Download MBBS Biochemistry PPT 69 Ketone Body Metabolism Lecture Notes

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Ketone Body

Metabolism
Ketogenesis And Ketolysis

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OR

Formation And Breakdown

Of Ketone Bodies

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Formation And Fates

Of

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Ketone Bodies

In Human Body
What are Ketone Bodies ?

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When ? Where? Why?

and How?

Ketone Bodies are Formed

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In Human Body?

? Ketone body Metabolism Includes:

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?Ketogenesis : Formation of Ketone

bodies

?Ketolysis: Breakdown and Utilization

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of Ketone bodies

?Ketosis: Imbalance in Ketogenesis

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and Ketolysis.
REVIEW!

?Main role of Glucose to body

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cells is to serve as primary

source of energy.

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?Glucose is completely

oxidized to CO2,H2O and

generate ATPs.

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?When body has very excess

Glucose available it is utilized

as below:

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? Required amount of Glucose

is ful y oxidized

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?Further Stored as Glycogen

? Stil further transformed to

fatty acids and stored as TAG.

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In Emergency Condition

? When cel ular Glucose uptake go below sub

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normal

? Fatty acids secondary source of energy undergo

-oxidation to form Acetyl-CoA.

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? Normally, Acetyl-CoA obtained from beta

oxidation of Fatty acids is further oxidized via

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TCA cycle.


In Emergency

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How Acetyl-CoA Gets Accumulated

And Diverted For Ketogenesis ?
? In Emergency Condition
? When Cel ular Glucose is low

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? In response to hormones Glucagon and

Epinephrine

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? There is increased Lipolysis and beta

oxidation Fatty acids.

? In emergency conditions

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? Cellular Glucose levels decreases
? This decreases cel ular Oxalo acetate

(OAA).

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?Since source of OAA is Glucose
(By Pyruvate Carboxylase Rxn).

? OAA is diverted for Gluconeogenesis

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which lowers cel ular OAA.
? OAA is the starting material required to

initiate and operate TCA .

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? Due to low levels of cel ular OAA, end

product of Fatty acid oxidation- Acetyl-

CoA is not utilized via TCA cycle.

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? The underutilized Acetyl-CoA in the

Mitochondrial matrix of Liver gets

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accumulated and diverted for

Ketogenesis.

Ketogenesis

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What Is Ketogenesis?

? Ketogenesis is biosynthesis

of Ketone bodies

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? In emergency conditions at

Mitochondrial matrix of

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Hepatocytes.

Condition In Which Ketogenesis Occurs

? Ketogenesis efficiently occur in

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Emergency conditions

?Fasting/Starvation Phase
?Low Cel ular Glucose Metabolism

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Site For Ketogenesis

OR

Where Does Ketogenesis

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Occurs ?

? Ketone bodies are

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biosynthesized in the

Liver/Hepatocytes at the

Mitochondrial Matrix

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? Ketone bodies formed in

Mitochondria of Hepatocyte come

out in cytosol

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? Later they are diffused into blood
? Transported to reach extrahepatic

/peripheral tissues

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Who is Precursor For

Ketogenesis ?
?Acetyl CoA is

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precursor/starting

material for

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Ketogenesis.

Source Of Acetyl-CoA For Ketogenesis
? Ketone bodies are formed from

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Acetyl CoA ,obtained through

beta oxidation of Fatty acids.

? Acetyl-CoA accumulated in

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Mitochondrial matrix due to

underutilization via TCA cycle is

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diverted for Ketogenesis.

Biochemical Basis for

Ketogenesis

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OR

What Favors Ketogenesis ?

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OR

Why Ketogenesis Occurs In

Emergency Condition ?

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What Factors



Promotes/Triggers

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Ketogenesis ?

? Normal Insulin activity do not

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promote Ketogenesis.

? Low Insulin activity promotes

Ketogenesis.

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? High Glucagon Promotes

Ketogenesis.
? Availability of Glucose in cells, do not

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promote Ketogenesis and form Ketone

bodies.

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? Unavailabity of Glucose in cells promote

Ketogenesis and form Ketone bodies

? Increased Lipolysis and Beta Oxidation of

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Fatty acids promotes Ketogenesis

? Under utilization of Acetyl-CoA via TCA and

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its accumulation in Mitochondrial matrix

triggers ketogenesis.

Biochemical Causes for Ketogenesis

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? In Emergency Condition

?Due to Cel ular Glucose

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deprivation

?Low Glucose metabolism

?Low Cel ular Oxaloacetate

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?Oxaloacetate diverted for

Gluconeogenesis

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?Low Operation of TCA cycle


Complex Str Of Acetyl-CoA Is

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Impermeable through Mitochondrial

Membrane

Way For KETOGENESIS

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Is To Remove Accumulated Acetyl-CoA

Out Of Mitochondrial Matrix
What Are Steps Of

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Ketogenesis?

Precursor For Ketogenesis

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? Accumulated Acetyl-CoA in

Mitochondrial matrix obtained from

Beta oxidation of Fatty acids in

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emergency condition.
? Accumulated Acetyl-CoA is diverted for

Ketogenesis since.

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?Acetyl-CoA is complex and impermeable

cannot cross mitochondrial membrane.

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?Acetyl-CoA is transformed to form Ketone

bodies during steps of Ketogenesis.

?Ketone bodies formed from Acetyl-CoA

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are simple, permeable and cross

mitochondrial membrane to come out of

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Hepatocytes.

