Download MBBS Biochemistry PPT 71 Cholesterol Metabolism Lecture Notes

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Cholesterol Metabolism

How Is Cholesterol

Generated,Operated,Destructed

In Human Body?
Chemical Structure Of Cholesterol

Recapitulation
Structural Aspects Of Cholesterol

? Cholesterol is a C27 compound.

? Cholesterol has a parent nucleus

Cyclo Pentano Perhydro

Phenantherene Ring.

Two Forms Of Body Cholesterol


Cholesterol Forms

Free Cholesterol And Esterified Cholesterol

?Free Cholesterol is a

derived Lipid (30%)

?Cholesterol Ester is a

simple Lipid and a body

Wax. (70%)


? Cholesteryl Ester is a storage

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

Sources Of Body Cholesterol












Endogenous And Exogenous

Sources Of Body Cholesterol

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

?80% Endogenously produced by

Liver (0.8 gram/day)

?20% Exogenously comes from

digestive tract (0.3 gm/day)

? Assume 400 mg is an intake of

dietary Cholesterol per day

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

novo synthesis


Exogenous Sources Of Cholesterol

(Animal Sterol)

Cholesterol Biosynthesis

Is To Provide

Endogenous Source Of Body

Cholesterol
Amount Of Cholesterol Biosynthesis

? Endogenously about 1

gm/day of Cholesterol is

biosynthesized.

? Ingestion of excess of

Carbohydrates elevates

Cholesterol biosynthesis.


Conditions Favoring

For

Cholesterol Biosynthesis

? Biosynthesis of Cholesterol takes

place:

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

Glucose

?On stimulation of Insulin
Glucose Regulates Cholesterol

Biosynthesis

? Increased free and excess of

cellular Glucose

? Increases rate of endogenous

Cholesterol biosynthesis

qAmount of Cholesterol

biosynthesis depends upon

qAvailability of Acetyl-CoA

obtained from Glucose

metabolism in a well fed

state.
Cholesterol Synthesis

Simplicity to Complexity

? Al 27 carbon units of

Cholesterol Structure are

biosynthesized using

? 2 carbon moiety Acetyl-CoA

units ,obtained from Glucose

metabolism.
Site Of Cholesterol Biosynthesis

Organs and Cel ular Site

For

Cholesterol Biosynthesis

Organs Involved For Cholesterol

Biosynthesis

? Liver (80% )
? Intestine (10%)
? Skin (5%)
? Adrenal Cortex
? Ovaries , Testes , Placenta
? Arterial walls (some extent)
? Cholesterol Synthesizing Enzymes

are partly located in:

?Cytoplasm
?Endoplasmic Reticulum

Requirements For Cholesterol

Biosynthesis
Requirements For

Reductive Biosynthesis Of Cholesterol

? Metabolic Precursor- Acetyl CoA

(Obtained from excess Glucose

metabolism)

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

Translocation Of Acetyl CoA

From

Mitochondrial Matrix

To

Cytosol
? Cholesterol is biosynthesized

from Cytosolic Acetyl CoA

? Which is transported from

Mitochondria via the Citrate

transport system.

Stages Of Cholesterol Biosynthesis
? Biosynthesis of Cholesterol is a

very complex process

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

? Stage 1.

? Acetyl-CoA forms HMG-CoA and Mevalonate.

? Stage 2.

? Mevalonate forms Active Isoprenoid units(C5)

? Stage 3.

? 6 Isoprenoid units form Squalene (C30)

? Stage 4.

? Squalene is converted to Lanosterol

? Stage 5.

? Lanosterol is converted to Cholesterol(C27)


Overview/Outline of Cholesterol Synthesis

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

Formation of C15 and C30 intermediates

? Michael Palmer 2014


Squalene cyclization yields the first sterol

intermediate

Demethylation, desaturation and saturation steps

convert Lanosterol to Cholesterol


UV-dependent synthesis of Cholecalciferol
Stage I

Synthesis Of HMG CoA

and

Mevalonate

It starts by the condensation of

three molecules of Acetyl

CoA(C2) with the formation of

HMG CoA (C6) by HMG CoA

Synthase (As like In Ketogenesis)




HMG CoA is Reduced to Mevalonic acid (C6)

by reaction requiring NADPH+H+ and enzyme

HMG CoA Reductase.

