo
-oxidation to form Acetyl-CoA.
? Normally, Acetyl-CoA obtained from beta
oxidation of Fatty acids is further oxidized via
TCA cycle.
In Emergency
How Acetyl-CoA Gets Accumulated
And Diverted For Ketogenesis ?
? In Emergency Condition
? When Cel ular Glucose is low
? In response to hormones Glucagon and
Epinephrine
? There is increased Lipolysis and beta
oxidation Fatty acids.
? In emergency conditions
? Cellular Glucose levels decreases
? This decreases cel ular Oxalo acetate
(OAA).
?Since source of OAA is Glucose
(By Pyruvate Carboxylase Rxn).
? OAA is diverted for Gluconeogenesis
which lowers cel ular OAA.
? OAA is the starting material required to
initiate and operate TCA .
? Due to low levels of cel ular OAA, end
product of Fatty acid oxidation- Acetyl-
CoA is not utilized via TCA cycle.
? The underutilized Acetyl-CoA in the
Mitochondrial matrix of Liver gets
accumulated and diverted for
Ketogenesis.
Ketogenesis
What Is Ketogenesis?
? Ketogenesis is biosynthesis
of Ketone bodies
? In emergency conditions at
Mitochondrial matrix of
Hepatocytes.
Condition In Which Ketogenesis Occurs
? Ketogenesis efficiently occur in
Emergency conditions
?Fasting/Starvation Phase
?Low Cel ular Glucose Metabolism
Site For Ketogenesis
OR
Where Does Ketogenesis
Occurs ?
? Ketone bodies are
biosynthesized in the
Liver/Hepatocytes at the
Mitochondrial Matrix
? Ketone bodies formed in
Mitochondria of Hepatocyte come
out in cytosol
? Later they are diffused into blood
? Transported to reach extrahepatic
/peripheral tissues
Who is Precursor For
Ketogenesis ?
?Acetyl CoA is
precursor/starting
material for
Ketogenesis.
Source Of Acetyl-CoA For Ketogenesis
? Ketone bodies are formed from
Acetyl CoA ,obtained through
beta oxidation of Fatty acids.
? Acetyl-CoA accumulated in
Mitochondrial matrix due to
underutilization via TCA cycle is
diverted for Ketogenesis.
Biochemical Basis for
Ketogenesis
OR
What Favors Ketogenesis ?
OR
Why Ketogenesis Occurs In
Emergency Condition ?
What Factors
Promotes/Triggers
Ketogenesis ?
? Normal Insulin activity do not
promote Ketogenesis.
? Low Insulin activity promotes
Ketogenesis.
? High Glucagon Promotes
Ketogenesis.
? Availability of Glucose in cells, do not
promote Ketogenesis and form Ketone
bodies.
? Unavailabity of Glucose in cells promote
Ketogenesis and form Ketone bodies
? Increased Lipolysis and Beta Oxidation of
Fatty acids promotes Ketogenesis
? Under utilization of Acetyl-CoA via TCA and
its accumulation in Mitochondrial matrix
triggers ketogenesis.
Biochemical Causes for Ketogenesis
? In Emergency Condition
?Due to Cel ular Glucose
deprivation
?Low Glucose metabolism
?Low Cel ular Oxaloacetate
?Oxaloacetate diverted for
Gluconeogenesis
?Low Operation of TCA cycle
Complex Str Of Acetyl-CoA Is
Impermeable through Mitochondrial
Membrane
Way For KETOGENESIS
Is To Remove Accumulated Acetyl-CoA
Out Of Mitochondrial Matrix
What Are Steps Of
Ketogenesis?
Precursor For Ketogenesis
? Accumulated Acetyl-CoA in
Mitochondrial matrix obtained from
Beta oxidation of Fatty acids in
emergency condition.
? Accumulated Acetyl-CoA is diverted for
Ketogenesis since.
?Acetyl-CoA is complex and impermeable
cannot cross mitochondrial membrane.
?Acetyl-CoA is transformed to form Ketone
bodies during steps of Ketogenesis.
?Ketone bodies formed from Acetyl-CoA
are simple, permeable and cross
mitochondrial membrane to come out of
Hepatocytes.