Steps Of Ketogenesis

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Isoprenesand
Steroids

Fatty acid

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2 Acetyl CoA

oxidation to CO2

Citric

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-oxidation

acid

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(excess

cycle

Thiolase

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acetyl CoA)

CoA

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Acetoacetyl CoA

acetyl CoA

HMG-CoA synthase

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CoA

MITOCHONDRIAL MATRIX

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Hydroxymethylglutaryl CoA

HMG-CoA-lyase

acetyl CoA

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Acetoacetate

NADH

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(non-enzymatic)

-Hydroxybutyrate

dehydrogenase

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Acetone

NAD+

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-Hydroxybutyrate

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Decarboxylation


q Acetoacetate produces -Hydroxybutyrate

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in a reduction reaction catalyzed by -

Hydroxybutyrate Dehydrogenase in the

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presence of NADH+H+



Formation of

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ketone bodies

HMG, 3-hydroxy-3-methylglutaryl

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Both enzymes

must be present in

mitochondria for

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Ketogenesis to take

place.

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Pathways of ketogenesis in the liver
? Three molecules of Acetyl-

CoA are involved during

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steps of Ketogenesis.

Description Of Reaction Of

Ketogenesis

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? Two molecules of Acetyl-CoA

formed as an end product of -

oxidation condenses with one

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another to form Acetoacetyl ?

CoA

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? This reaction is by a reversal of

the Thiolase reaction by an

enzyme Acetoacetyl-CoA Thiolase.

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nAcetoacetyl-CoA, which is the

starting material for

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Ketogenesis,

nMay also arises directly from

the terminal four carbons of a

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fatty acid during -oxidation.
? The further steps of Ketogenesis

involves:

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? Synthesis and breakdown of

Hydroxy Methyl Glutaryl-CoA/

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3-Hydroxy-3-Methylglutaryl-CoA

(HMG CoA) from Acetoacetyl-CoA.
? By two key Enzymes:
? HMG-CoA Synthase

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? HMG-CoA Lyase

?Subsequently in the

second step a third

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molecule of Acetyl CoA

is added to Acetoacetyl

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CoA.
nCondensation of Acetoacetyl-

CoA with another molecule of

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Acetyl-CoA to form 3-Hydroxy-

3-Methylglutaryl CoA (HMG

CoA)

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nCatalyzed by HMG-CoA

Synthase.

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? These two steps are identical

to the first two steps in the

Cholesterol biosynthesis

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pathway.
? In the third step 3-Hydroxy-3-

Methylglutaryl-CoA Lyase

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(HMG-CoA Lyase) split off

HMG-CoA

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? To release Acetyl-CoA and

Acetoacetate.

v Both Acetoacetate and -Hydroxybutyrate

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are permeable through mitochondrial

membrane.

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v Can be transported across the mitochondrial

membrane and plasma membrane of Liver

cells,

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Ketone bodies enter into blood stream to be

used as a fuel by extra hepatocytes /other

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cells of body.
6. In blood stream, small amounts

of Acetoacetate are

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spontaneously (non-

enzymatically) Decarboxylated

to Acetone.

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7. Acetone is a secondary

,volatile, Ketone body expired

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out by Lungs.

What are Ketone Bodies?
Ketone bodies are

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Ketone group containing compounds

Obtained from Acetyl-CoA

By Steps of Ketogenesis

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Permeable, Soluble

Intermediate Products, of Incomplete

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Oxidation of Fatty Acids

Produced in Emergency Conditions

At Mitochondrial Matrix Of Hepatocytes

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Due to Cel ular Glucose Deprivation

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Names of Three Ketone Bodies

? Three Ketone bodies present in

human body are:

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?Acetoacetate
?Acetone
?b- Hydroxybutyrate

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Structures Of

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Ketone Bodies

Acetoacetate

Is the First Ketone body

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To Be Formed

Hence Termed As

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Primary Ketone Body
1)Primary Ketone Body:(First Formed Ketone Body)

CH3-CO-CH2-COOH Acetoacetic Acid

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(Unstable Product)

2)Secondary Ketone bodies:(Derived From Primary Ketone Body)

CH3-CHOH-CH2-COOH -Hydroxybutyric Acid

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CH3-CO-CH3

Acetone

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(Non-metabolized product)

? True Ketone Bodies:

(Possess Ketone group in their structure)

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?Acetoacetate (Unstable)
?Acetone ( Volatile)
Features Of 3 Ketone Bodies

? Acetoacetate (Primary Ketone body)

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? Acetone (Secondary Ketone body)

? Beta Hydroxy Butyrate (Secondary KB)

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? Ketone bodies formed by Liver are

mobilized out

? Circulated in blood and they may

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enter extra hepatic tissues for its use.

? If not utilized remained in blood

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circulation(Ketonemia) and excreted

through urine(Ketonuria).
Acetone is soluble and volatile and

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cannot be detected in the blood and

expired out by Lungs.

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Odor of Acetone may be detected in

breath(Fruity Odor)

Also urine of a person has high level of

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ketone bodies in the blood (Ketonuria)

Condition where more Acetone is

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produced and expired out gives fruity

odor also termed as Acetone

Breath/ Kussmauls Breathing.

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Acetone Breath is noted in persons

with Prolonged Starvation and

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Diabetic Ketoacidosis.


? Hydroxy Butyrate is an acidic

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compound.

? High levels of Hydroxy Butyrate in

blood

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? May lower blood pH and leads to a

condition of Metabolic Acidosis.

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? Acidosis due to increased Ketone

bodies is termed as Ketoacidosis.

Significance Of

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Ketogenesis
? Ketogenesis becomes of

great significant during

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starvation.

? It improves survival phase of

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vital organs.

? Ketone bodies formed by

Ketogenesis serve as an

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? Alternative source of energy

for extra Hepatocytes.
Ketone Bodies Serves As alternative

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Fuel In Prolonged Starvation

?Brain adapts utilizing

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Ketone bodies in

starvation conditions

where there is poor

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availability of Glucose.
? After 3 days of starvation

Brain gets 25% of its energy

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from Ketone bodies

? After about 40 days of

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starvation, this goes up to

70% energy source to Brain.

