Download MBBS Biochemistry PPT 71 Cholesterol Metabolism Lecture Notes

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Generated,Operated,Destructed

In Human Body?
Chemical Structure Of Cholesterol

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Recapitulation
Structural Aspects Of Cholesterol

? Cholesterol is a C27 compound.

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? Cholesterol has a parent nucleus

Cyclo Pentano Perhydro

Phenantherene Ring.

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Two Forms Of Body Cholesterol


Cholesterol Forms

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Free Cholesterol And Esterified Cholesterol

?Free Cholesterol is a

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derived Lipid (30%)

?Cholesterol Ester is a

simple Lipid and a body

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Wax. (70%)


? Cholesteryl Ester is a storage

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and excretory form of
Cholesterol which is found in
most tissues.

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Sources Of Body Cholesterol

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Endogenous And Exogenous

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Sources Of Body Cholesterol

? About 1 g/day originates by biosynthesis
? About 0.3 g/day extracted from food

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?80% Endogenously produced by

Liver (0.8 gram/day)

?20% Exogenously comes from

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digestive tract (0.3 gm/day)

? Assume 400 mg is an intake of

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dietary Cholesterol per day

? It absorb about 50% Cholesterol
? 200 mg is absorbed from GIT
? 800 mg of Cholesterol is from de

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novo synthesis


Exogenous Sources Of Cholesterol

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(Animal Sterol)

Cholesterol Biosynthesis

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Is To Provide

Endogenous Source Of Body

Cholesterol

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Amount Of Cholesterol Biosynthesis

? Endogenously about 1

gm/day of Cholesterol is

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biosynthesized.

? Ingestion of excess of

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Carbohydrates elevates

Cholesterol biosynthesis.

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Conditions Favoring

For

Cholesterol Biosynthesis

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? Biosynthesis of Cholesterol takes

place:

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?In wel fed condition
?When excess of free cel ular

Glucose

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?On stimulation of Insulin
Glucose Regulates Cholesterol

Biosynthesis

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? Increased free and excess of

cellular Glucose

? Increases rate of endogenous

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Cholesterol biosynthesis

qAmount of Cholesterol

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biosynthesis depends upon

qAvailability of Acetyl-CoA

obtained from Glucose

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metabolism in a well fed

state.
Cholesterol Synthesis

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Simplicity to Complexity

? Al 27 carbon units of

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Cholesterol Structure are

biosynthesized using

? 2 carbon moiety Acetyl-CoA

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units ,obtained from Glucose

metabolism.
Site Of Cholesterol Biosynthesis

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Organs and Cel ular Site

For

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Cholesterol Biosynthesis

Organs Involved For Cholesterol

Biosynthesis

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? Liver (80% )
? Intestine (10%)
? Skin (5%)
? Adrenal Cortex

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? Ovaries , Testes , Placenta
? Arterial walls (some extent)
? Cholesterol Synthesizing Enzymes

are partly located in:

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?Cytoplasm
?Endoplasmic Reticulum

Requirements For Cholesterol

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Biosynthesis
Requirements For

Reductive Biosynthesis Of Cholesterol

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? Metabolic Precursor- Acetyl CoA

(Obtained from excess Glucose

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metabolism)

? Enzymes ,Coenzymes and Cofactors
? 16 NADPH +H+ (Through HMP Shunt)
? 36 ATPs

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Translocation Of Acetyl CoA

From

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Mitochondrial Matrix

To

Cytosol

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? Cholesterol is biosynthesized

from Cytosolic Acetyl CoA

? Which is transported from

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Mitochondria via the Citrate

transport system.

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Stages Of Cholesterol Biosynthesis
? Biosynthesis of Cholesterol is a

very complex process

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? To understand divided in 5 Stages
? Requires more than 25 steps.

? Stage 1.

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? Acetyl-CoA forms HMG-CoA and Mevalonate.

? Stage 2.

? Mevalonate forms Active Isoprenoid units(C5)

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? Stage 3.

? 6 Isoprenoid units form Squalene (C30)

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? Stage 4.

? Squalene is converted to Lanosterol

? Stage 5.

