Cholesterol is synthesized in the body from acetyl-CoA and transported in the blood by lipoproteins. It is essential for cell membrane structure and function but high levels can lead to health issues. Cholesterol synthesis is tightly regulated through feedback mechanisms. When cholesterol levels are high, SREBP is inhibited from increasing production of enzymes involved in cholesterol synthesis such as HMG-CoA reductase. Statins are commonly used to lower cholesterol by inhibiting this reductase. Diet and bile also contribute to cholesterol levels, which must be absorbed into intestinal cells and transported to the liver within lipoproteins before being used or excreted.
Subject : Nutrition, Unit- VI
This topic provides brief knowledge about lipid metabolism and it is prepared according to INC syllabus for first year BSc Nursing Students.
Lipid metabolism entails the oxidation of fatty acids to either generate energy or synthesize new lipids from smaller constituent molecules. Lipid metabolism is associated with carbohydrate metabolism, as products of glucose (such as acetyl CoA) can be converted into lipids.
Formation and utilization of ketone bodies; ketoacidosisJinal Tandel
Formation and utilization of ketone bodies is part of lipid metabolism. After completion of this topic one can understand about Ketogenesis, utilization of Ketone bodies and ketoacidosis
Cholesterol (from the Ancient Greek chole- (bile) and stereos (solid), followed by the chemical sufffix -ol for an alcohol) is an organic molecule. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membranes.
Cholesterol also serves as a precursor for the biosynthesis of steroid hormones, bile acid and vitamin D. Cholesterol is the principal sterol synthesized by all animals. In vertebrates, hepatic cells typically produce the greatest amounts. It is absent among prokaryotes (bacteria and archaea), although there are some exceptions, such as Mycoplasma, which require cholesterol for growth.
cholesterol is essential because it is involved in synthesis of
1. steroidal hormone
2.vitamin-d
3.bile acids
4. it is also structural component of cell membrane
IN PLASMA MEMBRANE
Cholesterol is important in the membrane as it helps to maintain cell membrane stability at varying temperatures. Cholesterol is bound to neighbouring phospholipid molecules via hydrogen bonds and therefore at low temperatures, reduces their packing.
2. TRANSPORTATION
Cholesteryl ester, a dietary lipid, is an ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Cholesteryl esters have a lower solubility in water due to their increased hydrophobicity. Esters are formed by replacing at least one –OH (hydroxyl) group with an –O–alkyl (alkoxy) group. They are hydrolyzed by pancreatic enzymes, cholesterol esterase, to produce cholesterol and free fatty acids
cholesterol is also important to maintain structure of lipoprotein
Cholesterol travels through the blood on proteins called “lipoproteins.” Two types of lipoproteins carry cholesterol throughout the body:
1.LDL (low-density lipoprotein), sometimes called “bad” cholesterol, makes up most of your body's cholesterol.
2.HDL (high-density lipoprotein) called “good cholesterol” makes a less part of your body’s cholesterol
cholesterol introduction , synthesis , degradation and functions.
different intermediate products , biochemical importance, fate of cholesterol: synthesis of bile acids (primary and secondary ) , synthesis of vitamin D and different steroid hormones
clinical significance of cholesterol: Hypercholesterolemia ANd hypocholesterolemia normal ranges and so on
Cholesterol Biosynthesis and catabolism for MBBS, Lab. MEd. BDS.pptxRajendra Dev Bhatt
Cholesterol is found exclusively in animals, hence it is often called as animal sterol.
The total body content of cholesterol in an
adult man weighing 70 kg is about 140 g i.e., around 2 g/kg body weight.
The level of cholesterol in blood is related to the development of atherosclerosis & MI.
Subject : Nutrition, Unit- VI
This topic provides brief knowledge about lipid metabolism and it is prepared according to INC syllabus for first year BSc Nursing Students.
Lipid metabolism entails the oxidation of fatty acids to either generate energy or synthesize new lipids from smaller constituent molecules. Lipid metabolism is associated with carbohydrate metabolism, as products of glucose (such as acetyl CoA) can be converted into lipids.
Formation and utilization of ketone bodies; ketoacidosisJinal Tandel
Formation and utilization of ketone bodies is part of lipid metabolism. After completion of this topic one can understand about Ketogenesis, utilization of Ketone bodies and ketoacidosis
Cholesterol (from the Ancient Greek chole- (bile) and stereos (solid), followed by the chemical sufffix -ol for an alcohol) is an organic molecule. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membranes.