?Thus Ketogenesis provides

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energy for vital organs and


?Maintain there minimal

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functions during prolonged

starvation
Aim Of Steps Of Ketogenesis

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OR

What Happens During Steps Of

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Ketogenesis?

? Ketone bodies can be simply

referred as

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? Condensed and modified

forms of Acetyl-CoA
?Ketone Bodies are partial y

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oxidized products of Fatty

Acids (Half broken products

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of Fatty acids)

? Obtained through steps of

Ketogenesis.

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? Ketogenesis takes place to transform

impermeable Acetyl CoA molecules ( which are

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impermeable through mitochondrial

membranes) to permeable Ketone bodies.

? This is By:

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? Condensation of Acetyl-CoA molecules

? Removal of complex impermeable CoA from

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Acetyl-CoA moieties.

? Forming permeable Acetoacetate (Ketone body)
? Main aim to operate

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Ketogenesis in Mitochondria

of Hepatocytes is:

?To remove complex

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impermeable CoA from

carbon units of Acetyl?CoA

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?Form permeable

Acetoacetate(4C) to mobilize

out of Liver.

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? Ketogenesis removes

impermeable and accumulated

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Acetyl-CoA out of Liver

Mitochondria .

? Thus steps of Ketogenesis

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prevent accumulation of Acetyl-

CoA in matrix of mitochondria.
? Ketogenesis retains and

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recycle CoA pool of

Mitochondrial matrix .

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? Carbon units of Acetyl-CoA are

removed as Acetoacetate.

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? Formation of permeable Ketone

body Acetoacetate

? Significantly removes accumulated

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carbon units of Acetyl-CoA

? In form of Acetoacetate (Ketone

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body) from Liver Mitochondrial

matrix.
Regulation of Ketogenesis

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qKetogenesis is regulated at three

crucial steps:

q Control of Free Fatty acid mobilization

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from Adipose tissue (Lipolysis)


q Activity of CAT I / Carnitine

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Palmitoyltransferase-I in Liver.

q Partition of Acetyl-CoA between the

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pathway of Ketogenesis and the Citric

acid cycle by OAA levels.

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Regulation of Ketogenesis

HMG COA Synthase

Is

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Regulatory Enzyme

of Ketogenesis
?HMG-CoA Synthase

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activity is induced by

increased fatty

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acids in blood.

? CoA-SH levels regulate

Ketogenesis to retain CoA

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pool in Mitochondrial matrix.

?Reduced CoA-SH levels

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stimulates HMG CoA Synthase

?Increased CoA-SH levels

inhibits HMG CoA Synthase

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Factors Responsible

For Increased Ketogenesis

? Normal y Ketogenesis takes place to

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smal extent when lowering of cellular

Glucose metabolism initiates.

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? Ketone bodies are generated moderate

levels in our bodies,

? During sleep

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?Between long duration between two

meals
?Rate of Ketogenesis and its

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efficiency directly

depends upon:

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?Insulin activity

?Levels of Cellular Glucose

?Levels of cellular OAA

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?Increased and

incomplete oxidation of

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Fatty acids increases

Ketogenesis.
? Condition where there is

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more cellular Glucose

deprivation

? More is efficiency of

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Ketogenesis.

?Thus conditions which

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accumulates excess of

Acetyl ?CoA in

Mitochondrial matrix.

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?Divert this Acetyl-CoA for

Ketogenesis.
Which Conditions Deprives

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Cellular Glucose And OAA

And

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Increases

Rate Of Ketogenesis ?

?Prolonged Starvation

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?Uncontrolled Condition of

Diabetes mellitus: Diabetic

Ketoacidosis

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?Severe Vomiting
?Toxemia of Pregnancy
? Deprivation of Cellular Glucose
? High rates of Lipolysis and Fatty acid

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Oxidation

? Low levels of cellular Oxaloacetate
? Under utilization of Acetyl CoA in TCA cycle

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? Large accumulated amounts of impermeable

Acetyl-CoA in mitochondrial matrix.

? Accumulated Acetyl-CoA diverted for

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Ketogenesis and

? Formation of soluble and permeable Ketone

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bodies which can be easily mobilized out of the

Mitochondrial matrix.

Inter Relationship

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Of

Carbohydrates And Lipid

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Metabolism
Fats Burns

In The Flame Of Carbohydrates

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MEANS

For Complete Oxidation

Of Fatty Acids

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There Needs Presence of

Sufficient Glucose In The Cells
?Thus low/non availability of

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Oxaloacetate in cells in emergency

condition

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?Does not oxidize Fatty acid Acetyl-

CoA completely via TCA cycle.

?This results in accumulation of Acetyl

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-CoA in Mitochondrial matrix

?Which then activates and diverts

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Acetyl-CoA for Ketogenesis.
? Fat burns under the flame of

Carbohydrates.

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? Complete oxidation of Acetyl-CoA

obtained through Fatty acid

oxidation via TCA cycle

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? Requires sufficient Oxaloacetate

which is a source from normal

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Glucose metabolism.

? Sufficient cellular Glucose (Flame)

keeps the availability of OAA

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? To initiate and operate TCA cycle

and completely oxidize the end

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product of beta oxidation of Fatty

acid Acetyl CoA to CO2 ,H2O and

ATP.

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? Entry of Acetyl CoA and its oxidation

through TCA/Citric acid cycle depends

on availability of Oxaloacetate.

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? Low concentration of Oxaloacetate is

noted :

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?If Glucose is unavailable (Starvation) or

improperly utilized (Diabetes mellitus).