Steps Of Ketogenesis
Isoprenesand
Steroids
Fatty acid
2 Acetyl CoA
oxidation to CO2
Citric
-oxidation
acid
(excess
cycle
Thiolase
acetyl CoA)
CoA
Acetoacetyl CoA
acetyl CoA
HMG-CoA synthase
CoA
MITOCHONDRIAL MATRIX
Hydroxymethylglutaryl CoA
HMG-CoA-lyase
acetyl CoA
Acetoacetate
NADH
(non-enzymatic)
-Hydroxybutyrate
dehydrogenase
Acetone
NAD+
-Hydroxybutyrate
Decarboxylation
q Acetoacetate produces -Hydroxybutyrate
in a reduction reaction catalyzed by -
Hydroxybutyrate Dehydrogenase in the
presence of NADH+H+
Formation of
ketone bodies
HMG, 3-hydroxy-3-methylglutaryl
Both enzymes
must be present in
mitochondria for
Ketogenesis to take
place.
Pathways of ketogenesis in the liver
? Three molecules of Acetyl-
CoA are involved during
steps of Ketogenesis.
Description Of Reaction Of
Ketogenesis
? Two molecules of Acetyl-CoA
formed as an end product of -
oxidation condenses with one
another to form Acetoacetyl ?
CoA
? This reaction is by a reversal of
the Thiolase reaction by an
enzyme Acetoacetyl-CoA Thiolase.
nAcetoacetyl-CoA, which is the
starting material for
Ketogenesis,
nMay also arises directly from
the terminal four carbons of a
fatty acid during -oxidation.
? The further steps of Ketogenesis
involves:
? Synthesis and breakdown of
Hydroxy Methyl Glutaryl-CoA/
3-Hydroxy-3-Methylglutaryl-CoA
(HMG CoA) from Acetoacetyl-CoA.
? By two key Enzymes:
? HMG-CoA Synthase
? HMG-CoA Lyase
?Subsequently in the
second step a third
molecule of Acetyl CoA
is added to Acetoacetyl
CoA.
nCondensation of Acetoacetyl-
CoA with another molecule of
Acetyl-CoA to form 3-Hydroxy-
3-Methylglutaryl CoA (HMG
CoA)
nCatalyzed by HMG-CoA
Synthase.
? These two steps are identical
to the first two steps in the
Cholesterol biosynthesis
pathway.
? In the third step 3-Hydroxy-3-
Methylglutaryl-CoA Lyase
(HMG-CoA Lyase) split off
HMG-CoA
? To release Acetyl-CoA and
Acetoacetate.
v Both Acetoacetate and -Hydroxybutyrate
are permeable through mitochondrial
membrane.
v Can be transported across the mitochondrial
membrane and plasma membrane of Liver
cells,
Ketone bodies enter into blood stream to be
used as a fuel by extra hepatocytes /other
cells of body.
6. In blood stream, small amounts
of Acetoacetate are
spontaneously (non-
enzymatically) Decarboxylated
to Acetone.
7. Acetone is a secondary
,volatile, Ketone body expired
out by Lungs.
What are Ketone Bodies?
Ketone bodies are
Ketone group containing compounds
Obtained from Acetyl-CoA
By Steps of Ketogenesis
Permeable, Soluble
Intermediate Products, of Incomplete
Oxidation of Fatty Acids
Produced in Emergency Conditions
At Mitochondrial Matrix Of Hepatocytes
Due to Cel ular Glucose Deprivation
Names of Three Ketone Bodies
? Three Ketone bodies present in
human body are:
?Acetoacetate
?Acetone
?b- Hydroxybutyrate
Structures Of
Ketone Bodies
Acetoacetate
Is the First Ketone body
To Be Formed
Hence Termed As
Primary Ketone Body
1)Primary Ketone Body:(First Formed Ketone Body)
CH3-CO-CH2-COOH Acetoacetic Acid
(Unstable Product)
2)Secondary Ketone bodies:(Derived From Primary Ketone Body)
CH3-CHOH-CH2-COOH -Hydroxybutyric Acid
CH3-CO-CH3
Acetone
(Non-metabolized product)
? True Ketone Bodies:
(Possess Ketone group in their structure)
?Acetoacetate (Unstable)
?Acetone ( Volatile)
Features Of 3 Ketone Bodies
? Acetoacetate (Primary Ketone body)
? Acetone (Secondary Ketone body)
? Beta Hydroxy Butyrate (Secondary KB)
? Ketone bodies formed by Liver are
mobilized out
? Circulated in blood and they may
enter extra hepatic tissues for its use.
