Lipoprotein metabolism

By Rezene A.
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Lipoproteins and their apoproteins

Lipids absorbed from the diet or synthesized in the body must be

transported between various cells and organs for utilization and
storage
Lipid compounds are relatively water insoluble thus they are
transported in plasma as lipoproteins
Lipids are said to be lipoproteins when they form complex with
apoproteins
They include Chylomicrons, VLDL, LDL and HDL

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 Lipoproteins and their apoproteins..

Function of apoproteins
They are divided by structure and function into classes A to H, with
most classes having subclasses, for E.g. apo A and apo C
They can form part of the structure of lipoproteins E.g .
Apo B: structural component of VLDL and chylomicrons
They are used as enzyme activators E.g.
Apo C-II: for Lipoprotein lipase
Apo A-I: for Lecithin: Cholesterol acyl transferase
They are used as enzyme inhibitors E.g.
Apo A-II and Apo C-III: for lipoprotein lipase
Apo C-I: Cholesteryl ester transfer protein
They act as ligands for interaction with lipoprotein receptors in
tissues E.g. Apo B-100, Apo E 3
 Chylomicron metabolism

Chylomicron is the largest of the lipoproteins and the least dense

It is assembled in intestinal mucosal cells

It has highest lipid content but lowest in protein

It carries dietary lipids to peripheral tissues TAG being the highest

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 Chylomicron metabolism..

Assembly of chylomicrons
Apo B-48 is synthesized in the rough ER and makes complex with
lipids to form chylomicron assembly in the smooth ER
This assembly requires Microsomal TAG transfer protein which
loads apo B-48 with lipid
This occurs before transition from the ER to the Golgi complex
Carbohydrate residues are added to this lipoprotein in the Golgi
The chylomicrons packaged in secretory vesicles of Golgi release from
the plasma membrane of the intestinal mucosal cell to the lymphatic
system and, ultimately, the blood
This chylomicron is called nascent chylomicron
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 Chylomicron metabolism..

Modification of nascent chylomicron particles

Nascent chylomicron is functionally incomplete

It releases from the intestine to the circulation
holding dietary lipids and apo B-48

In the blood, the nascent chylomicron is

rapidly modified, receiving apo E and C-II
The source of these apolipoproteins is
circulating HDL

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 Chylomicron metabolism..

Release of TAG from chylomicron

Chylomicrons are transported in blood mainly to adipose and

muscle tissue to release TAG in the form of FAs and glycerol

This TAG hydrolysis is undergone in the capillaries of the

aforementioned tissues by the lipoprotein lipase (LPL) enzyme
activated by Apo C-II
Adult liver does not have LPL but Hepatic lipase can be used
instead
Hepatic lipase has dual role
Acts as a ligand to facilitate remnant uptake
Hydrolyses remnant TAG and phospholipid 7
 Chylomicron metabolism..
Fate of chylomicron remnants
More than 90% of the chylomicron TAG is released in tissues by LPL,
this chylomicron is termed as chylomicron remnant
The particle decreases in size and increases in density
The C apoproteins are returned to HDL
Chylomicron remnants bind to Apo E receptors on hepatocytes for
endocytosis
This binding allows the endocytosis of chylomicron remnants by liver cells
The endocytosed vesicle then fuses with lysosome and the components
of the remnant are hydrolytically degraded releasing amino acids, free
cholesterol and fatty acids
The receptor is also recycled 8
 9
Fig. Metabolism of chylomicron
 Chylomicron metabolism..

Regulation of lipoprotein lipase (LPL) activity

LPL synthesis and transfer to the luminal surface of the capillary is
stimulated by insulin
There are isomers of LPL
These enzymes have different Km values for TAG
oThe adipose tissue LPL:
Has a large Km that allows the removal of fatty acids from
circulating lipoprotein particles and their storage as TAGs only
when plasma lipoprotein levels are elevated
oHeart muscle LPL:
Has a small Km that allows the heart continuing access to the
circulating fuel, even when plasma lipoprotein levels are low
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Note: Cardiac muscle has more LPL enzymes thus use fatty acids as major fuel
 Metabolism of VLDL