?Oxaloacetate is normally formed from

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Pyruvate by Pyruvate Carboxylase (

Anaplerotic reaction).

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? In Starvation or Diabetes mellitus

Liver Gluconeogenesis is

activated and Oxaloacetate is

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consumed in this pathway.

? Fatty acids are oxidized

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producing excess of Acetyl CoA

which is converted to Ketone

bodies:

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?In deprivation of

Glucose

?Acetyl CoA is under

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utilized and incomplete

oxidized via TCA cycle.

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Why Ketogenesis Occur?
Main aim for steps of Ketogenesis to

occur is:

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? To remove complex, impermeable

,accumulated Acetyl CoA in

Mitochondrial Matrix

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? By transforming Acetyl-CoA into

permeable Ketone bodies by removing

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CoA moiety.

? Maintain the levels of free CoA pool of

Mitochondrial matrix

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? During emergency conditions due to

low cellular Glucose.

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? There is alternatively increased beta

oxidation of Fatty acids, producing

Acetyl-CoA.

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? Deprivation of cellular Glucose also

depletes the levels of Oxalo Acetate

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which is an initiator of TCA cycle.
? Low levels of cellular OAA under

utilizes the Acetyl-CoA via TCA

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cycle.

? Acetyl-CoA which is obtained by

Fatty acid oxidation is less

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utilized via TCA cycle .

? This accumulates impermeable

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Acetyl-CoA in the Mitochondrial

matrix.

? To remove the accumulated,

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impermeable Acetyl-CoA out

from the Mitochondrial matrix,

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there occurs Ketogenesis .
Why Fatty Acids

Are Not Completely Oxidized

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In Emergency Conditions?

? Fatty acids in emergency conditions

are not completely oxidized to

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CO2,H2O and ATP.

? Fatty acids in emergency undergo

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Beta oxidation and produce Acetyl-

CoA

? But the produced Acetyl CoA is not

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further completely oxidized via TCA

cycle.
? Main facts to have incomplete

--- Content provided by⁠ FirstRanker.com ---

oxidation of Fatty acids in

emergency condition are :

--- Content provided by‌ FirstRanker.com ---

?Low levels of cel ular Glucose

and Oxaloacetate

What Makes

--- Content provided by FirstRanker.com ---

Liver Oxaloacetate

To Get Depleted

--- Content provided by⁠ FirstRanker.com ---

In Emergency Conditions?
Remember

?In emergency conditions

--- Content provided by‌ FirstRanker.com ---

where cellular Glucose is low

?Oxaloacetate levels also gets

depleted

--- Content provided by‍ FirstRanker.com ---

?Reasons for depletion of cel ular

OAA are:

--- Content provided by FirstRanker.com ---

?Glucose is the main source of

OAA

?OAA is, obtained by Pyruvate

--- Content provided by‍ FirstRanker.com ---

Carboxylase reaction

?Thus low availability of cellular

--- Content provided by‍ FirstRanker.com ---

Glucose brings low production of

OAA from Glucose in cells.
?OAA of Liver in

--- Content provided by FirstRanker.com ---

emergency condition is

diverted for

Gluconeogenesis and

--- Content provided by⁠ FirstRanker.com ---

transformed to Glucose.

?Which reduces actual

--- Content provided by⁠ FirstRanker.com ---

OAA levels in hepatocytes.

Remember

?OAA is an initiator of TCA

--- Content provided by‌ FirstRanker.com ---

operation and

?OAA is required for

--- Content provided by FirstRanker.com ---

complete oxidation for

Acetyl-CoA.

--- Content provided by​ FirstRanker.com ---

Fates Of Ketone Bodies

OR

Ketolysis/Breakdown

--- Content provided by⁠ FirstRanker.com ---

Of

Ketone Bodies

--- Content provided by⁠ FirstRanker.com ---

OR

Utilization Of Ketone bodies

Types And Fates Of

--- Content provided by⁠ FirstRanker.com ---

Three Ketone bodies
Uses Of Ketone bodies

?Ketone bodies serves as a

--- Content provided by⁠ FirstRanker.com ---

special and major source of

fuel/energy

--- Content provided by​ FirstRanker.com ---

?For certain tissues in

prolonged starvation

phase.

--- Content provided by FirstRanker.com ---

? In the starvation condition

where body has low

--- Content provided by⁠ FirstRanker.com ---

Glucose.

? Ketone bodies are used to

generate energy by several

--- Content provided by FirstRanker.com ---

extra hepatic tissues
Fate Of Acetoacetate

?Acetoacetate may be oxidized and serve as

--- Content provided by‍ FirstRanker.com ---

a source of energy to extrahepatocytes.

? If not oxidized to form usable energy,
it is converted to next two Ketone bodies

--- Content provided by⁠ FirstRanker.com ---

?Acetone and BHB

?If it is not utilized Acetoacetate excreted

--- Content provided by​ FirstRanker.com ---

out through urine.

Fate of -Hydroxybutyrate

?It is not technically a Ketone

--- Content provided by FirstRanker.com ---

according to IUPAC

nomenclature.

--- Content provided by FirstRanker.com ---

?It may be used up for energy

source or excreted out through

urine if not used.

--- Content provided by FirstRanker.com ---

Fate Of Acetone

?Acetone is not used as

an energy source,

--- Content provided by‍ FirstRanker.com ---

?But it is instead exhaled

or excreted as waste

--- Content provided by⁠ FirstRanker.com ---

through expiration.

Acetone

Do not Serve as Energy Source

--- Content provided by‍ FirstRanker.com ---

?Acetone being volatile ,

is not catabolized and

--- Content provided by‍ FirstRanker.com ---

oxidized

?To liberate energy in the

extra hepatocytes.