Cholesterol also serves as a precursor for the biosynthesis of steroid hormones, bile acid and vitamin D. Cholesterol is the principal sterol synthesized by all animals. In vertebrates, hepatic cells typically produce the greatest amounts. It is absent among prokaryotes (bacteria and archaea), although there are some exceptions, such as Mycoplasma, which require cholesterol for growth.
cholesterol is essential because it is involved in synthesis of
1. steroidal hormone
2.vitamin-d
3.bile acids
4. it is also structural component of cell membrane
IN PLASMA MEMBRANE
Cholesterol is important in the membrane as it helps to maintain cell membrane stability at varying temperatures. Cholesterol is bound to neighbouring phospholipid molecules via hydrogen bonds and therefore at low temperatures, reduces their packing.
2. TRANSPORTATION
Cholesteryl ester, a dietary lipid, is an ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Cholesteryl esters have a lower solubility in water due to their increased hydrophobicity. Esters are formed by replacing at least one –OH (hydroxyl) group with an –O–alkyl (alkoxy) group. They are hydrolyzed by pancreatic enzymes, cholesterol esterase, to produce cholesterol and free fatty acids
cholesterol is also important to maintain structure of lipoprotein
Cholesterol travels through the blood on proteins called “lipoproteins.” Two types of lipoproteins carry cholesterol throughout the body:
1.LDL (low-density lipoprotein), sometimes called “bad” cholesterol, makes up most of your body's cholesterol.
2.HDL (high-density lipoprotein) called “good cholesterol” makes a less part of your body’s cholesterol
cholesterol introduction , synthesis , degradation and functions.
different intermediate products , biochemical importance, fate of cholesterol: synthesis of bile acids (primary and secondary ) , synthesis of vitamin D and different steroid hormones
clinical significance of cholesterol: Hypercholesterolemia ANd hypocholesterolemia normal ranges and so on
Cholesterol Biosynthesis and catabolism for MBBS, Lab. MEd. BDS.pptxRajendra Dev Bhatt
Cholesterol is found exclusively in animals, hence it is often called as animal sterol.
The total body content of cholesterol in an
adult man weighing 70 kg is about 140 g i.e., around 2 g/kg body weight.
The level of cholesterol in blood is related to the development of atherosclerosis & MI.
the slides aim at providing explanations on cholesterol biosynthesis, regulations, functions of cholesterol, and their consequences. facts about lipoproteins have also been included. enjoy the reading
prepared by Asangalwisye Deo
St. john's University of Tanzania
Cholesterol is the major sterol in the animal tissues.
Cholesterol is present in tissues and in plasma either as free cholesterol or as a storage form, combined with a long-chain fatty acid as cholesteryl ester.
In plasma, both forms are transported in lipoproteins
removed from tissues by plasma high-density lipoprotein (HDL) and transported to the liver, where it is eliminated from the body either unchanged or after conversion to bile acids in the process known as reverse cholesterol transport
Cholesterol, which is transported in the blood in lipoproteins because of its absolute insolubility in water, serves as a stabilizing component of cell membranes and as a precursor of the bile salts and steroid hormones.
As a major component of blood lipoproteins, cholesterol can appear in its free, unesterified form in the outer shell of these macromolecules and as cholesterol esters in the lipoprotein core
Best Ayurvedic medicine for Gas and IndigestionSwastikAyurveda
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
1. “Cholesterol” the most feared among Lipids, speaks:
“ Consumed through the diet and produced in the body,
participate in innumerable cellular functions.
Implicated in several Health complications,
And blamed I am, for no fault of Mine.”
3. Objectives:
Cholesterol: Basic Structure, Functions
Details of Biosynthesis of Cholesterol
Regulation of the Cholesterol Synthesis
Absorption of Cholesterol, Transport
Excretion of Cholesterol
Bile Acids and Bile Salts
4. Cholesterol is an Alicyclic Compound, widely
distributed in Free and Esterified forms.
Member of sterol derivative.
Solid Alcohol of high molecular weight.
Molecular formula C27H45OH.
Introduction
5. History
Isolated from Gall stones in 1784.
Thirteen Nobel prizes has ben awarded to the scientists who
devoted most of their career in important discovery related to
Cholesterol.
