Chapter 14 : METABOLISM OF LIPIDS 317

Cholesterol 1. Chylomicrons : They are synthesized in

Apoprotein the intestine and transport exogenous (dietary)
Phospholipid triacylglycerol to various tissues. They consist of
highest (99%) quantity of lipid and lowest (1%)
concentration of protein. The chylomicrons are
Neutral core the least in density and the largest in size, among
Triacylglycerol the lipoproteins.
2. Very low density lipoproteins (VLDL) :
Cholesterol They are produced in liver and intestine and are
ester
responsible for the transport of endogenously
Shell (coat)
synthesized triacylglycerols.

Fig. 14.33 : A general structure of lipoprotein complex. 3. Low density lipoproteins (LDL) : They are
(Note : For the sake of clarity, only a part of the shell formed from VLDL in the blood circulation. They
and core are filled with the constituents). transport cholesterol from liver to other tissues.
4. High density lipoproteins (HDL) : They are
Hypocholesterolemia mostly synthesized in liver. Three different
A decrease in the plasma cholesterol, fractions of HDL (1, 2 and 3) can be identified
although less common, is also observed. by ultracentrifugation. HDL particles transport
Hyperthyroidism, pernicious anemia, mal- cholesterol from peripheral tissues to liver
absorption syndrome, hemolytic jaundice etc., (reverse cholesterol transport).
are some of the disorders associated with 5. Free fatty acids—albumin : Free fatty acids
hypocholesterolemia. in the circulation are in a bound form to
albumin. Each molecule of albumin can hold
about 20-30 molecules of free fatty acids.
LIPOPROTEINS This lipoprotein cannot be separated by
Lipoproteins are molecular complexes that electrophoresis.
consist of lipids and proteins (conjugated
proteins). They function as transport vehicles for
lipids in blood plasma. Lipoproteins deliver the
(–) Cathode
lipid components (cholesterol, triacylglycerol
etc.) to various tissues for utilization. Origin
Chylomicrons
Structure of lipoproteins
A lipoprotein basically consists of a neutral
lipid core (with triacylglycerol and/or cholesteryl LDL (E-lipoprotein)
ester) surrounded by a coat shell of
phospholipids, apoproteins and cholesterol Mobility
(Fig.14.33). The polar portions (amphiphilic) of VLDL (pre-E-lipoprotein)
phospholipids and cholesterol are exposed on
the surface of lipoproteins so that lipoprotein is
HDL (D-lipoprotein)
soluble in aqueous solution.

Classification of lipoproteins (+) Anode

Five major classes of lipoproteins are
identified in human plasma, based on their Fig. 14.34 : Electrophoresis of plasma (serum)
separation by electrophoresis (Fig.14.34). lipoproteins.
318 BIOCHEMISTRY

Apolipoproteins (apoproteins) since this apoprotein contains 48% of protein

coded by apo B gene (apo B100 is found in LDL
The protein components of lipoproteins are
and VLDL). Chylomicrons are produced when
known as apolipoproteins or, simply,
nascent particles combine with apo C II and apo
apoproteins. They perform the following
E, derived from HDL.
functions
1. Act as structural components of lipoproteins. The liver synthesizes nascent VLDL
containing apo B100 which are rich in triacyl-
2. Recognize the cell membrane surface
glycerols and cholesterol. Circulating HDL
receptors.
donates apo C II and apo E to convert nascent
3. Activate enzymes involved in lipoprotein VLDL to VLDL.
metabolism.
Role of lipoprotein lipase : The enzyme
The comparative characteristic features of lipoprotein lipase is present in the capillary walls
different lipoproteins with regard to electro- of adipose tissue, cardiac and skeletal muscle,
phoretic patterns, size, composition etc. are besides other tissues. It hydrolyses a portion
given in Table 14.5. of triacylglycerols present in chylomicrons
and VLDL to liberate free fatty acids and
Metabolism of lipoproteins glycerol. Lipoprotein lipase is activated by
—a general view apo C II.
A general picture of lipoprotein metabolism is
Uptake of chylomicron remnants by liver :
depicted in Fig.14.35.
As the triacylglycerols of chylomicrons and
Chylomicrons (nascent) are synthesized in the VLDL are degraded, they lose the apo C II which
small intestine during the course of fat is returned to HDL. The chylomicron remnants
absorption. They contain apoprotein B48 and are taken up by receptors present on the
mostly triacylglycerols. Apo B48 name is given hepatocytes of liver.