--- Content provided by⁠ FirstRanker.com ---

Ketolysis

What Is Ketolysis ?

Catabolism of Ketone bodies

--- Content provided by​ FirstRanker.com ---

? Ketolysis is breaking and

utilization of Ketone bodies as

--- Content provided by‍ FirstRanker.com ---

energy source

? In Mitochondrial matrix of Extra

Hepatocytes.

--- Content provided by‌ FirstRanker.com ---

n Ketone bodies have less potential

metabolic energy than fatty acids

from which they are derived.

--- Content provided by⁠ FirstRanker.com ---

n They make up for this deficiency

by serving as "water-soluble lipid

--- Content provided by​ FirstRanker.com ---

derivatives" that can be more

readily transported in blood.

n During Starvation and in bodies

--- Content provided by FirstRanker.com ---

of uncontrolled Diabetes mellitus,

Ketone bodies are produced in

--- Content provided by​ FirstRanker.com ---

large amounts

n They become substitutes for

Glucose as principal fuel for

--- Content provided by‍ FirstRanker.com ---

Brain cells.
Site Of Ketolysis

?Mitochondrial

--- Content provided by⁠ FirstRanker.com ---

Matrix of Extra

Hepatic Tissues.

--- Content provided by⁠ FirstRanker.com ---

? Thus primary tissues using Ketone

bodies when available are :

?Brain

--- Content provided by‌ FirstRanker.com ---

?Muscle
?Kidney
?Intestine
?But NOT in the Liver
? Ketolysis does not takes place in

--- Content provided by​ FirstRanker.com ---

Liver

? Due to absence of enzyme

--- Content provided by‍ FirstRanker.com ---

Thiophorase in Liver which is

required for Ketolysis.

n In early phase of starvation

--- Content provided by⁠ FirstRanker.com ---

Heart and skeletal muscles

primarily use Ketone bodies

--- Content provided by‌ FirstRanker.com ---

for energy

n Thereby preserving limited

Glucose and supply it for use

--- Content provided by⁠ FirstRanker.com ---

by Brain.
? Brain which normal y depends

on Glucose and do not have

--- Content provided by‍ FirstRanker.com ---

capacity to use Fatty acids.

? during starvation condition

--- Content provided by‍ FirstRanker.com ---

Brain adapts using Ketone

bodies as major energy source

for its survival

--- Content provided by​ FirstRanker.com ---

v Heart Muscle and the Renal cortex

--- Content provided by‌ FirstRanker.com ---

use Acetoacetate in preference to

Glucose in physiological conditions.

--- Content provided by‍ FirstRanker.com ---

v Brain adapts to utilization of

Acetoacetate during Starvation.
Steps Of Ketolysis

--- Content provided by‌ FirstRanker.com ---

Remember

? Ketone bodies will be broken

--- Content provided by FirstRanker.com ---

and utilized in only those

organs/tissues/ cells

? Which possess at least some

--- Content provided by​ FirstRanker.com ---

content of Glucose and Oxalo

acetate.

--- Content provided by‍ FirstRanker.com ---

? Ketolysis breaks Ketone

bodies and releases Acetyl ?

--- Content provided by FirstRanker.com ---

CoA

? The released Acetyl-CoA is

--- Content provided by‍ FirstRanker.com ---

then final y oxidized via TCA

cycle to CO2,H2O and ATPs.

--- Content provided by‌ FirstRanker.com ---

Conversion of Ketone

Bodies to Acetyl-CoA

--- Content provided by FirstRanker.com ---

n Ketone bodies as an energy source, b-

Hydroxybutyrate and Acetoacetate

--- Content provided by‍ FirstRanker.com ---

n Enter mitochondrial matrix of extra

hepatocytes

n Where they are converted to Acetyl

--- Content provided by FirstRanker.com ---

CoA,

n Which is further completely oxidized

--- Content provided by FirstRanker.com ---

by the TCA/ Citric acid cycle.
n b-Hydroxybutyrate is oxidized to

Acetoacetate in a reversible reaction

--- Content provided by FirstRanker.com ---

catalyzed by an isozyme of b-

Hydroxybutyrate Dehydrogenase of

extrahepatocytes.

--- Content provided by FirstRanker.com ---

n Remember that this reaction enzyme

is distinct from Liver enzyme b-

--- Content provided by‍ FirstRanker.com ---

Hydroxybutyrate Dehydrogenase.

Use Of Succinyl-CoA

For Thiophorase Reaction

--- Content provided by​ FirstRanker.com ---

In Ketolysis
? An Enzyme Thiophorase of

Ketolysis requires Succinyl-

--- Content provided by‍ FirstRanker.com ---

CoA for its reaction.

? Succinyl-CoA in this step of

--- Content provided by FirstRanker.com ---

Ketolysis is a donor of

Coenzyme A (?CoASH).

Enzyme Thiophorase

--- Content provided by‌ FirstRanker.com ---

Is Natural y

Absent In Liver
nKetone bodies are broken

--- Content provided by FirstRanker.com ---

down only in non hepatic

tissues

--- Content provided by‍ FirstRanker.com ---

nBecause enzyme Thiophorase is

natural y present in al tissues

except Liver.

--- Content provided by⁠ FirstRanker.com ---

n Also some availability of OAA to

utilize Acetyl-CoA through TCA cycle.

--- Content provided by⁠ FirstRanker.com ---

nIn extrahepatic tissues,

Acetoacetate is activated to

Acetoacetyl-CoA by Succinyl-CoA-

--- Content provided by​ FirstRanker.com ---

by catalytic activity of Acetoacetate

CoAtransferase/Thiophorase/Succi

--- Content provided by​ FirstRanker.com ---

nyl CoA Transferase.

nCoA is transferred from Succinyl-

CoA to form Acetoacetyl-CoA.