7. A single Hydroxyl group a C-3.
An Unsaturated center between C5-C6 atoms.
An Eight membered branched Hydrocarbon chain attached
to the D-ring at position 17.
Methyl Group (Designated C-19) attached at position 10 and
another methyl group (Designated C-18) at position 13.
8. Actual concentration of Cholesterol in Plasma of healthy
people 150-200 mg/dl
This value is almost Twice the Normal Concentration of
Blood Glucose.
This accounts for high solubility of Cholesterol in blood
which is due to Plasma Lipoproteins (LDL and VLDL) that
have the ability to bind and thereby solubilize large
amounts of Cholesterol.
9. 30% of Total Plasma Cholesterol –Free
70% - Cholesterol Esters ; where some long chain fatty
acid Linoleic Acid attached by an Ester Bond to
Hydroxyl (-OH group) on C3 of the A-Ring.
10. Cholesterol synthesis
• Synthesized in all tissues.
• Major sites for synthesis- liver, adrenal cortex, testes,
ovaries and intestine.
• All carbon atoms are derived from acetyl CoA.
• Enzymes involved in biosynthesis are partly located in ER
and partly in cytoplasm.
11. All of the carbon atoms of cholesterol are derived from
acetate.
Cholesterol Biosynthesis
12. Observation of their pattern of incorporation into cholesterol
led Konrad Bloch to propose that acetate was first converted to
isoprene units, C5 units that have the carbon skeleton of
isoprene.
Isoprene units are condensed to form a linear
precursor to cholesterol, and then cyclized.
13. Outline of Major Stages of Cholesterol Biosynthesis was :
Acetate Isoprenoid Intermediate Squalene
Cholesterol Cyclization
Product
14. Mevalonate is a Key Intermediate in
Cholesterol Biosynthesis
Cholesterol Biosynthesis begins with
condensation of two molecules of Acetyl
CoA
Catalysed by Thiolase
Next Step requires enzyme HMG CoA Synthase
Catalyses the condensation of a Third Acetyl CoA to
yield HMG CoA.
15. Synthesis of HMG CoA
HMG CoA Synthase is
present in both cytosol and
mitochondria of liver.
Mitochondrial-
ketogenesis
Cytosolic – cholesterol
synthesis
16. HMG CoA then reduced to Mevalonate by HMG CoA
reductase.
Activity of this Reductase Control of Rate of
Cholesterol synthesis.
17. HMG-CoA An important Intermediate for the
biosynthesis of both Cholesterol and
Ketone Bodies.
Biosynthesis of Cholesterol catalyzed by enzymes in
the Cytosol and
Endoplasmic reticulum.
Synthesis of Ketone Bodies Restricted to Mitochondrial
Matrix.
18. The Rate of Mevalonate Synthesis determines
the rate of cholesterol Biosynthesis
Primary regulation of Cholesterol Biosynthesis centred on the
HMG-CoA Reductase Reaction.
HMG-CoA Found in ER
887 AA in a single Polypeptide chain.
Structure of the enzyme deduced by
Michael Brown and Joseph Goldstein.
Has Two Domains.
19. Amino Terminal Domain Mol Wt. 35,000
Seven Hydrophobic
Segments
Thought to cross the
membrane.
Senses signals that lead to its degradation when cholesterol
levels are high.
Carboxyl-Terminal Domain Mol Wt. 62,000
Contains the Catalytic site of
the Enzyme.
Thought to protrude into the
Cytosol.
21. Rate of Synthesis of Reductase mRNA is controlled by the
Sterol Regulatory Element Binding Protein (SREBP).
SREBP( Transcription Factor) binds to the short DNA
Sequence Sterol Regulatory Element(SRE) on the 5’ side
of the Reductase gene When Cholesterol levels
are low.
Sterol Dependent Regulation of Gene
Expression
22. In its Inactive state, the SREBP resides in the
Endoplasmic Reticulum membrane, where it is
associated with SREBP Cleavage Activating Protein
(SCAP) An Integral Membrane Protein
When Cholesterol levels Fall SCAP escorts SREBP in
small membrane vesicles
to Golgi Complex.
Where it is released from the membrane by two
specific Proteolytic Cleavages.
23. First Cleavage frees a fragment of SREBP from SCAP.
The Second Cleavage releases the Regulatory Domain from
the membrane.
