1) Chylomicrons are assembled in the intestines and carry dietary lipids through the lymphatic system and bloodstream to tissues. They are formed when apo B-48 is loaded with lipids by MTP in the ER and Golgi. 2) Nascent chylomicrons acquire apo C and E from HDL in the bloodstream. Lipoprotein lipase on capillary walls hydrolyzes chylomicron triglycerides, providing fatty acids to tissues. 3) Remnant chylomicrons are taken up by the liver via apo E binding to hepatic receptors, where lipids are metabolized and reused or stored.

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LIPOPROTEINS
AHMAR BILAL (L1F20BSBT0084)
METABOLISMOF CHYLOMICRONS:
Chylomicrons are assembled in intestinal mucosal cells and carry dietary (exogenous) TAG,
cholesterol, fat-soluble vitamins, and cholesteryl esters to the peripheral tissues.
1. SYNTHESIS OF APOLIPOPROTEINS:
Apo B-48 is unique to chylomicrons. Its synthesis begins on the rough ER, and it is
glycosylated as it moves through the ER and Golgi. [Note: Apo B-48 is so named
because it constitutes the N-terminal 48% of the protein encoded by the gene for apo B.
Apo B-100, which is synthesized by the liver and found in VLDL and LDL, represents
the entire protein encoded by this gene. Posttranscriptional editing of a cytosine to a
uracil in intestinal apo B- 100 messenger RNA (mRNA) creates a nonsense (stop) codon,
allowing translation of only 48% of the mRNA.
2. ASSEMBLY OF CHYLOMICRONS:
The enzymes involved in TAG, cholesterol, and phospholipid synthesis are located in the
smooth ER. Assembly of the apolipoproteins and lipid into chylomicrons requires
microsomal triglyceride transfer protein ([MTP], which loads apo B-48 with lipid. This
occurs before transition from the ER to the Golgi, where the particles are packaged in
secretory vesicles. These fuse with the plasma membrane releasing the lipoproteins,
which then enter the lymphatic system and, ultimately, the blood. [Note: Chylomicrons
leave the lymphatic system via the thoracic duct that empties into the left subclavian vein.
3. MODIFICATIONOF NASCENT CHYLOMICRON PARTICLES:
The particle released by the intestinal mucosal cell is called a “nascent” chylomicron
because it is functionally incomplete. When it reaches the plasma, the particle is rapidly
modified, receiving apolipoproteins E (which is recognized by hepatic receptors) and C.
The latter includes apo C-II, which is necessary for the activation of lipoprotein lipase
(LPL), the enzyme that degrades the TAG contained in the chylomicron. The source of
these apolipoproteins is circulating HDL.
4. DEGRADATION OF TRIACYLGLYCEROL BY LIPOPROTEIN
LIPASE:
LPL is an extracellular enzyme that is anchored by heparan sulfate to the capillary walls
of most tissues, but predominantly those of adipose tissue and cardiac and skeletal
muscle. Adult liver does not have this enzyme. [Note: A hepatic lipase is found on the

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surface of endothelial cells of the liver. It plays some role in TAG degradation in
chylomicrons and VLDL and is particularly important in HDL metabolism. LPL,
activated by apo C-II on circulating lipoprotein particles, hydrolyzes the TAG contained
in these particles to yield fatty acids and glycerol. The fatty acids are stored (by the
adipose) or used for energy (by the muscle). If they are not immediately taken up by a
cell, the long-chain fatty acids are transported by serum albumin until their uptake does
occur. The glycerol is used by the liver, for example, in lipid synthesis or
gluconeogenesis. [Note: Patients with a deficiency of LPL or apo C-II (type 1
hyperlipoproteinemia, or familial LPL-deficiency) show a dramatic accumulation (1,000
mg/dl or greater) of chylomicron-TAG in the plasma even in the fasted state. These
individuals are at increased risk for acute pancreatitis.
5. REGULATION OF LIPOPROTEIN LIPASEACTIVITY:
LPL is synthesized by adipose tissue and by cardiac and skeletal muscle. Expression of
the tissue-specific isozymes is regulated by nutritional state and hormonal level. For
example, in the fed state (elevated insulin levels), LPL synthesis is increased in adipose
but decreased in muscle tissue. Fasting (decreased insulin) favors LPL synthesis in
muscle. [Note: The highest concentration of LPL is in cardiac muscle, reflecting the use
of fatty acids to provide much of the energy needed for cardiac function.