Two molecules of NADPH are consumed in

the reaction.
Stage 2

Formation Of Isoprenoid Unit

Isopentenyl Pyrophosphate (IPP)

? Mevalonate in three subsequent

steps is

?Phosphorylated with ATPs

?Dehydrated and

?Decarboxylated


? To form Isoprenoid unit(C5)-

Isopentenyl pyrophosphate(IPP).



Isomerization Of IPP To DPP

? Isopentenyl Pyrophosphate

(IPP-C5) is isomerized to

Dimethylal yl

Pyrophosphate (DPP-C5)

with the Isomerase activity


Stage 3

Synthesis Of Squalene (C30)
Formation Of

Geranyl Pyrophosphate

(GPP-C10)

?IPP (C5) and DPP (C5) get

condensed to form

Geranyl Pyrophosphate

(GPP-C10)
Formation OF

Farnesyl Pyrophospate

(FPP- C15)

? 1 molecule of GPP condenses with

1 molecule of IPP to form Farnesyl

Pyrophospahte (FPP-C15)
Conversion Of

FPP(C15) to Squalene (C30)

? Two molecules of FPP get

condensed to generate

Squalene.

? At smooth Endoplasmic

Reticulum with the catalytic

activity of Squalene Synthase

Coenzyme NADPH+H+ and

Cofactors Mg , Mn and Co


Sage 4

Conversion Of Squalene To Lanosterol


Stage 5

Transformation Of

Lanosterol To Cholesterol


? Lanosterol is converted to

Cholesterol with many

sequential steps


? With an intermediates

Zymosterol and Desmosterol
Regulation Of

Cholesterol Biosynthesis

HMG-CoA Reductase

? Is regulatory/ key enzyme of

Cholesterol Biosynthesis.

? This enzyme is stimulated and

inhibited as per requirement

of bodies need.
?Enzyme HMG-CoA reductase

has half-life of 3 hrs.

?Degradation of HMG-CoA

reductase depends on

Cholesterol levels.

Modes Of Cholesterol Regulation

?Hormonal Influence
?Covalent Modification
?Feedback Inhibition
Hormonal Regulation

? Insulin In wel fed state:

?Stimulates and increases HMG

CoA Reductase

?Increases Cholesterol

Biosynthesis

? Glucagon and Glucocorticoids in

emergency states:

?Inhibits HMG CoA Reductase.
?Decreases Cholesterol

Biosynthesis.


Covalent Modification

Of

Regulatory Enzyme

HMG CoA Reductase
Phosphorylation

And

Dephosphorylation

Of

HMG CoA Reductase

? Short-term regulation of

Cholesterol biosynthesis is by

? Phosphorylation &

dephosphorylation of Key

enzyme HMG CoA Reductase
? Phosphorylated ?HMG CoA

Reductase- Inactive Form

? Dephosphorylated-HMG CoA

Reductase- Active form

HMG CoA Reductase - Phosphorylation

HMG CoA Reductase ? OH

HMG CoA Reductase ? P

(active)

(inactive)

AMP-Activated

Protein Kinase (high activity)

(+)

phosphatase

AMP

kinase

(+)

(+)

AMP-Activated

increase cAMP

insulin

Protein Kinase

(low activity)

Glucagon/epi
?Under influence of Hormone

Insulin

?HMG CoA Reductase is

Dephosphorylated

?Which activates HMG-CoA

Reductase.

?This increases Cholesterol

Biosynthesis.

?Under influence of Hormone Glucagon

?HMG CoA Reductase is Phosphorylated by

cAMP-dependent Protein Kinases.

?Phosphorylation of the Enzyme

inactivates HMG-CoA Reductase

?This inhibits Cholesterol Biosynthesis.
?Glucagon, Sterols,

Glucocorticoids & low ATP

levels

?Inactivate HMG-CoA

Reductase.