Released Protein migrates to the Nucleus and binds the SRE of
the HMG- CoA Reductase Gene as well as other genes in the
Cholesterol Biosynthetic Pathway to enhance Transcription.
25. High Levels of Cholesterol:
Proteolytic Release of SREBP BLOCKED
SREBP in the Nucleus is Rapidly degraded.
These two events halt the transcription of genes
of the cholesterol biosynthetic pathways.
26. When Cholesterol concentration is Low
SCAP binds to Vesicular Proteins that facilitate the
transport of SCAP-SREBP to the golgi apparatus as
already described.
When Cholesterol is Present SCAP binds Cholesterol
Structural Change in
SCAP
It binds to another ER Protein called Insig.
27. Insig: Anchor that retains SCAP and thus SREBP in the ER in
the presence of Cholseterol.
Interactions between SCAP and Insig can also be forged when
Insig binds 25, hydroxycholesterol Metabolite of
Cholesterol.
Thus, two distinct Steroid Protein Interactions serve to prevent
the inappropriate amount of SCAP-SREBP to the Golgi
Complex.
29. Sterol-dependent regulation
Cholesterol High
• SCAP binds to insigs
(ER membrane proteins)
• SCAP-SREBP is
retained in the ER
• Downregulation of
cholesterol synthesis
Cholesterol Low
• SCAP escorts SREBP to
Golgi bodies
• Two proteases cleave
SREBP to a soluble
fragment that enters the
nucleus and binds SRE
• HMG CoA gene
transcription is activated
30. Sterol Accelerated Regulation
The enzyme is bipartite: its cytoplasmic domain carries out
catalysis and its membrane domain senses signals that lead to
its degradation.
The membrane domain may undergo structural changes in
response to increasing concentrations of sterols such as
lanosterol and 25-hydroxycholesterol.
Under these conditions, the reductase appears to bind to a
subset of Insigs that are also associated with the ubiquitinating
enzymes.
31. The reductase is polyubiquitinated
Subsequently extracted from the membrane in a process
that requires Gerenylgeraniol.
The extracted reductase is then degraded by the proteasome.
33. Enzyme phosphorylation and
dephosphorylation
AMP- activated protein kinase
(AMPK) for phosphorylation
switches off the enzyme.
Phosphoprotein phosphatase for
dephosphorylation.
Phosphorylated form of enzyme is
inactive.
Dephosphorylated form – active
Thus, Cholesterol Synthesis
ceases when ATP level is low.
34. Hormonal Regulation
• Insulin and thyroxine favor upregulation of enzyme
expression
• Glucagon and cortisol have opposite effect
36. The statin drugs are structural analogs of
HMG CoA, and are (or are metabolized to)
reversible, competitive inhibitors of HMG
CoA reductase.
Used to decrease
Plasma Cholesterol
Levels.
Inhibition by drugs
37. First stage in this sequence of this reactions :
Synthesis of the Five-Carbon Isoprenoid Intermediates
Isopentenyl Pyrophosphate and Dimethylallyl Pyrophosphate.
Requires ATP.
It takes Six Mevalonates and Ten Steps to make
Lanosterol, the First Tetracyclic Intermediate
38. 1. The CoA group of HMG-CoA is reduced to an alcohol in
an NADPH-dependent reduction catalyzed by
HMG- CoA reductase, yielding Mevalonate.
2. New OH group is phosphorylated by mevalonate-5
phosphotransferase.
3. The phosphate group is converted to a pyrophosphate
by phosphomevalonate kinase.
4. The molecule is decarboxylated and the resulting alcohol
dehydrated by pyrophosphomevalonate decarboxylase.
The formation of isopentenyl pyrophosphate
involves four reactions:
39.
40. Squalene (C30) is synthesized from six molecules
of isopentenyl pyrophosphate (C5)
Squalene is synthesized from isopentenyl pyrophosphate by the
reaction sequence.
C5 C10 C15 C30
This stage in the synthesis of cholesterol starts with the
isomerization of isopentenyl pyrophosphate to dimethylallyl
pyrophosphate.
41. Isopentenyl pyrophosphate and dimethylallyl pyrophosphate
undergo a Head- to-Tail condensation, in which one
pyrophosphate group is displaced and a 10-carbon chain,
Geranyl pyrophosphate, is formed.
Geranyl pyrophosphate undergoes another Head-to-tail
condensation with isopentenyl pyrophosphate, yielding the
15-carbon intermediate Farnesyl pyrophosphate.
