Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 71 Cholesterol Metabolism Notes. - biochemistry notes pdf, biochemistry mbbs 1st year notes pdf, biochemistry mbbs notes pdf, biochemistry lecture notes, paramedical biochemistry notes, medical biochemistry pdf, biochemistry lecture notes 2022 ppt, biochemistry pdf.
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