VLDLs are produced in the liver

They are composed predominantly of endogenous TAG
They carry this lipid from the liver to the peripheral tissues
They are secreted in their nascent form containing Apo B-100
They obtain apo C-II and apo E from circulating HDL
They release TAG as FA and glycerol in the peripheral tissues by
the action of lipoprotein lipase and remain as remnants
Lipoprotein lipase is activated by phospholipid and Apo C-II
while inhibited by Apo A-II and Apo C-III
Approximately 50% of the VLDL remnants are taken up from the
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blood by liver cells due to their apo E receptors
 Metabolism of VLDL..
Modification of circulating VLDL and formation of LDL
After VLDL releases TAG in the peripheral tissues, it decreases in size
and become denser
The VLDL surface components, the C and E apoproteins are returned
to HDL but Apo B-100 remains with it
There are some TAGs transferred from VLDL remnant to HDL in an
exchange reaction that concomitantly transfers some cholesteryl esters
from HDL to VLDL remnant
This exchange is accomplished by cholesterylester transfer protein
With the above modifications, the VLDL remnant is converted in the
plasma to intermediate density lipoprotein (IDL)
With the removal of additional TAGs from IDL by hepatic TAG
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lipase within hepatic sinusoids, LDL is generated
 13
Fig. Metabolism of VLDL and LDL
 Metabolism of LDL
LDL particles;
Have apo B-100 apoproteins
Contain much less TAG than their VLDL predecessors
Have high concentration of cholesterol and cholesteryl esters
Approximately 60% of the LDL is transported back to the liver,
where its apo B-100 binds to its receptors for LDL endocytosis to
occur
The remaining 40% of LDL particles is carried to extrahepatic
tissue cells such as adrenocortical, gonadal and other cells to release
cholesterol for the purpose of steroid hormone, vitamin D and
membrane synthesis 14
 Metabolism of LDL..
Receptor mediated endocytosis
1. It binds to cell surface membrane LDL receptors that recognize
apo B-100
oLDL receptors can also bind apo E thus they are known as apo
B-100/apo E receptors
oLDL receptors are negatively charged glycoproteins that are
clustered in pits on cell membranes
2. After binding, the LDL-receptor complex is internalized by
endocytosis
3. The vesicle containing LDL loses its clathrin coat and fuses with
other similar vesicles, forming larger vesicles called endosomes
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 Metabolism of LDL..
Receptor mediated endocytosis.

3. The pH of the endosome falls, which allows separation of the LDL

from its receptor
This is due to the proton-pumping activity of endosomal ATPase
4. The receptors then migrate to one side of the endosome, whereas
the LDLs stay free within the lumen of the vesicle
This structure is called CURL the Compartment for Uncoupling
of Receptor and Ligand
5. The receptors can be recycled, whereas the lipoprotein remnants
in the vesicle are transferred to lysosomes for hydrolysis to release
free cholesterol, amino acids, fatty acids, and phospholipids
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 Metabolism of LDL..
Receptor mediated endocytosis.

Effect of endocytosed cholesterol on cellular cholesterol

homeostasis

HMG-CoA reductase is inhibited by high cholesterol as a result

de novo cholesterol synthesis decreases

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

If the cholesterol is not required immediately for some structural

or synthetic purpose, it is esterified by Acyl CoA: Cholesterol
acyltransferase (ACAT) 17
 18
Fig. Cellular uptake and degradation of LDL
 Metabolism of LDL..

Uptake of chemically modified LDL by macrophage scavenger

receptors:
When there is excess blood LDL particles, specific receptor-
mediated uptake of LDL by hepatic and non hepatic tissue becomes
saturated

The Excess LDL particles are then ready for nonspecific uptake
of LDL by macrophages present near the endothelial cells of arteries

Macrophages have non specific receptors known as scavenger

receptor class A (SR-A)

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 Metabolism of LDL.
Uptake of chemically modified LDL..

These receptors can bind a broad range of ligands(LDLs) and

mediate the endocytosis of chemically modified (oxidized) LDL

Unlike the LDL receptor, the scavenger receptor is not down-

regulated in response to increased intracellular cholesterol

Cholesterylesters accumulate in macrophages and cause their

transformation into foam cells, which participate in the formation of
atherosclerotic plaque

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 Metabolism of HDL

It is the fourth class of lipoproteins

It is synthesized and secreted from both liver and small intestine
Apo C-II and apo E are synthesized in the liver and transferred
from liver HDL to intestinal HDL when the latter enters the
plasma
HDL perform a number of important functions
1. Reservoir of apolipoproteins
2. Uptake of unesterified cholesterol
3. Esterification of cholesterol
4. Reverse cholesterol transport (scaveges cholesterol from
peripheral tissue) 21
 Metabolism of HDL..

1. HDL as a reservoir of apolipoproteins:

HDL particles serve as a circulating reservoir of apo C-II and apo E

2. HDL uptake of unesterified cholesterol:

Nascent HDL are disk shaped containing primarily phospholipid
(largely phosphatidylcholine) and apolipoproteins A, C and E

They take up cholesterol from peripheral tissues and return it to the

liver as cholesteryl esters

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 Metabolism of HDL..