? If not utilized remained in blood
circulation(Ketonemia) and excreted
through urine(Ketonuria).
Acetone is soluble and volatile and
cannot be detected in the blood and
expired out by Lungs.
Odor of Acetone may be detected in
breath(Fruity Odor)
Also urine of a person has high level of
ketone bodies in the blood (Ketonuria)
Condition where more Acetone is
produced and expired out gives fruity
odor also termed as Acetone
Breath/ Kussmauls Breathing.
Acetone Breath is noted in persons
with Prolonged Starvation and
Diabetic Ketoacidosis.
? Hydroxy Butyrate is an acidic
compound.
? High levels of Hydroxy Butyrate in
blood
? May lower blood pH and leads to a
condition of Metabolic Acidosis.
? Acidosis due to increased Ketone
bodies is termed as Ketoacidosis.
Significance Of
Ketogenesis
? Ketogenesis becomes of
great significant during
starvation.
? It improves survival phase of
vital organs.
? Ketone bodies formed by
Ketogenesis serve as an
? Alternative source of energy
for extra Hepatocytes.
Ketone Bodies Serves As alternative
Fuel In Prolonged Starvation
?Brain adapts utilizing
Ketone bodies in
starvation conditions
where there is poor
availability of Glucose.
? After 3 days of starvation
Brain gets 25% of its energy
from Ketone bodies
? After about 40 days of
starvation, this goes up to
70% energy source to Brain.
?Thus Ketogenesis provides
energy for vital organs and
?Maintain there minimal
functions during prolonged
starvation
Aim Of Steps Of Ketogenesis
OR
What Happens During Steps Of
Ketogenesis?
? Ketone bodies can be simply
referred as
? Condensed and modified
forms of Acetyl-CoA
?Ketone Bodies are partial y
oxidized products of Fatty
Acids (Half broken products
of Fatty acids)
? Obtained through steps of
Ketogenesis.
? Ketogenesis takes place to transform
impermeable Acetyl CoA molecules ( which are
impermeable through mitochondrial
membranes) to permeable Ketone bodies.
? This is By:
? Condensation of Acetyl-CoA molecules
? Removal of complex impermeable CoA from
Acetyl-CoA moieties.
? Forming permeable Acetoacetate (Ketone body)
? Main aim to operate
Ketogenesis in Mitochondria
of Hepatocytes is:
?To remove complex
impermeable CoA from
carbon units of Acetyl?CoA
?Form permeable
Acetoacetate(4C) to mobilize
out of Liver.
? Ketogenesis removes
impermeable and accumulated
Acetyl-CoA out of Liver
Mitochondria .
? Thus steps of Ketogenesis
prevent accumulation of Acetyl-
CoA in matrix of mitochondria.
? Ketogenesis retains and
recycle CoA pool of
Mitochondrial matrix .
? Carbon units of Acetyl-CoA are
removed as Acetoacetate.
? Formation of permeable Ketone
body Acetoacetate
? Significantly removes accumulated
carbon units of Acetyl-CoA
? In form of Acetoacetate (Ketone
body) from Liver Mitochondrial
matrix.
Regulation of Ketogenesis
qKetogenesis is regulated at three
crucial steps:
q Control of Free Fatty acid mobilization
from Adipose tissue (Lipolysis)
q Activity of CAT I / Carnitine
Palmitoyltransferase-I in Liver.
q Partition of Acetyl-CoA between the
pathway of Ketogenesis and the Citric
acid cycle by OAA levels.
Regulation of Ketogenesis
HMG COA Synthase
Is
Regulatory Enzyme
of Ketogenesis
?HMG-CoA Synthase
activity is induced by
increased fatty
acids in blood.
? CoA-SH levels regulate
Ketogenesis to retain CoA
pool in Mitochondrial matrix.