TABLE 14.5 Characteristics of human plasma lipoproteins

Characteristic Chylomicrons VLDL LDL HDL

Electrophoretic mobility Origin Pre-` ` _
Density <0.96 0.96–1.006 1.006–1.063 1.063–1.21
Diameter (nm) 100–1,000 30–90 20–25 10–20
Apoproteins AI, AII B100, CI, CII B100 AI, AII, CI,
B48 CIII, E CII, CIII, D, E
Composition (%, approximate)
Protein 2 10 20 40
Lipid (total) 98 90 80 60
Lipid components (%)
Triacylglycerol 88 55 12 12
Cholesterol (free and ester) 4 24 59 40
Phospholipids 8 20 28 47
Free fatty acids 1 1 1
(VLDL : Very low density lipoproteins; LDL : Low density lipoproteins; HDL : High density lipoproteins).
Chapter 14 : METABOLISM OF LIPIDS 319

B48 B48

TGC CII TG E
C

Nascent Chylomicrons
chylomicrons
Small intestine

B100 CII B100

E

TGC CII TG E
C
CII Lipoprotein
Nascent E VLDL lipase Extrahepatic
VLDL tissues
Free fatty
A acids

CII PC E CII

HDL

E
B100 B100
Glycerol

Liver C TG E
C
To liver
LDL IDL

B48

TG E
C
Chylomicron
remnant

Extrahepatic tissues

Fig. 14.35 : Summary of metabolism of lipoproteins (Apoproteins–A, B48, B100, CII and E;
TG–Triacylglycerol; C–Cholesterol; P–Phospholipid; VLDL–Very low density lipoprotein;
IDL–Intermediate density lipoprotein; LDL–Low density lipoprotein; HDL–High density lipoprotein).

Conversion of VLDL to LDL Cholesterol ester transfer protein (CETP) :

During the course of VLDL metabolism, CETP is synthesized in the liver, and it facilitates
intermediate density lipoprotein (IDL) is formed the exchange of components between different
which lose apo-E and get converted to LDL.
lipoproteins. CETP can transfer cholesterol
The apo E is returned to HDL. LDL contains
high cholesterol (free and esterified) and esters from HDL to VLDL or LDL, in exchange
less triacylglycerol. for TG.
320 BIOCHEMISTRY