--- Content provided by FirstRanker.com ---

? Acetoacetate reacts with

Succinyl CoA to form

Acetoacetyl CoA in a

--- Content provided by​ FirstRanker.com ---

reaction catalyzed by

Succinyl-CoA

--- Content provided by FirstRanker.com ---

Transferase/Thiophorase .

?The Acetoacetyl-CoA is

split to Acetyl-CoA by

--- Content provided by​ FirstRanker.com ---

Thiolase and oxidized

in the Citric acid cycle.

--- Content provided by‍ FirstRanker.com ---

succinyl-CoA

transferase

--- Content provided by‍ FirstRanker.com ---

Conversion of Acetoacetate to Acetyl CoA.

Significance Of Ketolysis

? Ketone Bodies Serve as a

--- Content provided by FirstRanker.com ---

Fuel for Extrahepatic

Tissues on its oxidation in

--- Content provided by​ FirstRanker.com ---

extra hepatocytes in

Starvation condition.
Calorific value of

--- Content provided by⁠ FirstRanker.com ---

Ketone bodies is

7 Cal/gram

Calculation

--- Content provided by‌ FirstRanker.com ---

Of

Energetics From

--- Content provided by‍ FirstRanker.com ---

Degradation of Ketone bodies

in Peripheral tissue
Acetoacetate generates 19 ATPs

--- Content provided by FirstRanker.com ---

? One molecule of Acetoacetate in

Ketolysis liberates 2 Acetyl CoA,

which enter the Citric acid cycle.

--- Content provided by‍ FirstRanker.com ---

?Activation of an Acetoacetate

consumes 1 ATP ,

--- Content provided by‌ FirstRanker.com ---

?Total amount of ATP from

metabolism of 2 Acetyl CoA via TCA

cycle is 20 ? 1 = 19 ATP

--- Content provided by‍ FirstRanker.com ---

- Hydroxybutyrate generates 21.5

ATPs

--- Content provided by‍ FirstRanker.com ---

? Conversion of - Hydroxybutyrate

back into Acetoacetate generates 1

NADH+H+

--- Content provided by FirstRanker.com ---

? NADH+H+ produces an additional 2.5

ATP when enters ETC

--- Content provided by‌ FirstRanker.com ---

? Net generation is 19 +2.5 = 21.5 ATP


Balance and Imbalance

--- Content provided by‍ FirstRanker.com ---

In

Ketone Body Metabolism

? In normal physiological

--- Content provided by⁠ FirstRanker.com ---

conditions.

? There occurs balance in

--- Content provided by FirstRanker.com ---

Ketogenesis and Ketolysis
? When cel ular Carbohydrates and Lipids are

in proper proportionate.

--- Content provided by‍ FirstRanker.com ---

? Then formation and utilization of Ketone

bodies in the body is balanced and low.

? There is balance in Ketogenesis and Ketolysis

--- Content provided by​ FirstRanker.com ---

? A very low levels of blood Ketone bodies are

present in normal physiological healthy

condition.

--- Content provided by​ FirstRanker.com ---

?Normal blood levels of

--- Content provided by​ FirstRanker.com ---

Ketone bodies is approx.

less than 1 mg%.

--- Content provided by⁠ FirstRanker.com ---

Causes Of Ketosis
Levels Of Ketone Bodies

Increases

--- Content provided by FirstRanker.com ---

As

Starvation Phase Prolongs

?3 days starvation

--- Content provided by‍ FirstRanker.com ---

[KB]=3mM

?3 weeks starvation

--- Content provided by​ FirstRanker.com ---

[KB]=7mM
Rate Of Ketolysis

? Rate of Ketolysis in extra

--- Content provided by FirstRanker.com ---

hepatocytes is dependent upon :

?Cel ular levels of Glucose and

Oxaloacetate in extrahepatic

--- Content provided by⁠ FirstRanker.com ---

tissues .

?Rate of Ketolysis

--- Content provided by⁠ FirstRanker.com ---

decreases

?In more deprived

conditions of cellular

--- Content provided by​ FirstRanker.com ---

Glucose and OAA.
Imbalance In

Ketone Body Metabolism

--- Content provided by‌ FirstRanker.com ---

? Imbalance in Ketone body

metabolism is

--- Content provided by‍ FirstRanker.com ---

? Increased Ketogenesis and

decreased Ketolysis.
? No/Low Ketolysis in body cells
? Accumulates Ketone bodies in

--- Content provided by‍ FirstRanker.com ---

blood.

? Which leads to Ketonemia and

--- Content provided by FirstRanker.com ---

Ketonuria.

Ketosis
Ketosis

--- Content provided by‌ FirstRanker.com ---

?Ketosis is a col ective term

used to refer Ketonemia

and Ketonuria .

--- Content provided by‍ FirstRanker.com ---

?Ketosis is a result of

imbalance in Ketone

--- Content provided by​ FirstRanker.com ---

body metabolism.
?Ketosis is a condition

where there is increased

--- Content provided by⁠ FirstRanker.com ---

Ketogenesis and

decreased Ketolysis.

Ketonemia

--- Content provided by​ FirstRanker.com ---

? Ketonemia is an abnormal

increased levels of

--- Content provided by‍ FirstRanker.com ---

circulating Ketone Bodies in

Blood more than 1 mg%.
Ketonuria

--- Content provided by⁠ FirstRanker.com ---

?Ketonuria is an

abnormal excretion of

Ketone bodies in Urine.

