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Metabolisme

Lipoprotein plasma
Generalized structure of a plasma lipoprotein

Cholesteryl ester
and triacylglycerol
are found in the core
and free cholesterol
in the surface layer .
Four Major Groups of Plasma Lipoproteins
Have Been Identified
1. Chylomicrons , derived from intestinal absorption of
triacylglycerol and other lipids;
2. Very low density lipoproteins (VLDL, or pre-β-lipoproteins),
derived from the liver for the export of triacylglycerol;
3. Low-density lipoproteins (LDL, or β-lipoproteins), representing a
final stage in the catabolism of VLDL;
4. High-density lipoproteins (HDL, or α-lipoproteins), involved in
1. Cholesterol transport from tissues to Liver
2. VLDL and chylomicron metabolism (apoprotein exchange).
 Triacylglycerol is the predominant lipid in chylomicrons and VLDL,
 Cholesterol and phospholipid are the predominant lipids in
LDL and HDL, respectively.

Albumin-FFA is another lipoprotein with albumin as apoprotein and just only


fatty acids as their lipid, without any cholesterol, TG or phospholipids.
Composition of the Lipoproteins in Plasma of Humans
The major classes of lipoprotein particles.

Lipoproteins are
classified by density and
size, which are inversely
related.

1. VLDL, very low


density lipoprotein;

2. IDL, intermediate-
density lipoprotein;

3. LDL, low-density
lipoprotein;

4. HDL, high-density
lipoprotein.
The exogenous and endogenous lipoprotein
metabolic pathways

The exogenous pathway


transports dietary lipids to
the periphery and the
liver.

The endogenous
pathway transports
hepatic lipids to the
periphery.

LPL, lipoprotein lipase;


FFA, free fatty acid;
VLDL, very low density lipoprotein;
IDL, intermediate-density lipoprotein;
LDL, low-density lipoprotein;
LDLR, low-density lipoprotein receptor.
Plasma Lipoprotein ; Exogenous and
Endogenous pathways
Proteins in
Lipoproteins
Apolipoproteins in the Lipoproteins

The protein moiety of a lipoprotein is known as an


apolipoprotein or apoprotein, constituting
 nearly 70% of some HDL
 as little as 1% of chylomicrons

1. Some apolipoproteins are integral and cannot be


removed,
2. others are free to transfer to other lipoproteins
Apolipoproteins in the Lipoprotein

1. Apo A : the major apolipoproteins of HDL (β-lipoprotein)


2. Apo B-100. the main apolipoprotein of LDL (β-lipoprotein)
and in VLDL.
3. Apo B-48 (48% of B-100) in chylomicron
4. Apo C-I, C-II, and C-III are smaller polypeptides (molecular
mass 7000–9000 Da) freely transferable between
several different lipoproteins.
5. Apo E is found in chylomicrons, chylomicron remnants,
HDL, and VLDL, (normally 5–10% of total VLDL apoprotein )
Apolipoproteins carry out several roles:
(1) form part of the structure of the lipoprotein, eg, apo B-48;
(2) a. coenzyme (enzyme cofactors), eg,
a. Apo A-I for lecithin: cholesterol acyltransferase (LCAT),
b. Apo C-II for lipoprotein lipase,
b. enzyme inhibitors, eg,
a. apo A-II for lipoprotein lipase,
b. apo C-I for cholesteryl ester transfer protein; (CETP)
c. apo C-III for lipoprotein lipase
(3) act as ligands for interaction with lipoprotein receptors in tissues, eg,
a. apo A-I for the HDL receptor
b. apo B-100 and apo E for the LDL receptor,
c. apo E for the LDL-receptor-related protein (LRP), which has
been identified as the remnant receptor,

The functions of apo A-IV and apo D, however, are not yet clearly defined, although apo D is
believed to be an important factor in human neurodegenerative disorders.
LIPIDs of LIPOPROTEIN
Four Major Lipid Classes Are Present in Lipoproteins

Plasma lipids consist of


1. triacylglycerols (16%),
2. phospholipids (30%),
3. cholesterol (14%), and cholesteryl esters (36%)
4. unesterified long-chain fatty acids (4%).