?Reduced CoA-SH levels
stimulates HMG CoA Synthase
?Increased CoA-SH levels
inhibits HMG CoA Synthase
Factors Responsible
For Increased Ketogenesis
? Normal y Ketogenesis takes place to
smal extent when lowering of cellular
Glucose metabolism initiates.
? Ketone bodies are generated moderate
levels in our bodies,
? During sleep
?Between long duration between two
meals
?Rate of Ketogenesis and its
efficiency directly
depends upon:
?Insulin activity
?Levels of Cellular Glucose
?Levels of cellular OAA
?Increased and
incomplete oxidation of
Fatty acids increases
Ketogenesis.
? Condition where there is
more cellular Glucose
deprivation
? More is efficiency of
Ketogenesis.
?Thus conditions which
accumulates excess of
Acetyl ?CoA in
Mitochondrial matrix.
?Divert this Acetyl-CoA for
Ketogenesis.
Which Conditions Deprives
Cellular Glucose And OAA
And
Increases
Rate Of Ketogenesis ?
?Prolonged Starvation
?Uncontrolled Condition of
Diabetes mellitus: Diabetic
Ketoacidosis
?Severe Vomiting
?Toxemia of Pregnancy
? Deprivation of Cellular Glucose
? High rates of Lipolysis and Fatty acid
Oxidation
? Low levels of cellular Oxaloacetate
? Under utilization of Acetyl CoA in TCA cycle
? Large accumulated amounts of impermeable
Acetyl-CoA in mitochondrial matrix.
? Accumulated Acetyl-CoA diverted for
Ketogenesis and
? Formation of soluble and permeable Ketone
bodies which can be easily mobilized out of the
Mitochondrial matrix.
Inter Relationship
Of
Carbohydrates And Lipid
Metabolism
Fats Burns
In The Flame Of Carbohydrates
MEANS
For Complete Oxidation
Of Fatty Acids
There Needs Presence of
Sufficient Glucose In The Cells
?Thus low/non availability of
Oxaloacetate in cells in emergency
condition
?Does not oxidize Fatty acid Acetyl-
CoA completely via TCA cycle.
?This results in accumulation of Acetyl
-CoA in Mitochondrial matrix
?Which then activates and diverts
Acetyl-CoA for Ketogenesis.
? Fat burns under the flame of
Carbohydrates.
? Complete oxidation of Acetyl-CoA
obtained through Fatty acid
oxidation via TCA cycle
? Requires sufficient Oxaloacetate
which is a source from normal
Glucose metabolism.
? Sufficient cellular Glucose (Flame)
keeps the availability of OAA
? To initiate and operate TCA cycle
and completely oxidize the end
product of beta oxidation of Fatty
acid Acetyl CoA to CO2 ,H2O and
ATP.
? Entry of Acetyl CoA and its oxidation
through TCA/Citric acid cycle depends
on availability of Oxaloacetate.
? Low concentration of Oxaloacetate is
noted :
?If Glucose is unavailable (Starvation) or
improperly utilized (Diabetes mellitus).
?Oxaloacetate is normally formed from
Pyruvate by Pyruvate Carboxylase (
Anaplerotic reaction).
? In Starvation or Diabetes mellitus
Liver Gluconeogenesis is
activated and Oxaloacetate is
consumed in this pathway.
? Fatty acids are oxidized
producing excess of Acetyl CoA
which is converted to Ketone
bodies:
?In deprivation of
Glucose
?Acetyl CoA is under
utilized and incomplete
oxidized via TCA cycle.
Why Ketogenesis Occur?
Main aim for steps of Ketogenesis to
occur is:
? To remove complex, impermeable
,accumulated Acetyl CoA in
Mitochondrial Matrix
? By transforming Acetyl-CoA into
permeable Ketone bodies by removing
CoA moiety.
? Maintain the levels of free CoA pool of
Mitochondrial matrix
? During emergency conditions due to
low cellular Glucose.
? There is alternatively increased beta
oxidation of Fatty acids, producing
Acetyl-CoA.
? Deprivation of cellular Glucose also
depletes the levels of Oxalo Acetate
which is an initiator of TCA cycle.