LDL receptors and

supply of cholesterol Liver A
Cholesterol
to tissues P
CII E Extrahepatic
C
The most important Discoidal
tissues
function of LDL is to nascent HDL
C Cholesterol (C)
supply cholesterol to the AT
LC
extrahepatic tissues. The
LDL particles bind to the Bile acids and A
specific receptor pits cholesterol
(in bile)
(identified as glycoprotein) CII P C E
CE
on the cell membrane. The
HDL
shape of the pit is stabilized
by a protein called clathrin. Fig. 14.36 : Metabolism of high density lipoproteins (P–Phospholipid;
Apo B100 is responsible for C–Cholesterol; CE–Cholesteryl ester; A, CII, E–Apoproteins; LCAT–Lecithin
the recognition of LDL cholesterol acyltransferase).
receptor sites.
Deficiency of LDL receptors : A defect in LDL receptor-mediated endocytosis. In the liver, the
receptors results in the elevation of plasma LDL, cholesteryl esters are degraded to cholesterol.
hence plasma cholesterol. However, plasma The latter is utilized for the synthesis of bile acids
triacylglycerol concentration remains normal. and lipoproteins or excreted into bile (as
Deficiency of LDL receptors is observed in type cholesterol).
IIa hyperbetalipoproteinemia. This disorder is
associated with a very high risk of Cardioprotective function of HDL
atherosclerosis (particularly of coronary artery).
HDL is a good cholesterol and plays a
cardioprotective role. It is attributed to the
reverse cholesterol transport and removal of
METABOLISM OF HDL cholesterol from the peripheral tissue. Further,
High density lipoproteins are synthesized in HDL plays an antioxidant role (due to the
the liver as discoidal particles – nascent HDL. enzyme paroxanase activity) and protects LDL
They contain free cholesterol and phospholipids from getting oxidized. The result is that
(mostly lecithin) and apoproteins (A, CII, E etc.). atherogenesis and related complications like
heart attack are reduced.
Role of LCAT in HDL metabolism : The
plasma enzyme lecithin-cholesterol acyl-
transferase (LCAT) catalyses the esterification of DISORDERS OF PLASMA LIPOPROTEINS
free cholesterol (by fatty acid of lecithin) present
in the extrahepatic tissues and transfers to the
Inherited disorders of lipoproteins are
HDL. Apoprotein A promotes the activity of
encountered in some individuals resulting in
LCAT. HDL also accepts free cholesterol from
primary hyper- or hypolipoproteinemias. These
other lipoproteins in circulation and cell
are due to genetic defects in lipoprotein
membrane of peripheral tissues (Fig.14.36). Any
metabolism and transport. The secondary
free cholesterol taken up by HDL undergoes
acquired lipoprotein disorders are due to some
LCAT-catalysed esterification. Due to the
other diseases (e.g. diabetes mellitus, nephrotic
addition of cholesterol, HDL particles become
syndrome, atherosclerosis, hypothyrodism etc.),
spherical.
resulting in abnormal lipoprotein pattern
The HDL particles, with cholesteryl ester which often resembles the primary inherited
trapped inside, enter the hepatocytes by a condition.
 Chapter 14 : METABOLISM OF LIPIDS 321

TABLE 14.6 Classification and characteristics of hyperlipoproteinemias (hyperlipidemias)

Hyperlipopro- Increased plasma Increased plasma Probable metabolic Risk of Suggested

einemia Type lipoprotein(s) lipid (most) defect atherosclerosis treatment
I Chylomicrons Triacylglycerols Deficiency of lipoprotein May increase Low fat diet
lipase
IIa LDL Cholesterol Deficiency of LDL Very high (mostly in Low cholesterol fat
receptors coronary artery) diet; cholestyramine
IIb LDL and VLDL Triacylglycerols Overproduction of do do
and cholesterol apo-B
III IDL Triacylglycerols Abnormality in apo-E Very high (mostly in Low fat and low
and cholesterol peripheral vessels) caloric diet; clofibrate
IV VLDL Triacylglycerols Overproduction of TG May or may not Low fat and low
increase caloric diet; niacin
V Chylomicrons and VLDL Triacylglycerols do do