The free fatty acids (FFA), is metabolically the most active of the
plasma lipids.
METABOLISME LIPOPROTEIN PLASMA

1. Khilomikron  sisa khilomikron


2. VLDL  IDL  LDL
3. HDLn  mature HDL
Metabolisme Lipid dlm lipoprotein plasma

• Pemecahan TG oleh lipoprotein lipase


• Pertukaran lesitin dan kholesterol oleh enzim
LCAT
• Pertukaran apoprotein antar lipoprotein
FREE FATTY ACIDS ARE RAPIDLY METABOLIZED

The free fatty acids (FFA, nonesterified fatty


acids, unesterified fatty acids) arise in the
plasma from :
1. the breakdown of triacylglycerol in
adipose tissue
2. a result of the action of lipoprotein
lipase on the plasma triacylglycerols.
FREE FATTY ACIDS ARE RAPIDLY METABOLIZED

The free fatty acids are found in combination with albumin,


Concentrations varying between 0.1 and 2.0 μeq/mL of
plasma.

 Levels are low in the fully fed condition


 rise to 0.7–0.8 μeq/mL in the starved state.
 In uncontrolled diabetes mellitus, the level may rise to as
much as 2 μeq/mL.
FREE FATTY ACIDS ARE RAPIDLY METABOLIZED

Free fatty acids are


 removed from the blood extremely rapidly
 in the tissues.
– oxidized (fulfilling 25–50% of energy requirements in
starvation)
– esterified to form triacylglycerol
TRIACYLGLYCEROL TRANSPORT

TRIACYLGLYCEROL IS TRANSPORTED
– FROM THE INTESTINES IN CHYLOMICRONS &
– FROM THE LIVER IN VERY LOW DENSITY
LIPOPROTEINS
TRIACYLGLYCEROL IS TRANSPORTED FROM THE
INTESTINES IN CHYLOMICRONS

Chylomicrons are found in chyle formed only by the lymphatic system


draining the intestine. They are responsible for the transport of all dietary
lipids into the circulation.

VLDL; most VLDL in the plasma are of hepatic origin. They are the vehicles of
transport of triacylglycerol from the liver to the extrahepatic tissues.

There are striking similarities in the mechanisms of formation of


chylomicrons by intestinal cells and of VLDL by hepatic parenchymal cells.
The formation and secretion of chylomicrons by
intestinal cell
Apolipoprotein B-48, synthesized in the
RER of intestinal cells, is incorporated into
lipoproteins in the SER, the main site of
synthesis of triacylglycerol.

After addition of carbohydrate residues in


Golgi app, they are released from the cell
by reverse pinocytosis.

Chylomicrons pass into the lymphatic


system.

(RER, rough endoplasmic reticulum;


SER, smooth endoplasmic reticulum;
G, Golgi apparatus;
N, nucleus; C, chylomicrons;
E, endothelium;
Metabolic fate of chylomicrons
Metabolic fate of chylomicrons.

(A, apolipoprotein A; B-48, apolipoprotein B-48; ©, apolipoprotein C ; E, apolipoprotein E;


HDL, high-density lipoprotein ; TG, triacylglycerol; C, cholesterol and cholesteryl ester ;
PL, phospholipid; HL, hepatic lipase; LRP, LDL-receptor-related protein.)
Only the predominant lipids are shown.
CHYLOMICRONS & VERY LOW DENSITY
LIPOPROTEINS ARE RAPIDLY CATABOLIZED
The clearance of chylomicrons from the blood is rapid, the
half-time of disappearance being under 1 h in humans.
Larger particles are catabolized more quickly than smaller ones.