? Low levels of cellular OAA under
utilizes the Acetyl-CoA via TCA
cycle.
? Acetyl-CoA which is obtained by
Fatty acid oxidation is less
utilized via TCA cycle .
? This accumulates impermeable
Acetyl-CoA in the Mitochondrial
matrix.
? To remove the accumulated,
impermeable Acetyl-CoA out
from the Mitochondrial matrix,
there occurs Ketogenesis .
Why Fatty Acids
Are Not Completely Oxidized
In Emergency Conditions?
? Fatty acids in emergency conditions
are not completely oxidized to
CO2,H2O and ATP.
? Fatty acids in emergency undergo
Beta oxidation and produce Acetyl-
CoA
? But the produced Acetyl CoA is not
further completely oxidized via TCA
cycle.
? Main facts to have incomplete
oxidation of Fatty acids in
emergency condition are :
?Low levels of cel ular Glucose
and Oxaloacetate
What Makes
Liver Oxaloacetate
To Get Depleted
In Emergency Conditions?
Remember
?In emergency conditions
where cellular Glucose is low
?Oxaloacetate levels also gets
depleted
?Reasons for depletion of cel ular
OAA are:
?Glucose is the main source of
OAA
?OAA is, obtained by Pyruvate
Carboxylase reaction
?Thus low availability of cellular
Glucose brings low production of
OAA from Glucose in cells.
?OAA of Liver in
emergency condition is
diverted for
Gluconeogenesis and
transformed to Glucose.
?Which reduces actual
OAA levels in hepatocytes.
Remember
?OAA is an initiator of TCA
operation and
?OAA is required for
complete oxidation for
Acetyl-CoA.
Fates Of Ketone Bodies
OR
Ketolysis/Breakdown
Of
Ketone Bodies
OR
Utilization Of Ketone bodies
Types And Fates Of
Three Ketone bodies
Uses Of Ketone bodies
?Ketone bodies serves as a
special and major source of
fuel/energy
?For certain tissues in
prolonged starvation
phase.
? In the starvation condition
where body has low
Glucose.
? Ketone bodies are used to
generate energy by several
extra hepatic tissues
Fate Of Acetoacetate
?Acetoacetate may be oxidized and serve as
a source of energy to extrahepatocytes.
? If not oxidized to form usable energy,
it is converted to next two Ketone bodies
?Acetone and BHB
?If it is not utilized Acetoacetate excreted
out through urine.
Fate of -Hydroxybutyrate
?It is not technically a Ketone
according to IUPAC
nomenclature.
?It may be used up for energy
source or excreted out through
urine if not used.
Fate Of Acetone
?Acetone is not used as
an energy source,
?But it is instead exhaled
or excreted as waste
through expiration.
Acetone
Do not Serve as Energy Source
?Acetone being volatile ,
is not catabolized and
oxidized
?To liberate energy in the
extra hepatocytes.
Ketolysis
What Is Ketolysis ?
Catabolism of Ketone bodies
? Ketolysis is breaking and
utilization of Ketone bodies as
energy source
? In Mitochondrial matrix of Extra
Hepatocytes.
n Ketone bodies have less potential
metabolic energy than fatty acids
from which they are derived.
n They make up for this deficiency
by serving as "water-soluble lipid
derivatives" that can be more
readily transported in blood.
n During Starvation and in bodies
of uncontrolled Diabetes mellitus,
Ketone bodies are produced in
large amounts
n They become substitutes for
Glucose as principal fuel for
Brain cells.
Site Of Ketolysis
?Mitochondrial
Matrix of Extra
Hepatic Tissues.
? Thus primary tissues using Ketone
bodies when available are :
?Brain
?Muscle
?Kidney
?Intestine
?But NOT in the Liver
? Ketolysis does not takes place in
Liver
? Due to absence of enzyme
Thiophorase in Liver which is
required for Ketolysis.
n In early phase of starvation
Heart and skeletal muscles
primarily use Ketone bodies
for energy
n Thereby preserving limited
Glucose and supply it for use
by Brain.
? Brain which normal y depends
on Glucose and do not have
capacity to use Fatty acids.