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? Lanosterol is converted to Cholesterol(C27)


Overview/Outline of Cholesterol Synthesis

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Initial Activation Steps in Cholesterol Synthesis
Formation of a C10 intermediate GPP

Formation of C15 and C30 intermediates

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? Michael Palmer 2014


Squalene cyclization yields the first sterol

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intermediate

Demethylation, desaturation and saturation steps

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convert Lanosterol to Cholesterol


UV-dependent synthesis of Cholecalciferol
Stage I

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Synthesis Of HMG CoA

and

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Mevalonate

It starts by the condensation of

three molecules of Acetyl

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CoA(C2) with the formation of

HMG CoA (C6) by HMG CoA

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Synthase (As like In Ketogenesis)

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HMG CoA is Reduced to Mevalonic acid (C6)

by reaction requiring NADPH+H+ and enzyme

HMG CoA Reductase.

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Two molecules of NADPH are consumed in

the reaction.
Stage 2

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Formation Of Isoprenoid Unit

Isopentenyl Pyrophosphate (IPP)

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? Mevalonate in three subsequent

steps is

?Phosphorylated with ATPs

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?Dehydrated and

?Decarboxylated

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? To form Isoprenoid unit(C5)-

Isopentenyl pyrophosphate(IPP).

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Isomerization Of IPP To DPP

? Isopentenyl Pyrophosphate

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(IPP-C5) is isomerized to

Dimethylal yl

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Pyrophosphate (DPP-C5)

with the Isomerase activity

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Stage 3

Synthesis Of Squalene (C30)
Formation Of

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Geranyl Pyrophosphate

(GPP-C10)

?IPP (C5) and DPP (C5) get

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condensed to form

Geranyl Pyrophosphate

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(GPP-C10)
Formation OF

Farnesyl Pyrophospate

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(FPP- C15)

? 1 molecule of GPP condenses with

1 molecule of IPP to form Farnesyl

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Pyrophospahte (FPP-C15)
Conversion Of

FPP(C15) to Squalene (C30)

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? Two molecules of FPP get

condensed to generate

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Squalene.

? At smooth Endoplasmic

Reticulum with the catalytic

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activity of Squalene Synthase

Coenzyme NADPH+H+ and

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Cofactors Mg , Mn and Co


Sage 4

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Conversion Of Squalene To Lanosterol


Stage 5

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Transformation Of

Lanosterol To Cholesterol

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? Lanosterol is converted to

Cholesterol with many

sequential steps

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? With an intermediates

Zymosterol and Desmosterol

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Regulation Of

Cholesterol Biosynthesis

HMG-CoA Reductase

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? Is regulatory/ key enzyme of

Cholesterol Biosynthesis.

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? This enzyme is stimulated and

inhibited as per requirement

of bodies need.

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?Enzyme HMG-CoA reductase

has half-life of 3 hrs.

?Degradation of HMG-CoA

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reductase depends on

Cholesterol levels.

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Modes Of Cholesterol Regulation

?Hormonal Influence
?Covalent Modification
?Feedback Inhibition

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Hormonal Regulation

? Insulin In wel fed state:

?Stimulates and increases HMG

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CoA Reductase

?Increases Cholesterol

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Biosynthesis

? Glucagon and Glucocorticoids in

emergency states:

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?Inhibits HMG CoA Reductase.
?Decreases Cholesterol

Biosynthesis.

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Covalent Modification

Of

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Regulatory Enzyme

HMG CoA Reductase
Phosphorylation

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And

Dephosphorylation

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Of

HMG CoA Reductase

? Short-term regulation of

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Cholesterol biosynthesis is by

? Phosphorylation &

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dephosphorylation of Key

enzyme HMG CoA Reductase
? Phosphorylated ?HMG CoA

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Reductase- Inactive Form

? Dephosphorylated-HMG CoA

Reductase- Active form

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HMG CoA Reductase - Phosphorylation

HMG CoA Reductase ? OH

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HMG CoA Reductase ? P

(active)

(inactive)

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AMP-Activated

Protein Kinase (high activity)

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(+)

phosphatase

AMP

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kinase

(+)

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(+)

AMP-Activated

increase cAMP

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insulin

Protein Kinase

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(low activity)

Glucagon/epi
?Under influence of Hormone

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Insulin

?HMG CoA Reductase is

Dephosphorylated

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?Which activates HMG-CoA

Reductase.

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?This increases Cholesterol

Biosynthesis.

?Under influence of Hormone Glucagon

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?HMG CoA Reductase is Phosphorylated by

cAMP-dependent Protein Kinases.

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?Phosphorylation of the Enzyme

inactivates HMG-CoA Reductase

?This inhibits Cholesterol Biosynthesis.

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?Glucagon, Sterols,

Glucocorticoids & low ATP

levels

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?Inactivate HMG-CoA

Reductase.