Fatty acids originating from chylomicron triacylglycerol are


delivered
 mainly to adipose tissue, heart, and muscle (80%),
 while about 20% goes to the liver.
CHYLOMICRONS & VERY LOW DENSITY
LIPOPROTEINS ARE RAPIDLY CATABOLIZED

The liver does not metabolize native


chylomicrons or VLDL significantly;

Fatty acids in the liver must be secondary to their


metabolism in extrahepatic tissues.
The formation and secretion of very low density
lipoproteins by a hepatic cell
Apolipoprotein B-100, synthesized
in the RER, is incorporated into
lipoproteins in the SER, the main
site of synthesis of triacylglycerol.

After addition of carbohydrate


residues in G, they are released
from the cell by reverse pinocytosis.

VLDL are secreted into the space of


Disse and then into the hepatic
sinusoids through fenestrae in the
endothelial lining.
(RER, rough endoplasmic reticulum;
SER, smooth endoplasmic reticulum;
G, Golgi apparatus; N, nucleus;
VLDL, very low density lipoproteins;
E, endothelium; SD, space of Disse,
containing blood plasma.)
Synthesis of triacylglycerol and the secretion of
VLDL enhanced by :

(1) the fed state rather than the starved state;


(2) the feeding of diets high in carbohydrate (particularly if
they contain sucrose or fructose),  high rates of
lipogenesis and esterification of fatty acids;
(3) high levels of circulating free fatty acids;
(4) ingestion of ethanol;
(5) the presence of high concentrations of insulin and
low concentrations of glucagon, which enhance fatty
acid synthesis and esterification and inhibit their
oxidation .
Metabolic fate of very low density
Metabolic fate of VLDL
and production of LDL
lipoproteins (VLDL) and production of
low-density lipoproteins (LDL)

(A, apolipoprotein A; B-100, apolipoprotein B-100; ©, apolipoprotein C; E, apolipoprotein E; HDL, high-


density lipoprotein; TG, triacylglycerol; IDL, intermediate-density lipoprotein; C, cholesterol and
cholesteryl ester; PL, phospholipid.) Only the predominant lipids are shown. It is possible that some IDL
is also metabolized via the LRP, LDL-receptor-related protein.
Lipoprotein Lipase
 is located on the walls of blood capillaries,
 anchored to the endothelium by negatively charged
proteoglycan chains of heparan sulfate.

It has been found in :


heart, adipose tissue,
spleen, lung,
renal medulla, aorta,
diaphragm, lactating mammary gland,

it is not active in adult liver.


Lipoprotein Lipase
It is not normally found in blood;

Following injection of heparin, lipoprotein lipase is released


from its heparan sulfate binding sites into the circulation.

 Phospholipids and apo C-II are required as cofactors for


lipoprotein lipase activity,
 apo A-II and apo C-III act as inhibitors.
Lipoprotein Lipase

Heart lipoprotein lipase has a low Km for TG, about


one-tenth of that for the lipoprotein lipase in adipose
tissue.

This enables the delivery of fatty acids from triacylglycerol


to be redirected from adipose tissue to the heart in the
starved state when the plasma triacylglycerol decreases.

A similar redirection to the mammary gland occurs during


lactation, allowing uptake of lipoprotein triacylglycerol fatty
acid for milk fat synthesis.
Role of VLDL receptor and Insulin

The VLDL receptor plays an important part in


– the delivery of fatty acids from VLDL triacylglycerol to adipocytes by
binding VLDL
– bringing the VLDL into close contact with lipoprotein lipase.

In adipose tissue, insulin enhances


– lipoprotein lipase synthesis in adipocytes
– translocation of lipoprotein lipase to the luminal surface of the
capillary endothelium.
Cholesterol transport by
lipoprotein
Cholesterol transport
in lipoprotein
The Liver Is Responsible for
the Uptake of Remnant
Lipoproteins
Hepatic Lipase
 Hepatic lipase is bound to the sinusoidal surface of liver cells
and is also released by heparin.

 does not react readily with :


a. chylomicrons
b. VLDL

 but is involved in :
a. chylomicron remnant metabolism
b. HDL metabolism.
Hepatic lipase has a dual role

Hepatic lipase has a dual role:


(1) it acts as a ligand to facilitate remnant uptake
(2) it acts as enzyme that hydrolyzes remnant
triacylglycerol and phospholipid.