Finally, two molecules of farnesyl pyrophosphate join head to
head, with the elimination of both pyrophosphate groups, to
form squalene.
43. Geraniol, a component of rose oil, has the aroma of geraniums.
Farnesol is an aromatic compound found in the flowers of the
Farnese acacia tree.
Squalene , first isolated from the liver of sharks
(genus Squalus), has 30 carbons, 24 in the main
chain and 6 in the form of methyl group branches.
44.
45. The formation of lanosterol from squalene takes place in two
steps:
Squalene-2,3-epoxide is formed first catalysed by the
enzyme squalene mono-oxygenase; requires NADPH and
molecular O2.
In the next step, an enzyme cyclase brings about the
cyclisation of squalene to form lanosterol.
Cyclisation of squalene to form lanosterol
46. From Lanosterol to Cholesterol Takes Another
Twenty Steps
Approximately, Twenty Enzymatic Steps, Starting with
Lanosterol.
Comprise a series of Double Bond Reductions and
Demethylations.
Final Reaction : Reduction of the ∆7 double bond in 7-
dehydrocholesterol.
Alternative Pathway from Lanosterol to Cholesterol: Involves
Three Demethylations to give Zymosterol and then
Isomerization of ∆8 double bond to the ∆5 to produce
Desmosterol.
47. Enzymes Involved in the Transformation of Lanosterol to
Cholesterol are all located in the Endoplasmic reticulum.
48. Cholesterol Absorption
Cholesterol enters the Intestinal Lumen from Three Sources
I. Diet
II. Bile
III. Intestine
Almost all Cholesterol is present in Unesterified (Free Form)
For absorption Cholesterol must be solubilized.
Solubilised by the formation of
Micelles
Then, absorbed by an Active process involving
the Enterocyte protein NPC1L1
Drug Target for Cholesterol absorption
inhibitor EZETIMIBE
49. Absorption of Cholesterol and other sterols (Plant Sterols) is
limited by the presence of ABCG5/G8 transporter on
Enterocytes.
Pumps Excess Sterols back into the Lumen
for Excretion.
Most Cholesterol absorption occurs from the Jejunum to the
terminal Ileum of the small intestine.
50. Cholesterol Esterification
Why??
Enhance the Lipid carrying capacity of the lipoprotein
in the plasma.
Prevents Intracelleular toxicity of Free Cholesterol.
How??
By Enzymes Lecithin Cholesterol Acyl Transferase(LCAT) in
Plasma
ACAT ( Acylcholesterol Acyltransferase) within the Cell.
51.
52. Cholesterol Esters
• 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.
Fig. 8
53. Many Other Factors Influence the Cholesterol
Balance in tissues
Cell cholesterol increase is due to
Uptake of cholesterol-containing lipoproteins by receptors,
eg, the LDL receptor or the scavenger receptor.
Uptake of free cholesterol from cholesterol-rich lipoproteins
to the cell membrane.
Cholesterol synthesis, and
Hydrolysis of cholesteryl esters by the enzyme cholesteryl
ester hydrolase.
54. Decrease is due to
Efflux of cholesterol from the membrane to HDL via the
ATP-binding cassette transporters A1 (ABCA1) and G1
(ABCG1), or SR-B1 class B scavenger receptor B1 ;
Esterification of cholesterol by ACAT (acyl-
CoA:cholesterol acyltransferase); and
Utilization of cholesterol for synthesis of other steroids,
such as hormones, or bile acids in the liver.
55.
56. Transport of Cholesterol
After Absorption Cholesterol together with Triglycerides,
Phospholipids,and a number of
specific Apoproteins is assembled into
a large Lipoprotein called
CHYLOMICRON.
One Apoprotein Component (Apo B-48) Vital for the
formation and Secretion of Chylomicrons.
Patients with the deficiency of this apoprotein leads to a
condition called as Chylomicron Retention Disorder
Characterised by Excess lipid in Enterocytes and Fat
Malabsorption.
57. The liver is a major site of cholesterol synthesis.
Cholesterol and Triacylglycerols in excess of the liver's own
needs are exported into the blood in the form of very low
density lipoproteins.
Triacylglycerols in very low density lipoproteins are hydrolyzed
by lipases on capillary surfaces.
The resulting remnants, which are rich in cholesteryl esters, are
called intermediate -density lipoproteins.
