Understanding Lipoproteins
Thomas A. Hughes, M.D. (May, 2007)
www.utmem.edu/endocrinology Click “Laboratory”
“Lipids” are fats that circulate in the blood. Because fat does not mix with water (which is what
blood mostly is), it must be carried in particles (round balls made up of lipids and proteins) called
“Lipoproteins”. These lipoproteins are simply fat droplets surrounded by soap (called phospholipids)
similar to the fat droplets created when you wash greasy pans with detergent. Of course, lipoproteins
are much more organized than is the fat in your sink. The two fats found in all lipoproteins are
cholesterol and triglycerides.
Triglyceride is a fat you would recognize. Butter and oils are triglycerides. The fat on meat is
triglyceride as is the stuff that may hang over your belt or is deposited on your hips. Triglycerides are
the major source of energy for our body. The lipoprotein system is designed to move triglycerides
from the stomach (where they are released from food) or the liver (where they are synthesized from
sugar) to muscle and other body tissues that need the energy.
Cholesterol, on the other hand, looks like wax when purified. Cholesterol is required by every
cell of the body in order to make cell membranes
and without it, we would not exist. Because
cholesterol is so important, every cell in the body
can make it. However, a build up of cholesterol
leads to heart attacks. Unfortunately, there is no
way for the body to digest cholesterol, so it
cannot be utilized for energy. Therefore, the
only way to get rid of it, is to excrete it from the
body. The organ that expels cholesterol from the
body is the liver. As a result, the other function
of lipoproteins, besides moving triglyceride, is to
collect the excess cholesterol throughout the
body and deliver it to the liver for removal.
There are five major types of lipoproteins:
(see figure) chylomicrons (CM), very low
density lipoprotein (VLDL), intermediate
density lipoprotein (IDL), low density
lipoprotein (LDL), and high density lipoprotein
(HDL). Lipoproteins differ in size, the relative
amount of cholesterol and triglycerides they
carry, and the proteins that are attached to them.
These proteins control where they go, with
which cells they will interact, and how they are
used. The largest lipoproteins are CM’s and they
get progressively smaller from VLDL Æ IDL Æ
LDL Æ HDL. Similarly, CM’s have the largest
percentage of triglycerides (~90%) relative to cholesterol (~10%), while LDL and HDL have the least
triglyceride (~20%). However, each of these lipoproteins can vary in size within its own class, with
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the smaller particles being the most dangerous within each class.
Chylomicrons are assembled in the intestine from fat ingested with food. It is released into the
blood where it delivers its triglycerides to various tissues, such as fat tissue (for storage) and muscle
(for energy). The remaining triglycerides and cholesterol in the CM particles (now called remnants)
are removed from the blood by the liver.
VLDL is assembled by the liver in a manner similar to chylomicrons. The triglycerides come
from: (1) fat delivered by the chylomicron remnants as noted above, (2) fat coming back to the liver
from fat cells, and (3) sugar which is converted to fat in the liver. VLDL also delivers triglycerides to
fat and muscle tissue. What is left when much of the triglyceride is released, is a VLDL remnant
called IDL. The IDL particle can be removed from the blood by the liver or converted to LDL (in
most people about half goes is each direction). During the conversion to LDL, much of the remaining
triglyceride is removed such that the triglyceride composition drops from about 80% to 50% to 20%
for VLDL, IDL, and LDL, respectively. VLDL, IDL, and LDL particles that are not removed from the
blood by the liver have a high probability of being embedded in the walls of arteries where they
produce atherosclerosis (hardening of the arteries). Therefore, elevated levels of VLDL, IDL, or LDL
cholesterol or triglycerides lead to atherosclerosis and heart attacks.
When VLDL and chylomicrons are assembled, the lipids are attached to a protein called apoB.
There is only one apoB molecule per particle and this apoB remains with the particle while it is
converted to IDL and LDL.
Thus, we can determine the
number of VLDL, IDL, and LDL
particles by measuring apoB.