IDL may be
 taken up by the liver directly via the LDL (apo B-100, E)
receptor,
 be converted to LDL.
Role of Hepatic Lipase and Lipoprotein Lipase in HDL
metabolism
Reseptor lipoprotein pada sel
hepar

1. Reseptor LDL
2. LRP ; reseptor thd sisa khilomikron
3. Reseptor HDL
4. Reseptor IDL
VLDL, IDL & LDL

Only one molecule of apo B-100 is present in each of these


lipoprotein (VLDL, IDL & LDL) particles, and this is conserved
during the transformations.

Thus, each LDL particle is derived from a single precursor VLDL


particle.

In humans, a relatively large proportion of IDL forms LDL,


accounting for the increased concentrations of LDL in humans
compared with many other mammals.
LDL receptor pathway
LDL IS METABOLIZED VIA THE LDL RECEPTOR
The liver and many extrahepatic tissues express the LDL (apo B-
100, E) receptor.

 It is specific for apo B-100 but not B-48, (Apo B-48 lacks the
carboxyl terminal domain of B-100 containing the LDL receptor ligand),
 It also takes up lipoproteins rich in apo E.

Approximately 30% of LDL is degraded in extrahepatic tissues


and 70% in the liver.
LDL IS METABOLIZED VIA THE LDL RECEPTOR

A positive correlation exists between the incidence of


atherosclerosis and the plasma concentration of LDL
cholesterol.

The LDL (apoB-100, E) receptor is defective in familial


hypercholesterolemia, a genetic condition which
increases blood LDL cholesterol levels and causes
premature atherosclerosis.
HDL
Penggolongan HDL
• HDL nascent
• HDL mature
• HDL1
• HDL2
• HDL3
Structure of HDL
HDL TAKES PART IN LIPOPROTEIN CHOLESTEROL
METABOLISM
HDL is synthesized and secreted from both liver and
intestine.

Apo C and apo E are


1. synthesized in the liver
2. transferred from liver HDL to intestinal HDL when the
latter enters the plasma.
HDL metabolism and Reverse Cholesterol Transport
HDL function in
storage for Apo C and Apo E
A major function of HDL is to act as a storage for the apo C
and apo E required in the metabolism of chylomicrons and
VLDL.

Nascent HDL consists of discoid phospholipid bilayers


containing apo A and free cholesterol.

The nascent HDL are similar to the particles found in the


plasma of patients with
 a deficiency of the plasma enzyme LCAT
(lecithin:cholesterol acyltransferase )
 obstructive jaundice
Lecithin = phosphatidylcholine
HDL metabolism and
reverse cholesterol transport.
The liver and the intestine produce nascent HDLs.

Free cholesterol
• is acquired from macrophages and other peripheral
cells
• esterified by LCAT,  forming mature HDLs.

HDL cholesterol can be


 selectively taken up by the liver via SR-BI (scavenger
receptor class BI).
 transferred by CETP from HDLs to VLDLs and
chylomicrons, (which can then be taken up by the liver).
HDL metabolism and reverse cholesterol
transport.

LCAT, lecithin-cholesterol acyltransferase; CETP, cholesteryl ester transfer protein;


VLDL, very low density lipoprotein; IDL, intermediate-density lipoprotein;
LDL, low-density lipoprotein; HDL, high-density lipoprotein;
LDLR, low-density lipoprotein receptor; TG, triglyceride.
HDL TAKES PART IN METABOLISM of BOTH
LIPOPROTEIN TRIACYLGLYCEROL & CHOLESTEROL

1. LCAT -and the LCAT activator (apo A-I-) bind to the


discoidal particles,
2. the surface phospholipid and free cholesterol are
converted into lysolecithin and cholesteryl esters. The
nonpolar cholesteryl esters move into the hydrophobic
interior of the bilayer, whereas lysolecithin (lysophosphatidylcholine)
is transferred to plasma albumin.
3. Thus, a nonpolar core is generated, forming a spherical,
pseudomicellar HDL (= HDL3) covered by a surface film of
polar lipids and apolipoproteins.
4. This aids the removal of excess unesterified cholesterol from
lipoproteins and tissues.
Role of CETP in HDL metabolism
HDL TAKES PART IN BOTH LIPOPROTEIN TRIACYLGLYCEROL &
CHOLESTEROL METABOLISM

The class B scavenger receptor B1 (SR-B1) = HDL receptor with


a dual role in HDL metabolism.