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? Insulin, Thyroid hormone,

high ATP levels

? Activate the key enzyme

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HMG-CoA Reductase.
Cholesterol Biosynthesis Regulated By

Feed Back Inhibition

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? Sufficient amounts of body

Cholesterol regulate its

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biosynthesis

? By feed back inhibition of

Enzyme HMG CoA Reductase.

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? Ingestion of Cholesterol inhibits

endogenous cholesterol synthesis

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(control exerted at both transcriptional

and translational levels).

? Gene expression (mRNA production) is

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control ed by Cholesterol levels


Cholesterol Synthesis

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Transcription Control

? Rate of HMG-CoA Reductase

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mRNA synthesis is control ed

? By transcription factor Sterol

Regulatory Element Binding

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Protein (SREBP)
Competitive Inhibitors Of

Cholesterol Biosynthesis

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? Drugs like Statins- Lovastatin ,Simvastatin

? Competitive inhibitors of key Enzyme HMG

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CoA Reductase of Cholesterol biosynthesis.

? Decreases Endogenous Cholesterol

Biosynthesis

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Lovastatin Inhibits Cholesterol

Biosynthesis

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? Lovastatin (Mevinolin) blocks HMG-CoA

Reductase activity and prevents biosynthesis

of Cholesterol.

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? Lovastatin is an (inactive) Lactone

? In body, Lactone is hydrolyzed to

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Mevanolinic acid, which is a competitive

inhibitor of HMG CoA reductase.

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Drugs Lowering Cholesterol

? Statins ?

decrease HMG

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CoA Reductase

activity

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"Statins" Competitively Inhibit HMG-CoA Reductase
Effects Of "Statins"

(HMG-CoA Reductase Inhibitors)

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? Action: Competitively inhibits HMG-CoA Reductase, key enzyme for de

novo cholesterol biosynthesis.

? Effects Of Statins in Human body:

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? Cells express more LDL receptors

? Decreases serum LDL levels

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? Increased HDL levels

? Increased HDL/LDL ratio

? Suppresses production of VLDL in Liver

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? Advantages: Specific; Effective; Well-tolerated.

? Disadvantages: Hepatotoxicity; myopathy; most expensive; contradicted

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in pregnant and nursing women.

Bile salts inhibit

intestinal HMG CoA

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Reductase.
Cholesterol Transport

Lipoproteins Involved In Cholesterol

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Transport In Blood

?Chylomicrons/ULDL
?LDL

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?HDL
? Chylomicrons transport dietary

exogenous form of Cholesterol

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? From intestine to Liver through

lymph and blood

?LDL transports

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Endogenous Cholesterol


?From Liver to Extrahepatic

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tissues.
? HDL transports, Cholesterol

for its excretion

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? From Extrahepatic tissues to

Liver.

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Cholesterol Esterification

? In human body Cholesterol is present in

two forms:

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?Free Cholesterol (30%)
?Esterified Cholesterol (70%)
? Cholesterol when has to get

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excreted out of the body

? It gets esterified to Cholesterol

Ester and transported for its

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excretion.

Cholesterol Esterification Enzymes

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?Acyl Cholesterol Acyl

Transferase activity (ACAT)

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?Lecithin Cholesterol Acyl

Transferase activity (LCAT)

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Cholesterol Esterification

LCAT

(Lecithin: Cholesterol Acyltransferase)

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Formation of Cholesterol Esters in Lipoproteins
? Acyl-CoA: Cholesterol Acyl

Transferase (ACAT) is an ER

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membrane protein

? ACAT transfers fatty acid of CoA to

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C3 Hydroxyl group of Cholesterol

? Excess Cholesterol is stored as

Cholesterol esters in cytosolic lipid

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droplets

? LCAT activity is associated

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to Lipoprotein HDL.

? HDL is responsible for

transporting of Cholesterol

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Ester from extra

hepatocytes to Liver for its

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excretion.
Deficiency And Types Of LCAT By

Mutations In LCAT Gene

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? Familial LCAT deficiency- Complete

LCAT deficiency

? Fish-Eye disease- Partial deficiency.

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? Fish-eye disease progresses, corneal

cloudiness worsens

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? Can lead to severely impaired vision.

Functions Of Cholesterol
Fates of Cholesterol

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Diet

De novo synthesis

Cholesterol synthesized

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in extrahepatic tissues

Liver cholesterol

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pool

Secretion of HDL

Free cholesterol

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Conversion to bile salts/acids

and VLDL

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In bile

Fates Of Body Cholesterol

? Cholesterol in human body is component of various

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biomembranes of cells.