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MAHA AMER (L1S21BSBT0090)
INTRDUCTION:
LDL sometimes called “bad” cholesterol, makes up most of your body’s cholesterol. High
levels of LDL cholesterol raise your risk for heart disease and stroke
COMPOSITION OF LDL:
The LDL complex is essentially a droplet of triacylglycerols and cholesteryl esters encased in
a sphere made up of phospholipid, free cholesterol, and protein molecules known as
apoprotein B-100 (ApoB-100).

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FORMATION OF LDL:
LDL particles are formed when triglycerides are removed from VLDL by the lipoprotein
lipase enzyme (LPL) and they become smaller and denser containing a higher proportion of
cholesterol esters.
METABOLISM OF LOW-DENSITY LIPOPROTEINS:
a. LDL are end product of VLDL metabolism. LDL contain a high amount of cholesterol
and cholesterol esters and a low amount of triglycerides About 70% of LDL particles
are taken up by extrahepatic tissues.
b. The surface of hepatocytes is covered with LDL receptors. These receptors can
recognize Apo B100 found on LDL and therefore determine plasma LDL levels. That
is the more LDL receptors the greater the liver uptake is and the lower the serum
levels. In addition, LDL receptors also recognize Apo E found on LDL and
chylomicrons

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c. Adapter proteins are needed to cluster LDL receptors in close proximally on the
surface. In addition, a protein called clathrin present on the intracellular side helps
invaginating the cell surface to create a clathrin coated pit
d. An LDL particle uses the Apo B100 to bind to the negatively charged LDL receptors
in turn initiates receptor mediated endocytosis. This forms a vesicle inside the cell.
This vesicle quickly loses its clarithin coat and adaptor complexes and fuse with other
similar vesicles to give rise to endosome.
e. The surface of the endosome contains ATP pumps that decreases the internal pH
thereby allowing the separation on the receptors from the LDL particles. The LDL
particles remain inside while the LDL receptors migrate to the opposite side to give
rise to the compartment for uncoupling of receptor and ligand CURL.
The LDL receptors subsequently are recycled (when LDL receptors levels are
plentiful an enzyme called PCSK9 binds to LDL receptors and target them for
degradation inside the lysosome.
f. The LDL carrying endosome then combine with lysosomes. The hydrolytic enzymes
break down the LDL into its constituent parts. The cholesterol can either be reused or
converted by ACAT into cholesterol esters for storage.

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EFFECTS OF HIGH LEVEL OF CHOLESTEROL:
Effect of endocytosed cholesterol on cellular cholesterol homeostasis: The chylomicron
remnant-, IDL-, and LDL-derived cholesterol affects cellular cholesterol content in several
ways.
 First, expression of the gene for HMG COA reductase is inhibited by high cholesterol,
as a result of which, de novo cholesterol synthesis decreases. Additionally,
degradation of the reductase is accelerated.
 Second, synthesis of new LDL receptor protein is reduced by decreasing the
expression of the LDL receptor gene, thus limiting further entry of LDL cholesterol
into cells.
 Third, if the cholesterol is not required immediately for some structural or synthetic
purpose, it is esterified by acyl CoA: cholesterol acyltransferase (ACAT). ACAT
transfers a fatty acid from a fatty acyl COA to cholesterol, producing a cholesteryl
ester that can be stored in the cell. The activity of ACAT is enhanced in the presence
of increased intracellular cholesterol. Uptake of chemically modified LDL by
macrophage scavenger receptors.

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 In addition to the highly specific and regulated receptor-mediated pathway for LDL
uptake described above, macrophages possess high levels of scavenger receptor
activity (SRA).
 These receptors, known as scavenger receptor class A (SR-A), can bind a broad range
of ligands and mediate the endocytosis of chemically modified LDL in which the lipid
components or apo B have been oxidized.
Unlike the LDL receptor, the scavenger receptor is not downregulated in response to
increased intracellular cholesterol. Cholesteryl esters accumulate in macrophages and cause
their transformation into 'foam" cells, which participate in the formation of atherosclerotic
plaque.
 WHY LDL IS BAD?
When your body has too much LDL cholesterol, the LDL cholesterol can build up on the
walls of your blood vessels. This build-up is called “plaque.” As your blood vessels build up
plaque over time, the insides of the vessels narrow.
This narrowing block blood flow to and from your heart and other organs. When blood flow
to the heart is blocked, it can cause angina (chest pain) or heart attack.