3. Esterification of cholesterol:
When cholesterol is taken up by HDL, it is immediately esterified
by the plasma enzyme lecithin-cholesterol acyl transferase (LCAT),
also known as PCAT
P stands for phosphatidylcholine)
LCAT is activated by apo A-I
This enzyme transfers the fatty acid from carbon 2 of
phosphatidylcholine to cholesterol and produces cholesteryl ester in
the nascent HDL
So phosphatidylcholine remains as lysophosphatidylcholine
as FA is used for cholesterol esterification 23
 Metabolism of HDL..
Esterification of cholesterol..

As the discoidal nascent HDL accumulates cholesteryl esters, it

first becomes a spherical, relatively cholesteryl esterpoor HDL3
and, eventually, a cholesteryl esterrich HDL2 particle that carries
these esters to the liver
Cholesterol ester transfer protein moves some of the cholesteryl
esters from HDL to VLDL in exchange for TAG, relieving product
inhibition of LCAT
Because VLDL are catabolized to LDL, the cholesteryl esters are
ultimately taken up by the liver

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 Metabolism of HDL..

4. Reverse cholesterol transport

The selective transfer of cholesterol from peripheral cells to
HDL, and from HDL to
The steroidogenic cells for hormone synthesis
The liver for bile acid synthesis or
Disposal via the bile
Cholesterol effluxed from peripheral cells to HDL
Esterification of
cholesterol by LCAT
Cholesteryl esterrich HDL (HDL2)
The selective transfer of the cholesteryl esters
into liver and steroidogenic cells
Lipid-depleted HDL (HDL3)
This process is the key component of cholesterol homeostasis 25
 Metabolism of HDL..
Reverse cholesterol transport...

The efflux of cholesterol from peripheral cells is mediated by the

transport protein, ATP-binding cassette transporter A1(ABCA1)
Uses ATP hydrolysis to move cholesterol from the inner leaflet
of the membrane to the outer leaflet
The uptake of cholesteryl esters by the liver is mediated by a cell-
surface receptor, SR-B1 (scavenger receptor class B type 1) that
binds HDL2
Hepatic lipase also participates in the conversion of HDL2 to HDL3

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Fig. Metabolism of HDL 27
 Metabolism of HDL: Other Functions

HDL competes with LDL for binding sites on the membranes and
prevents internalization of LDL cholesterol in the cells of the arterial
walls

HDL stimulated prostacyclin synthesis by the endothelial cells

prevents thrombus formation

HDL helps in the removal of macrophages from the arterial walls

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Role of lipoprotein (a) in heart disease
Lipoprotein (a) or Lp(a) is a heterogeneous lipoprotein that shares
many properties with LDL
Its only distinguishing feature from LDL is the presence of an
additional protein, apo(a), that is covalently linked to apo B-100
Apo(a) is structurally homologous to plasminogen-The precursor of a
blood protease whose target is fibrin
Elevated Lp(a) levels increase the risk of coronary heart disease
This is because apo(a) competes with plasminogen to tissue
plasminogen activator thus fibrin breakdown is halted for plasmin
cannot be formed
Circulating levels of Lp(a) are determined primarily by genetics 29
Estrogen decreases Lp(a) while trans fats increase it
 Normal plasma Lipid Profile

Fasting Blood Level Ideal, Healthy Level

Total Cholesterol < 200 mg/dl

LDL-Cholesterol < 100 mg/dl

HDL-Cholesterol 60 mg/dl

Triglycerides < 150 mg/dl

 Primary Disorders of Plasma Lipoproteins
(Dyslipoproteinemias)

Inherited defects in lipoprotein metabolism lead to the

Primary condition of either hypo- or hyperlipoproteinemia.

A defect at lipoprotein formation, transport, or degradation

Diseases such as diabetes mellitus, hypothyroidism, nephrotic

syndrome, and atherosclerosis are associated with

Secondary abnormal lipoprotein patterns

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 Abnormalities in Lipoprotein metabolism (Dyslipoproteinemias)

Hypolipoproteinemia Defect Characteristics

Abetalipoproteinemia Defect in Blood TAGs are low;

TAG transfer Intestine and liver accumulate
protein for TAGs
loading of apo No VLDL synthesis in liver
B-100 with No LDL thus low blood
lipid cholesterol
Intestinal malabsorption
Familial apo B-100 Blood TAG
hypobetalipoproteinemia synthesis TAG in liver
VLDL Blood cholesterol
LDL