? Insulin, Thyroid hormone,

high ATP levels

? Activate the key enzyme

HMG-CoA Reductase.
Cholesterol Biosynthesis Regulated By

Feed Back Inhibition

? Sufficient amounts of body

Cholesterol regulate its

biosynthesis

? By feed back inhibition of

Enzyme HMG CoA Reductase.

? Ingestion of Cholesterol inhibits

endogenous cholesterol synthesis

(control exerted at both transcriptional

and translational levels).

? Gene expression (mRNA production) is

control ed by Cholesterol levels


Cholesterol Synthesis

Transcription Control

? Rate of HMG-CoA Reductase

mRNA synthesis is control ed

? By transcription factor Sterol

Regulatory Element Binding

Protein (SREBP)
Competitive Inhibitors Of

Cholesterol Biosynthesis

? Drugs like Statins- Lovastatin ,Simvastatin

? Competitive inhibitors of key Enzyme HMG

CoA Reductase of Cholesterol biosynthesis.

? Decreases Endogenous Cholesterol

Biosynthesis

Lovastatin Inhibits Cholesterol

Biosynthesis

? Lovastatin (Mevinolin) blocks HMG-CoA

Reductase activity and prevents biosynthesis

of Cholesterol.

? Lovastatin is an (inactive) Lactone

? In body, Lactone is hydrolyzed to

Mevanolinic acid, which is a competitive

inhibitor of HMG CoA reductase.


Drugs Lowering Cholesterol

? Statins ?

decrease HMG

CoA Reductase

activity

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

(HMG-CoA Reductase Inhibitors)

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

novo cholesterol biosynthesis.

? Effects Of Statins in Human body:

? Cells express more LDL receptors

? Decreases serum LDL levels

? Increased HDL levels

? Increased HDL/LDL ratio

? Suppresses production of VLDL in Liver

? Advantages: Specific; Effective; Well-tolerated.

? Disadvantages: Hepatotoxicity; myopathy; most expensive; contradicted

in pregnant and nursing women.

Bile salts inhibit

intestinal HMG CoA

Reductase.
Cholesterol Transport

Lipoproteins Involved In Cholesterol

Transport In Blood

?Chylomicrons/ULDL
?LDL
?HDL
? Chylomicrons transport dietary

exogenous form of Cholesterol

? From intestine to Liver through

lymph and blood

?LDL transports

Endogenous Cholesterol


?From Liver to Extrahepatic

tissues.
? HDL transports, Cholesterol

for its excretion

? From Extrahepatic tissues to

Liver.

Cholesterol Esterification

? In human body Cholesterol is present in

two forms:

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

excreted out of the body

? It gets esterified to Cholesterol

Ester and transported for its

excretion.

Cholesterol Esterification Enzymes

?Acyl Cholesterol Acyl

Transferase activity (ACAT)


?Lecithin Cholesterol Acyl

Transferase activity (LCAT)


Cholesterol Esterification

LCAT

(Lecithin: Cholesterol Acyltransferase)

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

Transferase (ACAT) is an ER

membrane protein

? ACAT transfers fatty acid of CoA to

C3 Hydroxyl group of Cholesterol

? Excess Cholesterol is stored as

Cholesterol esters in cytosolic lipid

droplets

? LCAT activity is associated

to Lipoprotein HDL.

? HDL is responsible for

transporting of Cholesterol

Ester from extra

hepatocytes to Liver for its

excretion.
Deficiency And Types Of LCAT By

Mutations In LCAT Gene

? Familial LCAT deficiency- Complete

LCAT deficiency

? Fish-Eye disease- Partial deficiency.

? Fish-eye disease progresses, corneal

cloudiness worsens

? Can lead to severely impaired vision.

Functions Of Cholesterol
Fates of Cholesterol

Diet

De novo synthesis

Cholesterol synthesized

in extrahepatic tissues

Liver cholesterol

pool

Secretion of HDL

Free cholesterol

Conversion to bile salts/acids

and VLDL

In bile

Fates Of Body Cholesterol

? Cholesterol in human body is component of various

biomembranes of cells.