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MADIHA ASAD (L1S21BSBT0110)
METABOLISM OF HIGH-DENSITY LIPOPROTEINS:
HDLs comprise a heterogeneous family of lipoproteins with a complex metabolism that is not
yet completely understood. HDL particles are formed in blood by the addition of lipid to apo A-
1, an apolipoprotein made by the liver and intestine and secreted into blood. HDLs are also
formed within the liver and intestine. Apo A-1 accounts for about 70% of the apolipoprotein in
HDL. HDLs perform a number of important functions, including the following.
1. Apolipoprotein Supply:
HDL particles serve as a circulating reservoir of apo C-II (the apolipoprotein that is
transferred to VLDL and chylomicrons and is an activator of LPL) and apo E (the
apolipoprotein required for the receptor-mediated endocytosis of IDLs and chylomicron
remnants).
2. Uptake of Unesterified Cholesterol:
Nascent HDLs are disc-shaped particles containing primarily phospholipid (largely
phosphatidylcholine) and apolipoprotein A, C, and E. They take up cholesterol from nonhepatic
(peripheral) tissues and return it to the liver as cholesteryl esters.
HDL particles are excellent acceptors of unesterified cholesterol as a result of their high
concentration of phospholipids, which are important solubilizers of cholesterol.
Esterification of Cholesterol:
When cholesterol is taken up by HDL, it is immediately esterified by the plasma enzyme lecithin
cholesterol acyltransferase (LCAT, also known as PCAT, in which “P” stands for
phosphatidylcholine, the source of the fatty acid). This enzyme is synthesized and secreted by the
liver.
LCAT binds to nascent HDL, and is activated by apo A-I. LCAT transfers the fatty acid from
carbon 2 of phosphatidylcholine to cholesterol. This produces a hydrophobic cholesteryl ester,
which is sequestered in the core of the HDL, and lysophosphatidylcholine, which binds to
albumin. Esterification maintains the cholesterol concentration gradient, allowing continued
efflux of cholesterol to HDL.
As the discoidal nascent HDL accumulates cholesteryl esters, it first becomes a spherical,
relatively cholesteryl ester–poor HDL3 and, eventually, a cholesteryl ester–rich HDL2 particle
that carries these esters to the liver. CETP moves some of the cholesteryl esters from HDL to
VLDL in exchange for TAG, relieving product inhibition of LCAT. Because VLDLs are
catabolized to LDL, the cholesteryl esters transferred by CETP are ultimately taken up by the
liver.

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1Synthesis of intracellular cholesteryl ester by ACAT
Lecithin cholesterol acyl transferase (LCAT) is the extracellular enzyme that esterifies
cholesterol using phosphatidylcholine (lecithin) as the source of the fatty acid. Here, CoA is
coenzyme A.
HIGH DENSITY LIPOPROTEIN SYNTHESIS AND ESTERIFICATION:
1. The apolipoprotein A-1 is synthesized in liver and to some extent in intestines that is the
core structural protein of HDL and after its synthesis it is released in blood circulatory
system and it circulates past the capillaries of extra hepatic cells, cardiac muscle cells and
adipocytes as well as hepatocytes and enterocytes.
2. This circulating Apo-A1 picks up free cholesterol and phospholipids that are effluxed
from hepatocytes, enterocytes, extra-hepatocytes via transporter membrane protein called
ABCA-1.
Phospholipids can be easily transported into the Apo- A1 but cholesterol requires a
shuttle and that is ABCA-1 and as the result a nascent immature disc shaped HDL
molecule is formed. A defect in ABCA-1 causes a condition called Tangiers disease in
which people cannot produce mature HDL particles leading to low HDL levels.
3. In addition to these HDL particles also obtain free cholesterol from free circulating
lipoproteins called chylomicrons and very low density lipoproteins. As the nascent HDL
accumulates more cholesterol, its shapes changes from disk shaped to round but still it is
immature.
4. the cholesterol obtained from cells and other lipoproteins is unesterdified and must
remain on the surface of immature HDL molecule giving it disc like shape. For the HDL