? Cholesterol helps in nerve impulse conduction
? Cholesterol is a precursor for

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? Bile acids
? Vitamin D
? Steroidal Hormones-

? Aldosterone

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? Estrogen
? Progesterone
? Testosterone

?Remember Cholesterol

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is not an energy

producing Lipid.

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Cholesterol Degradation

and Excretion
? About 1 gram of Cholesterol is

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catabolized and excreted out

of body via Bile.

? Cholesterol is mostly converted

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to Bile acids and Bile salts and

excreted.

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?Thus Cholesterol is

excreted in form of Bile

acids and Bile salts.

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Bile Acids Formed From Cholesterol

? Primary Bile Acids:

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? Cholic Acid

? Cheno Deoxy Cholic Acid

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? Secondary Bile Acids:

? Glycocholic Acid

? Taurocholic Acid

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? De- Oxycholic Acid

? Lithocholic Acid

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Bile acids are Derived from Cholesterol
? Bile acids , Bile Salts and

Cholesterol are carried through bile

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to intestine for its excretion.

? Thus half of body Cholesterol is

degraded to Bile acids and excreted

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through feces.

? Cholesterol is modified by

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intestinal bacterial flora to

? Cholestenol and

Coprostenol which are then

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excreted out in feces.
Balance Of Cholesterol Metabolism

? A person is healthy when there is

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a perfect balance between

?Cholesterol Biosynthesis
?Cholesterol Utilization

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?Cholesterol Excretion

? This minimizes chances of

Cholesterol deposition in blood

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and tissues.
? Bile acids synthesized from

Cholesterol in Liver are carried

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through bile

? Released into intestine and

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reabsorbed in Jejunum and

Ileum.

Bile Acids are Transformed

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To

Bile Salts
Role Of Bile Salts

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? Bile Salts are effective detergents
? They are biosynthesized in the Liver
? Stored & concentrated in the Gallbladder
? Bile salts in Intestine facilitates in

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digestion and absorption of intraluminal

lipids

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? Through formation of emulsions and

mixed micel es.

Efficiency OF Bile Salts Recycling

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Blood Cholesterol

And Its

Clinical Significance

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OPTIMAL CHOLESTEROL LEVELS


Adult Normal Reference Ranges

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Of Lipid Profile

ANALYTE

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REFERENCE RANGE

Total cholesterol

140-200 mg/dL

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HDL cholesterol

40-75 mg/dL

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LDL cholesterol

50-130 mg/dL

Triglyceride

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60-150 mg/dL

125

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Remember

Blood Cholesterol is associated to

Lipoproteins in 2 forms:

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v Free cholesterol (30%)
v Esterified Cholesterol (70%)

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Hypercholesterolemia

Causes, Conditions And

Consequences

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Hypercholesterolemia

?Abnormal high levels of

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Cholesterol more than

reference range in blood

circulation is termed as

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Hypercholesterolemia.
Classification of

Plasma Cholesterol Concentrations

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Total cholesterol

Classification

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(mg/dl)

< 200

Desirable

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200 - 239

Borderline

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> 240

High

LDL Cholesterol

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? Less than 100 mg/dl Optimal

? 100 to 129 mg/dl Near or above optimal GOOD

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Cholesterol

? 130 to 159 mg/dl Borderline high

? 160 to 189 mg/dl High

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? 190 mg/dl and above Very high/ BAD Cholesterol
HDL Cholesterol

Scavenging Action

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Less than 40 mg/dl

Low level. A major risk factor for CAD

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40 to 59 mg/dl

Moderate levels considered significant low risk

60 mg/dl and above

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High level. Considered protective against CAD

> 100 mg/dl very high is considered as bad

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Types And Causes Of

Hypercholesterolemia

? Primary Causes: Genetic (Non modifiable)

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? LDL Receptor defects

? CETP inhibition

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? Age, Gender

? Secondary Causes- Life style derangements

? Wrong eating habits

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? Sedentary life style

? Addictions-Smoking , Alcoholism

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Clinical Conditions Of

Hypercholesterolemia

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? Obesity- Diabetes mel itus

(Increased Intake / increased Biosynthesis )

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? Nephrotic Syndrome ? Protein loss

(Defective Lipoprotein metabolism which is not internalized)

? Obstructive Jaundice

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(Bile duct obstruction no excretion and regurgitation of Bile in

Blood)

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? Hypothyroidism

(Decreased Catabolism and decreased Excretion)

Inherited Hypercholesterolemia

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? Inherited Hypercholesterolemia is a

genetic cause

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? Caused due to defective LDL

receptors on tissues.