? Cholesterol helps in nerve impulse conduction
? Cholesterol is a precursor for
? Bile acids
? Vitamin D
? Steroidal Hormones-

? Aldosterone
? Estrogen
? Progesterone
? Testosterone

?Remember Cholesterol

is not an energy

producing Lipid.

Cholesterol Degradation

and Excretion
? About 1 gram of Cholesterol is

catabolized and excreted out

of body via Bile.

? Cholesterol is mostly converted

to Bile acids and Bile salts and

excreted.

?Thus Cholesterol is

excreted in form of Bile

acids and Bile salts.


Bile Acids Formed From Cholesterol

? Primary Bile Acids:

? Cholic Acid

? Cheno Deoxy Cholic Acid

? Secondary Bile Acids:

? Glycocholic Acid

? Taurocholic Acid

? De- Oxycholic Acid

? Lithocholic Acid

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

Cholesterol are carried through bile

to intestine for its excretion.

? Thus half of body Cholesterol is

degraded to Bile acids and excreted

through feces.

? Cholesterol is modified by

intestinal bacterial flora to

? Cholestenol and

Coprostenol which are then

excreted out in feces.
Balance Of Cholesterol Metabolism

? A person is healthy when there is

a perfect balance between

?Cholesterol Biosynthesis
?Cholesterol Utilization
?Cholesterol Excretion

? This minimizes chances of

Cholesterol deposition in blood

and tissues.
? Bile acids synthesized from

Cholesterol in Liver are carried

through bile

? Released into intestine and

reabsorbed in Jejunum and

Ileum.

Bile Acids are Transformed

To

Bile Salts
Role Of Bile Salts

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

digestion and absorption of intraluminal

lipids

? Through formation of emulsions and

mixed micel es.

Efficiency OF Bile Salts Recycling
Blood Cholesterol

And Its

Clinical Significance

OPTIMAL CHOLESTEROL LEVELS


Adult Normal Reference Ranges

Of Lipid Profile

ANALYTE

REFERENCE RANGE

Total cholesterol

140-200 mg/dL

HDL cholesterol

40-75 mg/dL

LDL cholesterol

50-130 mg/dL

Triglyceride

60-150 mg/dL

125

Remember

Blood Cholesterol is associated to

Lipoproteins in 2 forms:

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


Hypercholesterolemia

Causes, Conditions And

Consequences

Hypercholesterolemia

?Abnormal high levels of

Cholesterol more than

reference range in blood

circulation is termed as

Hypercholesterolemia.
Classification of

Plasma Cholesterol Concentrations

Total cholesterol

Classification

(mg/dl)

< 200

Desirable

200 - 239

Borderline

> 240

High

LDL Cholesterol

? Less than 100 mg/dl Optimal

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

Cholesterol

? 130 to 159 mg/dl Borderline high

? 160 to 189 mg/dl High

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

Scavenging Action

Less than 40 mg/dl

Low level. A major risk factor for CAD

40 to 59 mg/dl

Moderate levels considered significant low risk

60 mg/dl and above

High level. Considered protective against CAD

> 100 mg/dl very high is considered as bad

Types And Causes Of

Hypercholesterolemia

? Primary Causes: Genetic (Non modifiable)

? LDL Receptor defects

? CETP inhibition

? Age, Gender

? Secondary Causes- Life style derangements

? Wrong eating habits

? Sedentary life style

? Addictions-Smoking , Alcoholism



Clinical Conditions Of

Hypercholesterolemia

? Obesity- Diabetes mel itus

(Increased Intake / increased Biosynthesis )

? Nephrotic Syndrome ? Protein loss

(Defective Lipoprotein metabolism which is not internalized)

? Obstructive Jaundice

(Bile duct obstruction no excretion and regurgitation of Bile in

Blood)

? Hypothyroidism

(Decreased Catabolism and decreased Excretion)

Inherited Hypercholesterolemia

? Inherited Hypercholesterolemia is a

genetic cause

? Caused due to defective LDL

receptors on tissues.