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to become mature, the cholesterol must be esterdified and moved to the core of the HDL.
This is done by the plasma enzyme called LCAT that associates with HDL. LCAT, which
is activated by Apo-A1, catalyzes the transfer of a fatty acid from phospholipids to
cholesterol, thereby, forming cholesterol esters. This forms mature HDLs.
(A complete (familial LCAT deficiency) or partial (fish eye disease, that is characterized
by the accumulation of cholesterol in the corners of eyes leading to blurry appearance)
deficiency in LCAT causes a decrease in serum HDL (the immature, disc-shaped HDLs
are quickly broken down)
METABOLISM:
5. Mature HDL can also receive triglycerides in exchange for cholesterol from Apo B
containing lipoproteins including chylomicrons, low density lipoprotein and very low
density lipoprotein. This is mediated by enzyme CETP.
6. The triglycerides received by HDL are metabolized and absorbed by the hepatocytes of
liver via the activity of hepatic lipase.
7. The majority of cholesterol in HDL is absorbed by hepatic cells of liver, which is
mediated by a surface receptor called scavengers receptor type B (SR-B1).
8. The transfer of cholesterol and triglycerides to the liver causes the formation of small,
lipid poor HDL containing the core protein Apo – A1. The Apo-A1 is ultimately filtered
by glomeruli and absorbed by the renal tubules. The kidneys are responsible for majority
of Apo-A1 break down.

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REVERSE CHOLESTEROL TRANSPORT PATHWAY:
 Peripheral cells obtain cholesterol from circulating lipoproteins or in some cases from De
novo cholesterol synthesis. Some of the cells (like adrenal cells) can use it to synthesize
hormones (like glucocorticoids).
Other cells can get rid of the cholesterol by secreting it onto the skin (like sebocytes,
keratinocytes) while others can secrete into the lumen of intestines (enterocytes)
 The majority of other cells however depend on the reverse cholesterol transport pathway
to permit intracellular accumulation of unwanted cholesterol. Macrophages play central
role in this pathway, which maintains cholesterol homeostasis and reduces
atherosclerosis.
Pathway:
1. As the macrophages accumulates cholesterol from the environment due to its engulfing
properties, some of it is converted to oxysterols (oxidized form of cholesterol)
2. Oxysterols activate a nuclear hormone transcription factor called LXR.
3. This upregulates the production and expression of two cell membrane transporters called
ATP binding cassette proteins known as ABCA-1 and ABCG-1(they allow the efflux of
cholesterol out of the cell).
The former causes the efflux of intracellular cholesterol onto circulating Apo-A1 proteins
(immature HDL) while the latter causes the efflux of intracellular cholesterol onto
circulating mature HDL particles.
4. Once cholesterol is effluxed out of the cell and transferred onto HDL, there are two ways
by which it can be taken up by liver:
4a) The mature HDL particle can travel to the liver and binds to SR-B1 on the
hepatocytes. Once bound, cholesterol can move into the cell.
4b) The enzyme CETP can transfer the cholesterol to other Apo-B containing
lipoproteins (like LDL), which in turn travel to the liver to bind to LDL receptor
and undergo receptor mediated endocytosis.
5. Once the cholesterol is in the liver there are several ways by which it can be eliminated
either be converted into bile acids and secreted into bile or it can be secreted directly into
bile. The latter is carried out by membrane transporters ABCG-5 and ABCG-8.
Following is the flowsheet diagram elaborating the whole process.

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ROLE OF LIPOPROTEIN (A) IN HEART DISEASE:
Lipoprotein (a) is a particle that, when present in large quantities in the plasma, is associated
with an increased risk of coronary heart disease. Lp(a) is nearly identical in structure to an LDL
particle. Its distinguishing feature is the presence of an additional apolipoprotein molecule,
apo(a), that is covalently linked at a single site to apo B-100.
Circulating levels of Lp(a) are determined primarily by genetics. However, factors such as diet
may play some role, as trans fatty acids have been shown to increase Lp(a), whereas ω-3 fatty
acids decrease it.
Where, Apo(a) is structurally homologous to plasminogen, the precursor of a blood protease
whose target is fibrin, the main protein component of blood clots. It is hypothesized that elevated
Lp(a) slows the breakdown of blood clots that trigger heart attacks because it competes with
plasminogen for binding to fibrin. The physiologic function of Lp(a) in unknown. Niacin reduces
Lp(a), as well as LDL-cholesterol and TAGs, and raises HDL.

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References:
 Lippincott biochemistry book edition 6.
 https://www.youtube.com/watch?v=zPFe61fddVE
 https://www.youtube.com/watch?v=4t2XTcc288c