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 Abnormalities in Lipoprotein metabolism (Dyslipoproteinemias)
Hyperlipoproteinemia
Familial hyperlipoproteinemia
(Type-I)
Familial hyperlipoproteinemia
(Type-II)
Familial hyperlipoproteinemia
(Type-III )
Familial hyperlipoproteinemia Overproduction of
(Type-IV)
Defect Characteristics
Deficiency of LPL Hypertriacylglycerolemia
or Abnormal LPL Increased levels Chylomicrons and
Apo C-II deficiency VLDL
Low levels of LDL and HDL
Coronary disease
Defective LDL Elevated LDL levels and
receptors or Hypercholesterolemia
Mutation in ligand Predispose to Atherosclerosis &
region of apo B-100 Coronary disease
Due to abnormality Increase in chylomicron and VLDL
in apo E remnants
Deficiency in Predispose to hypercholesterolemia
remnant clearance & atherosclerosis
High cholesterol, VLDL,
VLDL Subnormal LDL and HDL
Commonly Elevated blood TAG
associated with Type Predispose to atherosclerosis &
2 DM & Obesity CHD
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 Serum Cholesterol, Atherosclerosis & Coronary Disease
Elevated plasma cholesterol levels (>5.2 mmol/L or >220mg/dl) are
believed to be a major factor in promoting atherosclerosis
Atherosclerosis- abnormal deposition of cholesterol and cholesteryl
ester from the plasma lipoproteins into the artery wall
There is an inverse relationship between HDL and coronary heart
disease
The LDL:HDL cholesterol ratio (>3:1)
is a good predictor
Susceptibility to atherosclerosis
varies widely among species
Humans are the most susceptible

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 Mechanism of atherosclerosis
The initial step of an atherosclerotic lesion is
The formation of a fatty streak in the subintimal space

Visible as a yellow-white linear streak

It bulges slightly into the lumen of the vessel.

These streaks are initiated when one or more known vascular risk
factors reach a critical threshold at the site of future lesions
Elevated intra-arterial pressure (arterial hypertension),

Circulating levels of LDL, VLDL and Chylomicrons remnants

Low levels of circulating HDL

Cigarette smoking

Chronic elevations in blood glucose levels 35

 Mechanism of atherosclerosis

Excess LDL cross the arterial wall through the endothelial cells and
get oxidized by free radicals

In response to the inflammation (chemoattractant cytokines )

generated by these oxidized LDLs, adhesion molecules are expressed
on the endothelial cells to enable the enterace of monocytes which are
transformed to macrophages in the sub-endothelial cells

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 Mechanism of atherosclerosis
Unlike the classic LDL receptors
Macrophage-bound receptors are high capacity, low-specificity
receptors (scavenger receptors type A)

They bind and internalize more oxidatively modified LDLs to

become subintimal foam cells

As the foam cells accumulate, they deform the overlying

endothelium forming lipid plague(core) after they die

The plague may rapture and form thrombus which inhibits blood
flow in the arteries leading to heart attack

Prevention: Aspirin and HMG-CoA reductase inhibitors (statins)

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 Clinical Significance of Lipoprotein Metabolism
Fatty Liver
Abnormal accumulation of certain fats

Hepatic TAG synthesis provides the immediate stimulus for the

formation and secretion of VLDL

Impaired VLDL formation or secretion leads to

Non mobilization of lipid components from the liver

Results in fatty liver

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 Fatty Liver

Causes of fatty liver fall into two main categories

I. Increased synthesis of TAGs
II. Defective VLDL synthesis
A) Increased synthesis of TAGs

High carbohydrate diet

High fat feeding

Starvation

Diabetes mellitus

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 Fatty Liver..

B) Defective VLDL synthesis - a metabolic block in the production of

plasma lipoproteins allows TAGs to accumulate.
The lesion may be due to
(1) A block in apolipoproteins synthesis
a. Protein energy malnutrition
b. Impaired absorption
c. Presence of inhibitors of endogenous protein synthesis
d. Hypobetalipoproteinemia-defective apo B gene
(2) A failure in provision of phospholipids of lipoproteins
Due to deficiency of choline, methionine, inositol & essential
FA 41
 Fatty Liver.
Defective VLDL synthesis........

(3) Impaired Glycosylation

Orotic acid also causes fatty liver; it interferes with glycosylation

of the lipoprotein

4) Impaired secretion of VLDL

Oxidative stress is a common cause for membrane disruption of

lipoproteins

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 Fatty Liver.

2) Alcoholic fatty liver

Alcoholism:
Fat accumulation
Hyperlipidemia
Ultimately cirrhosis

Liver in alcoholism:

Impaired fatty acid oxidation and increased lipogenesis

Interference with the action of transcription factors

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Lipotropic agents
They are substances which facilitate mobilization of fat and prevent
accumulation of fat in liver

They include;

Choline, Inositol

Methionine and other essential amino acids,

Vitamins: Antioxidant vitamins, Vitamin B12, Folic acid

Synthetic antioxidants

All have the apparent effect of removal of fats from the liver cells, and
thus prevent the formation of fatty liver
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