1. In the liver and in steroidogenic tissues, it binds HDL via


apo A-I, cholesteryl ester is selectively delivered to the
cells, but the particle itself, including apo A-I, is not taken
up.

2. In the tissues, SR-B1 mediates the acceptance of


cholesterol from the cells to the HDL, transports it to the
liver for excretion via the bile (either as cholesterol or
after conversion to bile acids) in the process known as
reverse cholesterol transport.
Role of HDL
Apo-HDL remove ox. Lipids from LDL
HDL Inhibit the expression of Adhesion molecules
CLINICAL ASPECTS

1. Imbalance in the Rate of Triacylglycerol


Formation & Export Causes Fatty Liver
2. Ethanol Also Causes Fatty Liver
Abnormalities of lipoprotein metabolism
hypertriacylglycerolemia.

Abnormalities of lipoprotein metabolism cause various hypo-


or hyper-lipoproteinemias .

The most common of these is in diabetes mellitus, where


insulin deficiency causes :
1. excessive mobilization of FFA
2. underutilization of chylomicrons and VLDL,

leading to hypertriacylglycerolemia.
Hypercholesterolemia
Most other pathologic conditions affecting lipid transport are
due primarily to inherited defects, some of which cause
hypercholesterolemia and premature atherosclerosis.

Obesity —particularly abdominal obesity— is a risk factor for


-increased mortality, -hypertension,
-type 2 diabetes mellitus, -hyperlipidemia,
-hyperglycemia,
-various endocrine dysfunctions
Fatty Liver

lipid—mainly as triacylglycerol —can accumulate in the liver.


Extensive accumulation is regarded as a pathologic condition.

1. Nonalcoholic fatty liver disease (NAFLD) is the most


common liver disorder worldwide. When accumulation of
lipid in the liver becomes chronic, inflammatory and fibrotic
changes may develop leading to

2. nonalcoholic steatohepatitis (NASH), which can progress to


liver diseases including

3. cirrhosis, hepatocarcinoma, and liver failure.


Frederickson Classification of Hyperlipoproteinemias

LPL, lipoprotein lipase; apo, apolipoprotein; FCS, familial chylomicronemia syndrome;


FH, familial hypercholesterolemia; FDB, familial defective apoB;
ARH, autosomal recessive hypercholesterolemia; ADH, autosomal dominant hypercholesterolemia;
FCHL, familial combined hyperlipidemia; FDBL, familial dysbetalipoproteinemia;
FHTG, familial hypertriglyceridemia.
SUMMARY
 Since nonpolar lipids are insoluble in water, for transport between the
tissues in the aqueous blood plasma they are combined with
amphipathic lipids and proteins to make water-miscible lipoproteins.

 Four major groups of lipoproteins are recognized: Chylomicrons


transport lipids resulting from digestion and absorption. Very low
density lipoproteins (VLDL) transport triacylglycerol from the liver.
Low-density lipoproteins (LDL)deliver cholesterol to the tissues, and
high-density lipoproteins (HDL) remove cholesterol from the tissues
and return it to the liver for excretion in the process known as reverse
cholesterol transport.
SUMMARY
 Chylomicrons and VLDL are metabolized by hydrolysis of their
triacylglycerol, and lipoprotein remnants are left in the
circulation. These are taken up by liver, but some of the
remnants (IDL), resulting from VLDL form LDL, which is taken
up by the liver and other tissues via the LDL receptor.

 Apolipoproteins constitute the protein moiety of lipoproteins.


They act as enzyme activators (eg, apo C-II and apo A-I) or as
ligands for cell receptors (eg, apo A-I, apo E, and apo B-100).