These are important
measurements, because the
greater the number of particles,
the more atherosclerosis they
produce. In addition, the smaller,
denser VLDL, IDL, and LDL
particles are more likely to get
into the artery wall than larger
particles and, thus cause more
atherosclerosis. Therefore, we
estimate the size of VLDL and
IDL by calculating the number of
molecules of cholesterol and
triglycerides that are attached to
each particle. If the increase in
VLDL and IDL lipids is due to an
increased number of particles that are normal in size, then there is a higher risk of a heart attack than a
similar increase in lipids due to larger particles. Of course, even large particles are not good, but they
are not as bad as many, small particles. Similarly, we estimate the LDL size by its position following
ultracentrifugation (see “Patient Curve” on report). The farther to the right that the LDL peak is seen,
the more dense it is (abnormal position: >3.5). Again, dense LDL is worse than “normal” density
LDL.
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ApoC-III is another protein attached to VLDL, IDL, and HDL. It inhibits the removal of
triglycerides from these particles as well as prevents the removal of the VLDL and IDL particles from
the blood by the liver. Therefore, an increase in apoC-III usually causes an increase in VLDL and
IDL. Elevated apoC-III is frequently seen in obesity, diabetes, and renal disease. Another important
abnormality is the presence of Lp(a). Lp(a) is an unusual form of LDL which is inherited. It is
identified as an extra peak between LDL and HDL (see “Patient Curve”) and does not respond well to
treatment. Levels of greater than 20 mg/dl are associated with an increased risk of heart attacks.
HDL’s job is to remove cholesterol from tissues where it is made in abundance, such as arteries,
and deliver it to the liver for excretion. Small HDL (HDL-D = dense) is best at picking up cholesterol
while large HDL (HDL-L = light) is best at delivering cholesterol to the liver. HDL-D is converted to
HDL-L as it collects cholesterol. Some of the cholesterol in HDL can be transferred to VLDL, IDL,
and LDL, in fact, most of the cholesterol in IDL and LDL came from HDL in this manner. This is not
bad as long as IDL and LDL are
Cholesterol Removal
efficiently removed by the liver.
Unfortunately, the liver is saturated
Liver
with LDL at a level of 25 mg/dl (a
level that most people have at
birth) so that at the typical LDL
HDL-D
Arterial
levels seen in this country (120 to
LpA-I
HDL-L
Bowel
Plaque
140 mg/dl), much of this
LpA-I
cholesterol is simply returned to
the arteries (a bad thing). However, if HDL-L is functioning well, it will deliver this cholesterol to the
liver instead of transferring it to IDL and LDL. In general, high levels of HDL-L cholesterol and low
levels of HDL-D are associated with good HDL function, whereas low HDL-L with high HDL-D
indicates poor HDL function. In addition, there are two sets of HDL particles that differ in their
protein composition and substantially differ in their ability to remove cholesterol. The major protein in
HDL is apoA-I. ApoA-I is required for every step in the transfer of cholesterol from arteries to the
liver and, therefore, higher levels are protective. The other major protein in HDL is apoA-II. ApoA-II
is found only on some HDL particles (mostly found in HDL-M = middle) and it inhibits each step of
cholesterol transfer. Therefore, high levels of apoA-II are likely to increase the risk of heart attack.
As a result, the most powerful protection from a heart attack is a high level of LpA-I (HDL particles
containing only apoA-I – not to be confused with Lp(a)).
In summary, detrimental findings are:
Elevated:
VLDL: triglycerides, cholesterol, apoB, apoC-III, and particle number (esp with normal size)
IDL: triglycerides, cholesterol, apoB, apoC-III, and particle number (esp with normal size)
LDL: cholesterol, apoB, particle number, and density
Lp(a): cholesterol
Total HDL: apoA-II
HDL-D: cholesterol
Reduced:
HDL-L: cholesterol
HDL-M: cholesterol
Beneficial findings: Elevated total HDL and HDL-L cholesterol; elevated apoA-I and LpA-I
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