? during starvation condition
Brain adapts using Ketone
bodies as major energy source
for its survival
v Heart Muscle and the Renal cortex
use Acetoacetate in preference to
Glucose in physiological conditions.
v Brain adapts to utilization of
Acetoacetate during Starvation.
Steps Of Ketolysis
Remember
? Ketone bodies will be broken
and utilized in only those
organs/tissues/ cells
? Which possess at least some
content of Glucose and Oxalo
acetate.
? Ketolysis breaks Ketone
bodies and releases Acetyl ?
CoA
? The released Acetyl-CoA is
then final y oxidized via TCA
cycle to CO2,H2O and ATPs.
Conversion of Ketone
Bodies to Acetyl-CoA
n Ketone bodies as an energy source, b-
Hydroxybutyrate and Acetoacetate
n Enter mitochondrial matrix of extra
hepatocytes
n Where they are converted to Acetyl
CoA,
n Which is further completely oxidized
by the TCA/ Citric acid cycle.
n b-Hydroxybutyrate is oxidized to
Acetoacetate in a reversible reaction
catalyzed by an isozyme of b-
Hydroxybutyrate Dehydrogenase of
extrahepatocytes.
n Remember that this reaction enzyme
is distinct from Liver enzyme b-
Hydroxybutyrate Dehydrogenase.
Use Of Succinyl-CoA
For Thiophorase Reaction
In Ketolysis
? An Enzyme Thiophorase of
Ketolysis requires Succinyl-
CoA for its reaction.
? Succinyl-CoA in this step of
Ketolysis is a donor of
Coenzyme A (?CoASH).
Enzyme Thiophorase
Is Natural y
Absent In Liver
nKetone bodies are broken
down only in non hepatic
tissues
nBecause enzyme Thiophorase is
natural y present in al tissues
except Liver.
n Also some availability of OAA to
utilize Acetyl-CoA through TCA cycle.
nIn extrahepatic tissues,
Acetoacetate is activated to
Acetoacetyl-CoA by Succinyl-CoA-
by catalytic activity of Acetoacetate
CoAtransferase/Thiophorase/Succi
nyl CoA Transferase.
nCoA is transferred from Succinyl-
CoA to form Acetoacetyl-CoA.
? Acetoacetate reacts with
Succinyl CoA to form
Acetoacetyl CoA in a
reaction catalyzed by
Succinyl-CoA
Transferase/Thiophorase .
?The Acetoacetyl-CoA is
split to Acetyl-CoA by
Thiolase and oxidized
in the Citric acid cycle.
succinyl-CoA
transferase
Conversion of Acetoacetate to Acetyl CoA.
Significance Of Ketolysis
? Ketone Bodies Serve as a
Fuel for Extrahepatic
Tissues on its oxidation in
extra hepatocytes in
Starvation condition.
Calorific value of
Ketone bodies is
7 Cal/gram
Calculation
Of
Energetics From
Degradation of Ketone bodies
in Peripheral tissue
Acetoacetate generates 19 ATPs
? One molecule of Acetoacetate in
Ketolysis liberates 2 Acetyl CoA,
which enter the Citric acid cycle.
?Activation of an Acetoacetate
consumes 1 ATP ,
?Total amount of ATP from
metabolism of 2 Acetyl CoA via TCA
cycle is 20 ? 1 = 19 ATP
- Hydroxybutyrate generates 21.5
ATPs
? Conversion of - Hydroxybutyrate
back into Acetoacetate generates 1
NADH+H+
? NADH+H+ produces an additional 2.5
ATP when enters ETC
? Net generation is 19 +2.5 = 21.5 ATP
Balance and Imbalance
In
Ketone Body Metabolism
? In normal physiological
conditions.
? There occurs balance in
Ketogenesis and Ketolysis
? When cel ular Carbohydrates and Lipids are
in proper proportionate.
? Then formation and utilization of Ketone
bodies in the body is balanced and low.
? There is balance in Ketogenesis and Ketolysis
? A very low levels of blood Ketone bodies are
present in normal physiological healthy
condition.
?Normal blood levels of
Ketone bodies is approx.
less than 1 mg%.