? Increases LDL ?Cholesterol in blood



Consequences Of

Hypercholesterolemia


Consequences of High Cholesterol





Consequences Of

Hypercholesterolemia

? Increased risk of Atherosclerosis
? Stimulates plaque/thrombus

formation

? May occlude arteries and
? Leads to tissue infarction

? Infarction is irreversible

damage to tissues due to

absence of Oxygen and

Nutrient.

? Infarction of Brain is Stroke

? Infarction of Heart is MI


Signs And Symptoms Of

Hypercholesterolemia


MORTALITY RELATED

DUE TO

HIGH CHOLESTEROL

? 1 cause of death: Cardio-vascular diseases

? 3 cause of death: Cerebro-vascular



diseases

? 1 + 3 = ~ 40% of al deaths

(Higher risk for Alzheimer & Chronic Liver

disease)









Trends Of Increased Cholesterol And

Death Rates

HDL cholesterol levels lower than

<40 mg/dl)

increase a person's risk of

developing coronary artery

disease, especially in people who

also have high total cholesterol

levels.
? HDL Cholesterol levels greater

than 100 mg/dl

?Also increase risk in developing

coronary artery disease and

Stroke.

CHOLESTEROL PROFILE

IMPROVEMENT STRATEGY
vIMPROVING DIET


vLIFE STYLE MODIFICATIONS

v REGULAR EXERCISE

vSMOKING, ALCOHILISM CESSATION

vSTRESS REDUCTION

v WEIGHT CONTROL


v BEHAVIOR CHANGE



? When diet changes fail.

? Hypolipidemic drugs will

reduce serum Cholesterol and

Triacylglycerol.
Therapeutic Principle:

Lowering Blood Cholesterols

Inhibition of Cholesterol

biosynthesis


Inhibition of Cholesterol

uptake from GIT

Inhibition of Bile acid reuptake


LDL apheresis (Taking away)

Inhibition of Cholesterol Ester

Transfer Protein (CETP) to some

extent increases HDL levels.


? Cholestyramine Resins:

Block reabsorption of bile acids.

? Sitosterols:

acts by blocking the absorption of

Cholesterol from the

gastrointestinal tract.

? Mevocore or Lovastatin:

inhibitors of HMG-CoA Reductase


Drugs Inhibitors of Intestinal Cholesterol Uptake

Effect Of Long Duration Of Drug Usage
Hypocholesterolemia

Causes, Conditions And Consequences

Hypocholesterolemia

?Abnormal low levels of

Cholesterol below

reference range in blood

circulation is termed as

Hypocholesterolemia.
Causes Of Hypocholesterolemia

? Poor Ingestion

? Low Biosynthesis

? More Uptake &Utilization

? More Excretion

? Increased Hypolipidemics

Conditions Of Hypocholesterolemia

Physiological y Cholesterol low in Children's

? Malnutrition

(Decreased Dietary Glucose & Cholesterol)

? Malabsorption

(Poor absorption of Cholesterol in biliary insufficiency)

? Hyperthyroidism

( Increased utilization)

? Pernicious Anemia

? Hemolytic Anemia
(Increased utilization for erythropoiesis and for composition

of bile for bilirubin excretion through bile)

? Liver Disorders

(Decreased biosynthesis)


Consequences Of

Hypocholesterolemia

? Affects all functions of Cholesterol
? Improper structural aspects of cell membrane
? Cells,tissues,organs defects
? Steroidogenesis decreased
? Low Vitamin D
? Poor nerve impulse conduction
? Neurological disorders



Overview Of Cholesterol Metabolism

Role of Transporters

ABCG5 (G5) and ABCG8 (G8)

? ABCG5 (G5) and ABCG8 (G8) Cholesterol

transporter

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

sitosterolemia, a recessive disorder

? Characterized by Cholesterol accumulation and

premature coronary atherosclerosis

This post was last modified on 05 April 2022