Very Low-Density Lipoproteins

VLDLs are produced by the parenchymal cells of the liver from lipids and
apoprotein constituents in a way similar to that of chylomicron formation in
enterocytes. However, while the triacylglycerol core of chylomicrons is
derived exclusively from absorbed dietary lipids, the fatty acids required for
the formation of VLDL triacylglycerol are derived from :-
1.Stored fat released from adipose tissue as fatty acids;
2.Conversion of carbohydrates to fatty acids in the liver; and
3.Hydrolysis of lipoprotein triacylglycerols on capillary endothelia and in
the liver.
Synthesis of apoprotein B-100 is required for VLDL secretion. VLDLs are
also triglyceride-rich, but cholesterol content is higher than that of
chylomicrons. Their function is to carry triglycerides synthesized in the liver
and intestines to capillary beds in adipose tissue and muscle, where they are
hydrolyzed by lipoprotein lipase to provide fatty acids that can be oxidized to
produce energy. The amount of VLDL secreted by the liver is extremely
variable and can be affected in a number of ways. A primary determinant of
VLDL output is the flux of free fatty acids entering the liver. The liver
responds to an increase in free fatty acids by synthesis of more and larger
VLDLs. If the fatty acid flux to the liver is large, the rate of secretion of
triacylglycerols in VLDLs can become saturated. The resulting triacylglycerol
deposition in cytoplasmic droplets is seen in “fatty liver.”
A high-carbohydrate diet results in a substantial elevation of plasma VLDL
concentrations. A high-cholesterol diet alters the composition of VLDL, with
cholesterol esters substituting for triacylglycerol as core components, and
leads to a marked increase in apo E synthesis.
Newly secreted VLDL undergoes changes in the plasma . Nascent VLDL
have only apoB-100 and acquires apo C and E from HDL. LDL contains
exclusively apo B-100, indicating that VLDL is the principal precursor of
LDL. In humans, as the core triacylglycerols removed (by lipoprotein lipase)
and the C apoproteins are lost, approximately half of the VLDL is rapidly
removed by the liver via the apo B-100–apo E receptor pathway. The rest
remains in circulation as VLDL remnants. Since some of these remnants
have a density of between 1.006 and 1.019, they are called IDLs and are
analogous to chylomicron remnants. The remaining IDLs are subjected to
further catabolism by hepatic lipase. In VLDL and IDL, the cholesterol is
converted to cholesteryl esters by the enzyme (Lecithin – cholesterol –acyl-
transferase) LCAT. Leading to the formation of LDL which is a cholesteryl-
ester rich particles containing almost exclusively apo B-100.
Low Density Lipoprotein (LDL):
Lipoprotein lipase is located on the walls of blood capillaries bound to the endothelium by
negatively charged heparan sulfate. It has been found in heart, adipose tissue, spleen, lung,
renal medulla, aorta, diaphragm, and lactating mammary gland, although it is not active in adult
liver. It is not normally found in blood.
The liver and many extrahepatic tissues poses the LDL (apo B-100, E) receptor. It is so
designated because it is specific for apo B-100 but not B-48, and it also takes up lipoproteins
rich in apo E. Approximately 30% of LDL is degraded in extrahepatic tissues and 70% in the
liver. 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 formation and metabolism :
HDL is synthesized and secreted from both liver and intestine (see Figure). However, apo C
and apo E are synthesized in the liver and transferred from liver HDL to intestinal HDL when the
latter enters the plasma. A major function of HDL is to act as a repository(transporter) 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. lecithin:cholesterol
acyltransferase (LCAT)—and the LCAT activator apo A-I—bind to the discoidal particles, and
the surface phospholipid and free cholesterol are converted into cholesteryl esters and
lysolecithin . The nonpolar cholesteryl esters move into the hydrophobic interior of the bilayer,
whereas lysolecithin is transferred to plasma albumin. Thus, a nonpolar core is generated,
forming a spherical, pseudomicellar HDL covered by a surface film of polar lipids and
apolipoproteins. This aids the removal of excess unesterified cholesterol from lipoproteins and
tissues . In the liver and in steroidogenic tissues, HDL, binds via apo A-I, and cholesteryl ester is
selectively delivered to the cells, although the particle itself, including apo A-I, is not taken up. In
the tissues, on the other hand,HDL receptors mediates the acceptance of cholesterol from the
cells by HDL, which then 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 .
 % triacylglycerol
Density (g/mL % % %
Class Diameter (nm) & cholesterol
) protein cholesterol phospholipid
ester
>1.063 HDL 5–15 33 30 29 4-8
1.019–1.063 LDL 18–28 25 46-50 21-22 8-10
1.006–1.019 IDL 25–50 18 29 22 31
0.95–1.006 VLDL 30–80 10 22 18 50
Chylomicron
<0.95 75-1200 1-2 8 7 83-84
s

Oxidation of Fatty acids(B-Oxidation)

Although fatty acids are both oxidized to acetyl-CoA and synthesized from acetyl-CoA, fatty acid
oxidation is not the simple reverse of fatty acid biosynthesis but an entirely different process taking place
in a separate compartment of the cell. Each step in fatty acid oxidation utilizes NAD+ and FAD as
coenzymes, and generates ATP. It is an aerobic process, requiring the presence of oxygen.Increased fatty
acid oxidation is a characteristic of starvation and of diabetes mellitus, leading to ketone body production
by the liver (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in
diabetes, cause ketoacidosis, which is ultimately fatal.

Oxidation of Fatty Acids Occurs in Mitochondria.Fatty acids must first be converted to an active
intermediate before they can be catabolized. This is the only step in the complete degradation of a fatty
acid that requires energy from ATP. In the presence of ATP and coenzyme A, the enzyme acyl-CoA
synthetase (thiokinase) catalyzes the conversion of a fatty acid (or free fatty acid) to an "active fatty
acid" or acyl-CoA, which uses one high-energy phosphate with the formation of AMP and PPi (Figure
22–1). The PPi is hydrolyzed by inorganic pyrophosphatase with the loss of a further high-energy
phosphate, ensuring that the overall reaction goes to completion. Acyl-CoA synthetases are found in the
endoplasmic reticulum, peroxisomes, and inside and on the outer membrane of mitochondria.
Formation of Ketone bodies and Ketogenesis :-

This occurs when there is a high rate of fatty acid oxidation in the liver.
Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces
considerable quantities of acetoacetate and (β -hydroxybutyrate). Acetoacetate continually undergoes
spontaneous decarboxylation to yield acetone. These three substances are collectively known as the
ketone bodies. Extrahepatic tissues utilize them as respiratory substrates. The net flow of ketone bodies
from the liver to the extrahepatic tissues results from active hepatic synthesis coupled with very low
utilization.