--- Content provided by FirstRanker.com ---

? If blood levels of Ketone

bodies crosses more than the

--- Content provided by FirstRanker.com ---

renal threshold levels of KB

(3mg%) it causes-Ketonuria.
Ketoacidosis

--- Content provided by‍ FirstRanker.com ---

? Ketoacidosis is Acidosis caused due

to increased Ketone bodies.

? Ketoacidosis is a type of Metabolic

--- Content provided by FirstRanker.com ---

Acidosis .

? It is caused due to imbalance in

--- Content provided by​ FirstRanker.com ---

Ketone bodies metabolism.

? During KETOACIDOSIS

? Excessive build-up of Ketone

--- Content provided by​ FirstRanker.com ---

bodies results in Ketosis

eventual y

--- Content provided by​ FirstRanker.com ---

? Leading to a fal in blood pH

due to the acidic Ketone

bodies.

--- Content provided by​ FirstRanker.com ---

Ketosis (Ketoacidosis)

Acetone odor in the breath

Acetoacetate and Acetone in urine

--- Content provided by​ FirstRanker.com ---

Biochemical Basis Of Ketosis

?Cel ular Deprivation

--- Content provided by‌ FirstRanker.com ---

Of Glucose

?Low Insulin Activity
Conditions Of Ketosis

--- Content provided by⁠ FirstRanker.com ---

Conditions Of Ketosis

? Prolonged Starvation
? Diabetic Ketoacidosis
(Uncontrol ed Diabetes Mel itus)

--- Content provided by FirstRanker.com ---

? Hyperemesis gravidarum

(Severe Vomiting in first trimester )

? Unbalanced diet i.e. high fat, low

--- Content provided by FirstRanker.com ---

carbohydrate diet

? Renal Glycosuria

--- Content provided by​ FirstRanker.com ---

? Alcoholics after binge drinking

and subsequent starvation

Biochemical Consequences

--- Content provided by‌ FirstRanker.com ---

Of Ketosis
?Ketone bodies

accumulation in body

--- Content provided by⁠ FirstRanker.com ---

?May result to negative

long term effects.

--- Content provided by FirstRanker.com ---

?Ketosis create more load

on Lungs and Kidneys

--- Content provided by​ FirstRanker.com ---

?To expire and excrete

out Ketone Bodies.
? Ketoacidosis lowers blood pH

--- Content provided by FirstRanker.com ---

affects Enzyme activities

? Deranges overal Metabolism
? Affects Normal energy

--- Content provided by‍ FirstRanker.com ---

metabolism

? Affects Water and

Electrolytes Balance

--- Content provided by​ FirstRanker.com ---

? Increased Ketone bodies in

blood is neutralized by alkali

--- Content provided by​ FirstRanker.com ---

reserve (blood buffers HCO3-)

? Very excess of Ketone bodies in

blood exhaust HCO3- ,this leads

--- Content provided by FirstRanker.com ---

to Metabolic acidosis.
? If Ketone bodies are far high than

capacity of alkali reserve to

--- Content provided by⁠ FirstRanker.com ---

neutralize them they will result in

acidemia ?

--- Content provided by‍ FirstRanker.com ---

? Uncompensated acidosis with a

decrease in blood pH (Acid Base

Imbalance) which is a serious that

--- Content provided by⁠ FirstRanker.com ---

results in death if not treated.

Clinical Features Of Ketosis
Acid Base Imbalance

--- Content provided by‌ FirstRanker.com ---

? Metabolic Ketoacidosis
? Reduced Alkali reserve(HCO3_)
? Kussamaul's Respiration
(Acetone Breath)

--- Content provided by‌ FirstRanker.com ---

Water and Electrolytes

Imbalance

--- Content provided by​ FirstRanker.com ---

? Osmotic Diuresis (Loss of water and

electrolytes along with Ketone bodies)

? Dehydration

--- Content provided by‍ FirstRanker.com ---

? Sodium Loss (Hyponatremia)
? Coma
? Death

--- Content provided by‌ FirstRanker.com ---

Diagnosis Of Ketosis

Detection Of Ketone Bodies

Analysis Of

--- Content provided by FirstRanker.com ---

Serum Electrolytes

Arterial Blood Gas

--- Content provided by⁠ FirstRanker.com ---

? Volatile Ketone Body ,Acetone is

expired out through Lungs

--- Content provided by⁠ FirstRanker.com ---

? It can be smelled in Ketotic

persons as Acetone breath (With

Fruity odor)

--- Content provided by‌ FirstRanker.com ---

? Ketone bodies excreted in Urine

can be detected by carrying

Rothera's Test on Urine specimen.

--- Content provided by⁠ FirstRanker.com ---

? Positive Rothera's Test with

Magenta color ring in the tube

--- Content provided by FirstRanker.com ---

confirms Ketonuria.

?Ketoacidosis is detected

by analyzing :

--- Content provided by FirstRanker.com ---

?The Blood pH,

Bicarbonates.
? A patient with Diabetic Ketoacidosis

--- Content provided by FirstRanker.com ---

shows:

?Urine Benedicts Test- Positive

--- Content provided by‍ FirstRanker.com ---

?Urine Rothera's Test- Positive

? A patient with prolonged Starvation

shows:

--- Content provided by⁠ FirstRanker.com ---

?Urine Benedicts Test- Negative

?Urine Rothera's Test- Positive

--- Content provided by‍ FirstRanker.com ---

Management Of Ketosis
?Increasing Cellular Glucose
?Increase Insulin Activity
?Manages condition of

--- Content provided by FirstRanker.com ---

Ketosis.