Half of them are taken up by the liver for processing, and half
are converted into low-density lipoprotein by the removal of
more triacylglycerol.
58.
59. Low-density lipoprotein is the major carrier of cholesterol in
blood
The shell also contains a single copy of apo B-100 which
Is recognized by target cells.
They solubilize hydrophobic lipids
The role of LDL is to transport cholesterol to peripheral
tissues and regulate de novo cholesterol synthesis at these
sites.
The process of LDL uptake is Receptor-mediated
endocytosis.
Low-Density Lipoproteins Plays a Central
Role in Cholesterol Metabolism
60. It contains a core of some 1500 cholesterol molecules
esterified to fatty acids most commonly linoleate.
A shell of phospholipids and unesterified cholesterol
molecules surrounds this highly hydrophobic core.
61. Apo B-100 on the surface of an LDL
particle binds to a specific receptor
protein on the plasma membrane of
nonhepatic cells.
The receptors for LDL are localized
in specialized regions called coated
pits contain a specialized
protein called Clathrin.
The receptor- LDL complex is
internalized by Endocytosis; that is,
the plasma membrane in the vicinity
of the complex invaginates and then
fuses to form an Endocytic vesicle.
Receptor-mediated endocytosis
62. These vesicles, containing LDL, subsequently fuse with
Lysosomes, acidic vesicles that carry a wide array of degradative
enzymes.
The protein component of LDL is hydrolyzed to free amino acids.
The cholesteryl esters in LDL are hydrolyzed by a Lysosomal acid
Lipase.
The LDL receptor itself usually returns unharmed to the plasma
membrane.
63.
64. The round-trip time for a receptor is about 10 minutes; in its lifetime
of about a day, it may bring many LDL particles into the cell.
The released unesterified cholesterol can then be used for
membrane biosynthesis.
Alternatively, it can be reesterified for storage inside the cell.
In fact, free cholesterol activates acyl CoA:cholesterol
acyltransferase (ACAT), the enzyme catalyzing this reaction.
65. Reesterified cholesterol contains mainly oleate and
palmitoleate,, in contrast with the cholesterol esters in LDL,
which are rich in linoleate, a polyunsaturated fatty acid.
It is imperative that the cholesterol be reesterified.
High concentrations of unesterified cholesterol disrupt the
integrity of cell membranes.
66. The amino acid sequence of the human LDL receptor
reveals the mosaic structure of this 115-kd protein,839
Amino acids which is composed of five different types of
domains.
The amino-terminal region of the mature receptor is the site
of LDL binding.
Michael S. Brown and Joseph L. Goldstein were awarded the
1985 Nobel Prize for Physiology and Medicine for their
identification of the Low Density Lipoprotein (LDL)
Receptor[5] and its relation to Choletserol metabolism
and Familial Hypercholesterolemia.
The LDL Receptor Is a Transmembrane Protein
Having Five Different
Functional Regions
67. It consists of a cysteine-rich sequence of about 40 residues that is
repeated, with some variation, seven times.
A cluster of negatively charged side chains in this LDL-binding
domain interacts with a positively charged site on an apo B-100
molecule on the surface of an LDL particle.
The third domain, which is very rich in
serine and threonine residues,
contains O-linked sugars.
68. These oligosaccharides may function as struts to keep the
receptor extended from the membrane so that the LDL-
binding domain is accessible to LDL.
The fourth type of domain consists of 22 hydrophobic
residues that span the plasma membrane.
The fifth domain consists of 50 residues and emerges on the
cytoplasmic side of the membrane, where it controls the
interaction of the receptor with coated pits and participates in
endocytosis.
69. In addition to the highly specific and regulated receptor-
mediated pathway for LDL uptake, macrophages possess
high levels of scavenger receptor activity known as
scavenger receptor class A (SR-A).
Of particular concern is the oxidation of the excess blood
LDL to form oxidized LDL in which the lipid components or
apo B have been oxidized.
The scavenger receptor is not down-regulated in response
to increased intracellular cholesterol.
Uptake of chemically modified LDL by
macrophage scavenger receptors
70. • The oxLDL when taken up macrophages become engorged to
form foam cells.
• These foam cells become trapped in the walls of the blood
vessels and contribute to the formation of atherosclerotic
plaques that cause arterial narrowing and lead to heart
attacks.
71.