Causes Of Ketosis
Levels Of Ketone Bodies
Increases
As
Starvation Phase Prolongs
?3 days starvation
[KB]=3mM
?3 weeks starvation
[KB]=7mM
Rate Of Ketolysis
? Rate of Ketolysis in extra
hepatocytes is dependent upon :
?Cel ular levels of Glucose and
Oxaloacetate in extrahepatic
tissues .
?Rate of Ketolysis
decreases
?In more deprived
conditions of cellular
Glucose and OAA.
Imbalance In
Ketone Body Metabolism
? Imbalance in Ketone body
metabolism is
? Increased Ketogenesis and
decreased Ketolysis.
? No/Low Ketolysis in body cells
? Accumulates Ketone bodies in
blood.
? Which leads to Ketonemia and
Ketonuria.
Ketosis
Ketosis
?Ketosis is a col ective term
used to refer Ketonemia
and Ketonuria .
?Ketosis is a result of
imbalance in Ketone
body metabolism.
?Ketosis is a condition
where there is increased
Ketogenesis and
decreased Ketolysis.
Ketonemia
? Ketonemia is an abnormal
increased levels of
circulating Ketone Bodies in
Blood more than 1 mg%.
Ketonuria
?Ketonuria is an
abnormal excretion of
Ketone bodies in Urine.
? If blood levels of Ketone
bodies crosses more than the
renal threshold levels of KB
(3mg%) it causes-Ketonuria.
Ketoacidosis
? Ketoacidosis is Acidosis caused due
to increased Ketone bodies.
? Ketoacidosis is a type of Metabolic
Acidosis .
? It is caused due to imbalance in
Ketone bodies metabolism.
? During KETOACIDOSIS
? Excessive build-up of Ketone
bodies results in Ketosis
eventual y
? Leading to a fal in blood pH
due to the acidic Ketone
bodies.
Ketosis (Ketoacidosis)
Acetone odor in the breath
Acetoacetate and Acetone in urine
Biochemical Basis Of Ketosis
?Cel ular Deprivation
Of Glucose
?Low Insulin Activity
Conditions Of Ketosis
Conditions Of Ketosis
? Prolonged Starvation
? Diabetic Ketoacidosis
(Uncontrol ed Diabetes Mel itus)
? Hyperemesis gravidarum
(Severe Vomiting in first trimester )
? Unbalanced diet i.e. high fat, low
carbohydrate diet
? Renal Glycosuria
? Alcoholics after binge drinking
and subsequent starvation
Biochemical Consequences
Of Ketosis
?Ketone bodies
accumulation in body
?May result to negative
long term effects.
?Ketosis create more load
on Lungs and Kidneys
?To expire and excrete
out Ketone Bodies.
? Ketoacidosis lowers blood pH
affects Enzyme activities
? Deranges overal Metabolism
? Affects Normal energy
metabolism
? Affects Water and
Electrolytes Balance
? Increased Ketone bodies in
blood is neutralized by alkali
reserve (blood buffers HCO3-)
? Very excess of Ketone bodies in
blood exhaust HCO3- ,this leads
to Metabolic acidosis.
? If Ketone bodies are far high than
capacity of alkali reserve to
neutralize them they will result in
acidemia ?
? Uncompensated acidosis with a
decrease in blood pH (Acid Base
Imbalance) which is a serious that
results in death if not treated.
Clinical Features Of Ketosis
Acid Base Imbalance
? Metabolic Ketoacidosis
? Reduced Alkali reserve(HCO3_)
? Kussamaul's Respiration
(Acetone Breath)
Water and Electrolytes
Imbalance
? Osmotic Diuresis (Loss of water and
electrolytes along with Ketone bodies)
? Dehydration
? Sodium Loss (Hyponatremia)
? Coma
? Death
Diagnosis Of Ketosis
Detection Of Ketone Bodies
Analysis Of
Serum Electrolytes
Arterial Blood Gas
? Volatile Ketone Body ,Acetone is
expired out through Lungs
? It can be smelled in Ketotic
persons as Acetone breath (With
Fruity odor)
? Ketone bodies excreted in Urine
can be detected by carrying
Rothera's Test on Urine specimen.
? Positive Rothera's Test with
Magenta color ring in the tube
confirms Ketonuria.