? In Starvation Oral or

intravenous Glucose infusion

--- Content provided by​ FirstRanker.com ---

? In Diabetic Ketoacidosis

infuse Insulin dosage with

--- Content provided by‌ FirstRanker.com ---

Check on Serum Potassium

levels.
Prevention Of Ketosis

--- Content provided by FirstRanker.com ---

? Avoiding cel ular Glucose deprivation

prevents Ketosis.

? A Patient of Diabetes mellitus (Type I) to

--- Content provided by‍ FirstRanker.com ---

prevent Ketosis should control his/her

blood Glucose.

--- Content provided by​ FirstRanker.com ---

? With proper dosage of Insulin and

maintaining cellular Glucose in cells.

--- Content provided by‍ FirstRanker.com ---

Ketogenic Substances

? Substances Promoting Ketogenesis and

increases Ketone bodies are:

--- Content provided by⁠ FirstRanker.com ---

?Low Cel Glucose
?Excess Fatty acids
?Ketogenic Amino acids
?High Glucagon

--- Content provided by‌ FirstRanker.com ---

?Low Insulin

Prevent Ketogenic Diet
Antiketogenic Substances

--- Content provided by‌ FirstRanker.com ---

? Substances inhibiting Ketogenesis and

decreasing Ketone bodies:

?Sufficient Cel ular Glucose

--- Content provided by​ FirstRanker.com ---

?Glucogenic Amino acids
?Glycerol
?Normal Insulin activity

Most Common Cause Of

--- Content provided by​ FirstRanker.com ---

Ketoacidosis

Diabetic Ketoacidosis

--- Content provided by‌ FirstRanker.com ---

Type I Diabetes Mellitus

Complication
? Diabetic Ketoacidosis is an

--- Content provided by‍ FirstRanker.com ---

Immediate complication of severe

uncontrol ed cases of Diabetes

mel itus(Type I/IDDM)

--- Content provided by​ FirstRanker.com ---

KETOSIS In Diabetes Mellitus

The Absence of Insulin in Diabetes mellitus

--- Content provided by‍ FirstRanker.com ---

? Liver Glucose Metabolism Altered

? inhibition of glycolysis

? activation of fatty acid

--- Content provided by​ FirstRanker.com ---

? activation of gluconeogenesis

mobilization by adipose tissue

--- Content provided by‌ FirstRanker.com ---

? Deficit of oxaloacetate

? Large amounts of acetyl CoA which can not be

utilized in Krebs cycle

--- Content provided by‌ FirstRanker.com ---

? Large amounts of ketone bodies (moderately strong acids)

? Severe Acidosis (ketosis)

--- Content provided by FirstRanker.com ---

Impairment of the tissue function, most importantly in the central

nervous system
In Diabetic patients events that can lead to ketosis are:

--- Content provided by FirstRanker.com ---

? Relative or absolute deficiency of insulin

? Mobilization of free fatty acids (from adipose Lipolysis)

? Increased delivery of free fatty acids to the liver

--- Content provided by⁠ FirstRanker.com ---

? Increased uptake and oxidation of free fatty acids by the liver

? Accelerated production of ketone bodies by the liver

--- Content provided by‍ FirstRanker.com ---

? When there is not enough Insulin in the

blood in cases of IDDM

? Cellular Glucose deprivation affects its

--- Content provided by⁠ FirstRanker.com ---

efficient use to produce energy.

? Thus, the body utilizes the Lipids for its

--- Content provided by‌ FirstRanker.com ---

energy.

? Excessive Lipid degradation with low

Glucose contents , leads to ketones build

--- Content provided by​ FirstRanker.com ---

up in the blood .
? Ketone bodies then spill over into the

urine so that the body can get rid of

--- Content provided by​ FirstRanker.com ---

them.

? Acetone can be exhaled through the

--- Content provided by​ FirstRanker.com ---

lungs. This gives the breath a fruity odor.

? Ketones that build up in the body for a

long time lead to serious illness and

--- Content provided by‌ FirstRanker.com ---

coma. (Diabetic Ketoacidosis)

? Ketone bodies Acetoacetate

--- Content provided by‌ FirstRanker.com ---

and Beta Hydroxy Butyrate

are acidic

? When produced in excess over

--- Content provided by‌ FirstRanker.com ---

long periods in Diabetes,

causes Diabetic ketoacidosis.
? In a case of severe Diabetic

--- Content provided by‌ FirstRanker.com ---

Ketoacidosis

? The Ketone bodies in the

--- Content provided by‌ FirstRanker.com ---

blood and urine may reach

Life threatening

concentrations.

--- Content provided by FirstRanker.com ---

? Blood Ketone bodies may be

up to 100 mg%

--- Content provided by⁠ FirstRanker.com ---

(Normal1mg%)

? Urinary excretion of Ketone

bodies may be as high as 5 gm

--- Content provided by​ FirstRanker.com ---

/day.

(Normal 125 mg/day)

--- Content provided by‌ FirstRanker.com ---

Clinical Features OF DKA

Creates Medical Emergency

--- Content provided by‍ FirstRanker.com ---

Biochemical Basis Of

Diabetes Ketoacidosis (DKA)

--- Content provided by‍ FirstRanker.com ---

Biochemical Alterations In DKA



? Hyperglycemia

--- Content provided by FirstRanker.com ---

? Metabolic Ketoacidosis
? Hyperventilation
? Kussmaul's Respiration
? Low Bicarbonate ions
? Severe Dehydration /Water Imbalance

--- Content provided by⁠ FirstRanker.com ---

? Electrolyte Imbalance
? Acid Base Imbalance
? Coma
? Death

--- Content provided by⁠ FirstRanker.com ---

--- Content provided by​ FirstRanker.com ---

Formation, Utilization, and Excretion of Ketone bodies


Endocrine Interaction And

--- Content provided by​ FirstRanker.com ---

Communication With Liver