Hyperlipoproteinemias 5. Type IV : This is due to overproduction of

Elevation in one or more of the lipoprotein endogenous triacylglycerols with a concomitant
fractions constitutes hyperlipoproteinemias. rise in VLDL. Type IV disorder is usually
These disorders may be either primary or associated with obesity, alcoholism, diabetes
secondary. Some authors use hyperlipidemias or mellitus etc.
dyslipidemias instead of hyperlipoproteinemias. 6. Type V : Both chylomicrons and VLDL are
Frederickson’s classification of hyperliporo- elevated. This is mostly a secondary condition,
teinemias—based on the electrophoretic patterns due to disorders such as obesity, diabetes and
of plasma lipoproteins—is widely accepted to excessive alcohol consumption etc.
understand these disorders. It is given in
Table 14.6 and briefly discussed hereunder. Hypolipoproteinemias
1. Type I : This is due to familial lipoprotein Although low levels of plasma lipids (not
lipase deficiency. The enzyme defect causes HDL!) within the normal range may be beneficial
increase in plasma chylomicron and triacyl- to the body, very low lipid levels are
glycerol levels. undesirable. These are commonly associated
2. Type IIa : This is also known as hyperbeta- with certain abnormalities
lipoproteinemia and is caused by a defect in LDL 1. Familial hypobetalipoproteinemia : It is an
receptors. Secondary type IIa hyperlipopro- inherited disorder probably due to an
teinemia is observed in association with diabetes impairment in the synthesis of apoprotein B. The
mellitus, hypothyroidism, nephrotic syndrome plasma LDL concentration in the affected
etc. This disorder is characterized by individuals is between 10 to 50% of normal
hypercholesterolemia. values. This disorder is harmless, and the
3. Type IIb : Both LDL and VLDL increase individuals have healthy and long life.
along with elevation in plasma cholesterol and 2. Abetalipoproteinemia : This is a rare
triacylglycerol. This is believed to be due to disorder due to a defect in the synthesis of
overproduction of apo B. apoprotein B. It is characterized by a total
4. Type III : This is commonly known as absence of `-lipoprotein (LDL) in plasma.
broad beta disease and characterized by the Triacylglycerols are not found in plasma, but
appearance of a broad `-band corresponding to they accumulate in liver and intestine. Serum
intermediate density lipoprotein (IDL) on cholesterol level is low. Abetalipoproteinemia is
electrophoresis. associated with decreased absorption of fat

Biochemistry [21]
322 BIOCHEMISTRY

and fat-soluble vitamins. Impairment in physical (Fig.14.37). In the normal liver, Kupffer cells
growth and mental retardation are commonly contain lipids in the form of droplets. In fatty
observed. liver, droplets of triacylglycerols are found in the
Familial alpha-lipoprotein deficiency (Tangier entire cytoplasm of hepatic cells. This causes
disease) : The plasma HDL particles are almost impairment in metabolic functions of liver. Fatty
absent. Due to this, the reverse transport of liver is associated with fibrotic changes and
cholesterol is severely affected leading to the cirrhosis, Fatty liver may occur due to two main
accumulation of cholesteryl esters in tissues. An causes.
absence of apoprotein C II—which activates 1. Increased synthesis of triacylglycerols
lipoprotein lipase—is also found. The plasma
triacylglycerol levels are elevated. The affected 2. Impairment in lipoprotein synthesis.
individuals are at an increased risk for atheros- 1. Increased triacylglycerol synthesis :
clerosis. Mobilization of free fatty acids from adipose
tissue and their influx into liver is much higher
FATTY LIVER than their utilization. This leads to the
overproduction of triacylglycerols and their
The normal concentration of lipid (mostly accumulation in liver. Diabetes mellitus,
phospholipid) in liver is around 5%. Liver is not starvation, alcoholism and high fat diet are
a storage organ for fat, unlike adipose tissue. associated with increased mobilization of fatty
However, in certain conditions, lipids— acids that often cause fatty liver. Alcohol also
especially the triacylglycerols—accumulate inhibits fatty acid oxidation and, thus, promotes
excessively in liver, resulting in fatty liver fat synthesis and its deposition.

+ Niemann-Pick disease, caused by a defect in the enzyme sphingomyelinase, results in

the accumulation of sphingomyelins in liver and spleen.

+ About a dozen glycolipid storage diseases are known. These include Gaucher’s disease
and Krabbe’s disease.

+ Hypercholesterolemia is associated with atherosclerosis and coronary heart diseases.

Consumption of polyunsaturated fatty acids and fiber decreases cholesterol in
circulation. Drugs—such as lovastatin, cholestyramine, compactin and clofibrate—
reduce plasma cholesterol.

+ Cholelithiasis, a cholesterol gall stone disease, is caused by a defect in the absorption

of bile salts from the intestine or biliary tract obstruction.

+ High density lipoproteins—in association with lecithin-cholesterol acyltrans-

ferase (LCAT)—are responsible for the transport and elimination of cholesterol from
the body.

+ Hyperlipoproteinemias are a group of disorders caused by the elevation of one or more

of plasma lipoprotein fractions.

+ Excessive accumulation of triacylglycerols causes fatty liver which can often be

prevented by the consumption of lipotropic factors (choline, betaine, methionine).