72. Excretion of cholesterol
By conversion into bile acids and bile salts- excreted in the
feces.
By secretion of cholesterol in bile- transported to intestine
for elimination.
In the intestine cholesterol is converted by bacteria into
coprostanol and cholestanol before excretion.
73. Bile Salts
• Bile acids & salts are effective detergents.
• Synthesized in the liver.
• Stored & concentrated in the gallbladder.
• Discharged into gut and aides in absorption of intraluminal
lipids, cholesterol, & fat soluble vitamins.
• Bile acid refers to the protonated form while bile salts refers to
the ionized form
– The pH of the intestine is 7 and the pKa of bile salts is 6,
which means that 50% are protonated.
74. Synthesis of Bile Salts
• Rate-limiting step performed by the 7α-hydroxylase and is
regulated by bile salt concentration
• End product: Cholic acid & Chenocholic acid
Fig. 9 Fig. 10
75.
76. The primary bile acids enter the bile as glycine or taurine
conjugates.
Conjugation takes place in peroxisomes.
In humans, the ratio of the glycine to the taurine conjugates
is normally 3:1.
In the alkaline bile, the bile acids and their conjugates are
assumed to be in a salt form—hence the term“bile salts.”
A portion of the primary bile acids in the intestine is
subjected to further changes by the activity of the intestinal
bacteria.
77.
78. • Products of fat digestion, including cholesterol absorbed
in the first 100 cm of small intestine, the primary and
secondary bile acids are absorbed almost exclusively in the
ileum, and 98–99% is returned to the liver via the portal
circulation.
• However, lithocholic acid, because of its insolubility, is not
reabsorbed to any significant extent.
• Only a small fraction of the bile salts escapes absorption and
is therefore eliminated in the feces.
Most Bile Acids Return to the Liver
in the Enterohepatic Circulation
81. The activity of the enzyme is feedback-regulated via the nuclear
bile acid-binding receptor Farnesoid X receptor (FXR).
When the size of the bile acid pool in the enterohepatic circulation
increases, FXR is activated and transcription of the cholesterol 7-
hydroxylase gene is suppressed.
Chenodeoxycholic acid is particularly important .
Also enhanced by cholesterol of endogenous and dietary origin
and regulated by insulin, glucagon, glucocorticoids, and thyroid
hormone.
Bile Acid Synthesis Is Regulated at the 7-α
Hydroxylase Step
82. • The movement of cholesterol from the liver
into the bile must be accompanied by the
simultaneous secretion of phospholipid and
bile salts.
• If this dual process is disrupted and more
cholesterol enters the bile than can be
solubilized by the bile salts and lecithin
present, the cholesterol may precipitate in
the gallbladder, initiating the occurrence of
cholesterol gallstone disease—cholelithiasis
Bile salt deficiency: Cholelithiasis
83. References:
Lehninger’s Principles of Biochemistry- 5th Edition
Biochemistry 7th Edition : Jeremy M berg,John L. Tymoczko,
Lubert Stryer
Harper’s Illustrated Biochemistry- 28th Edition
Lippincott’s Illustrated Reviews Biochemistry: Fifth Edition
Teitz Textbook of Clinical Chemistry and Molecular Diagnostics-
Fifth Edition
Alicyclic- having both alipathic (chain) and cyclic ring structure.
molecular weight: 386.65 g/mol
knowledge of the sterane skeleton structure and numbering system in important no only to the clinical labaratorians but also to the practicing clinicians because cholesterol is the starting point in many different metabolic pathways---- vitamin D synthesis, Steroid Hormone synthesis, Bile Acid metabolism
Because the enzymes modifying the sterane cholesterol ring or its derivatives are known by their site and type of reaction (21 alpha hydroxylase)----Cortisol synthesis.---- The diagnosis of many disease states consequently depends on isolating the site of enzyme dysfunctions (E.G 21 alpha hydroxylase deficiency in Adrenogenital Syndrome).
The “head” is the end to which pyrophosphate is joined.
Diet- Animal Products, Egg yolk, sea food, etc.
Bile Micelle Formation, Amphipathic can be easily transported.
Once, secreted by enterocytes, chylomicrons enter the lymphatics, which eventually empty into the thoracic duct and enter the systemic venous circulation at the junction of the left subclavian vein and the left internal jugular vein.
Oleate, Palmitoleate ---- which are monounsaturated fatty acids