?Ketoacidosis is detected
by analyzing :
?The Blood pH,
Bicarbonates.
? A patient with Diabetic Ketoacidosis
shows:
?Urine Benedicts Test- Positive
?Urine Rothera's Test- Positive
? A patient with prolonged Starvation
shows:
?Urine Benedicts Test- Negative
?Urine Rothera's Test- Positive
Management Of Ketosis
?Increasing Cellular Glucose
?Increase Insulin Activity
?Manages condition of
Ketosis.
? In Starvation Oral or
intravenous Glucose infusion
? In Diabetic Ketoacidosis
infuse Insulin dosage with
Check on Serum Potassium
levels.
Prevention Of Ketosis
? Avoiding cel ular Glucose deprivation
prevents Ketosis.
? A Patient of Diabetes mellitus (Type I) to
prevent Ketosis should control his/her
blood Glucose.
? With proper dosage of Insulin and
maintaining cellular Glucose in cells.
Ketogenic Substances
? Substances Promoting Ketogenesis and
increases Ketone bodies are:
?Low Cel Glucose
?Excess Fatty acids
?Ketogenic Amino acids
?High Glucagon
?Low Insulin
Prevent Ketogenic Diet
Antiketogenic Substances
? Substances inhibiting Ketogenesis and
decreasing Ketone bodies:
?Sufficient Cel ular Glucose
?Glucogenic Amino acids
?Glycerol
?Normal Insulin activity
Most Common Cause Of
Ketoacidosis
Diabetic Ketoacidosis
Type I Diabetes Mellitus
Complication
? Diabetic Ketoacidosis is an
Immediate complication of severe
uncontrol ed cases of Diabetes
mel itus(Type I/IDDM)
KETOSIS In Diabetes Mellitus
The Absence of Insulin in Diabetes mellitus
? Liver Glucose Metabolism Altered
? inhibition of glycolysis
? activation of fatty acid
? activation of gluconeogenesis
mobilization by adipose tissue
? Deficit of oxaloacetate
? Large amounts of acetyl CoA which can not be
utilized in Krebs cycle
? Large amounts of ketone bodies (moderately strong acids)
? Severe Acidosis (ketosis)
Impairment of the tissue function, most importantly in the central
nervous system
In Diabetic patients events that can lead to ketosis are:
? Relative or absolute deficiency of insulin
? Mobilization of free fatty acids (from adipose Lipolysis)
? Increased delivery of free fatty acids to the liver
? Increased uptake and oxidation of free fatty acids by the liver
? Accelerated production of ketone bodies by the liver
? When there is not enough Insulin in the
blood in cases of IDDM
? Cellular Glucose deprivation affects its
efficient use to produce energy.
? Thus, the body utilizes the Lipids for its
energy.
? Excessive Lipid degradation with low
Glucose contents , leads to ketones build
up in the blood .
? Ketone bodies then spill over into the
urine so that the body can get rid of
them.
? Acetone can be exhaled through the
lungs. This gives the breath a fruity odor.
? Ketones that build up in the body for a
long time lead to serious illness and
coma. (Diabetic Ketoacidosis)
? Ketone bodies Acetoacetate
and Beta Hydroxy Butyrate
are acidic
? When produced in excess over
long periods in Diabetes,
causes Diabetic ketoacidosis.
? In a case of severe Diabetic
Ketoacidosis
? The Ketone bodies in the
blood and urine may reach
Life threatening
concentrations.
? Blood Ketone bodies may be
up to 100 mg%
(Normal1mg%)
? Urinary excretion of Ketone
bodies may be as high as 5 gm
/day.
(Normal 125 mg/day)
Clinical Features OF DKA
Creates Medical Emergency
Biochemical Basis Of
Diabetes Ketoacidosis (DKA)
Biochemical Alterations In DKA
? Hyperglycemia
? Metabolic Ketoacidosis
? Hyperventilation
? Kussmaul's Respiration
? Low Bicarbonate ions
? Severe Dehydration /Water Imbalance
? Electrolyte Imbalance
? Acid Base Imbalance
? Coma
? Death
Formation, Utilization, and Excretion of Ketone bodies
Endocrine Interaction And
Communication With Liver
This post was last modified on 05 April 2022