? Increases LDL ?Cholesterol in blood

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Consequences Of

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Hypercholesterolemia


Consequences of High Cholesterol

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Consequences Of

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Hypercholesterolemia

? Increased risk of Atherosclerosis
? Stimulates plaque/thrombus

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formation

? May occlude arteries and
? Leads to tissue infarction

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? Infarction is irreversible

damage to tissues due to

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absence of Oxygen and

Nutrient.

? Infarction of Brain is Stroke

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? Infarction of Heart is MI


Signs And Symptoms Of

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Hypercholesterolemia


MORTALITY RELATED

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DUE TO

HIGH CHOLESTEROL

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? 1 cause of death: Cardio-vascular diseases

? 3 cause of death: Cerebro-vascular

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diseases

? 1 + 3 = ~ 40% of al deaths

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(Higher risk for Alzheimer & Chronic Liver

disease)

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Trends Of Increased Cholesterol And

Death Rates

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HDL cholesterol levels lower than

<40 mg/dl)

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increase a person's risk of

developing coronary artery

disease, especially in people who

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also have high total cholesterol

levels.
? HDL Cholesterol levels greater

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than 100 mg/dl

?Also increase risk in developing

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coronary artery disease and

Stroke.

CHOLESTEROL PROFILE

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IMPROVEMENT STRATEGY
vIMPROVING DIET

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vLIFE STYLE MODIFICATIONS

v REGULAR EXERCISE

vSMOKING, ALCOHILISM CESSATION

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vSTRESS REDUCTION

v WEIGHT CONTROL

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v BEHAVIOR CHANGE

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? When diet changes fail.

? Hypolipidemic drugs will

reduce serum Cholesterol and

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Triacylglycerol.
Therapeutic Principle:

Lowering Blood Cholesterols

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Inhibition of Cholesterol

biosynthesis

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Inhibition of Cholesterol

uptake from GIT

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Inhibition of Bile acid reuptake


LDL apheresis (Taking away)

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Inhibition of Cholesterol Ester

Transfer Protein (CETP) to some

extent increases HDL levels.

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? Cholestyramine Resins:

Block reabsorption of bile acids.

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? Sitosterols:

acts by blocking the absorption of

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Cholesterol from the

gastrointestinal tract.

? Mevocore or Lovastatin:

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inhibitors of HMG-CoA Reductase


Drugs Inhibitors of Intestinal Cholesterol Uptake

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Effect Of Long Duration Of Drug Usage
Hypocholesterolemia

Causes, Conditions And Consequences

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Hypocholesterolemia

?Abnormal low levels of

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Cholesterol below

reference range in blood

circulation is termed as

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Hypocholesterolemia.
Causes Of Hypocholesterolemia

? Poor Ingestion

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? Low Biosynthesis

? More Uptake &Utilization

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? More Excretion

? Increased Hypolipidemics

Conditions Of Hypocholesterolemia

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Physiological y Cholesterol low in Children's

? Malnutrition

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(Decreased Dietary Glucose & Cholesterol)

? Malabsorption

(Poor absorption of Cholesterol in biliary insufficiency)

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? Hyperthyroidism

( Increased utilization)

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? Pernicious Anemia

? Hemolytic Anemia
(Increased utilization for erythropoiesis and for composition

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of bile for bilirubin excretion through bile)

? Liver Disorders

(Decreased biosynthesis)

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Consequences Of

Hypocholesterolemia

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? Affects all functions of Cholesterol
? Improper structural aspects of cell membrane
? Cells,tissues,organs defects
? Steroidogenesis decreased

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? Low Vitamin D
? Poor nerve impulse conduction
? Neurological disorders

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Overview Of Cholesterol Metabolism

Role of Transporters

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ABCG5 (G5) and ABCG8 (G8)

? ABCG5 (G5) and ABCG8 (G8) Cholesterol

transporter

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? Acts in Liver and Intestine
? Prevent accumulation of dietary cholesterol.
? Mutations in either G5 or G8 Genes cause

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sitosterolemia, a recessive disorder

? Characterized by Cholesterol accumulation and

premature coronary atherosclerosis

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