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Choleterol Metabolism
Cholesterol
"Cholesterol is the most highly decorated small molecule in biology.
Thirteen Nobel Prizes have been awarded to scientists who
devoted major parts of their careers to cholesterol. Ever since it
was isolated from gallstones in 1784, cholesterol has exerted an
almost hypnotic fascination for scientists from the most diverse
areas of science and medicine.
The very property that makes it useful in cell membranes, namely
its absolute insolubility in water, also makes it lethal."
-Michael Brown and Joseph Goldstein
Nobel Lectures (1985)
Cholesterol Carbon Numbering
Regulating Cholesterol Synthesis
• Normal healthy adults synthesize cholesterol at a
rate of approximately 1g/day and consume
approximately 0.3g/day. A relatively constant
level of cholesterol in the blood (150–200 mg/dL)
is maintained primarily by controlling the level
of de novo synthesis. The level of cholesterol
synthesis is regulated in part by the dietary
intake of cholesterol. Cholesterol from both diet
and synthesis is utilized in the formation of
membranes and in the synthesis of the steroid
hormones and bile acids. The greatest proportion
of cholesterol is used in bile acid synthesis.
• The synthesis of mevalonate is the committed
step in cholesterol formation. The enzyme
catalyzing this irreversible step,
3-hydroxy-3-methylglutaryl CoA reductase (HMGCoA reductase), is an important control site in
cholesterol biosynthesis.
HMG-CoA reductase is an integral membrane
protein in the endoplasmic reticulum
How Is Cholesterol Produced?
Fates of 3-Hydroxy-3-Methylglutaryl
CoA
Bile Salts
• (1ry.bile salt)
Deoxycholic acid
(secondary bile acid)
Steroid Hormones
Vitamin D Is Derived from Cholesterol by the
Ring-Splitting Activity of Light
Cholesterol is also the precursor of vitamin D, which
plays an essential role in the control of calcium
and phosphorus metabolism.
7-Dehydrocholesterol (provitamin D3) is photolyzed
by the ultraviolet light of sunlight to provitamin
D3,which spontaneously isomerizes to vitamin D3
Vitamin D Synthesis
The Complex Regulation of Cholesterol Biosynthesis
Takes Place at Several
Levels
Cholesterol can be obtained from the diet or it can be
synthesized de novo. An adult on a low-cholesterol
diet typically synthesizes about 800 mg of
cholesterol per day. The liver is the major site of
cholesterol synthesis in mammals, although the
intestine also forms significant amounts. The rate of
cholesterol formation by these organs is highly
responsive to the cellular level of cholesterol. This
feedback regulation is mediated primarily by
changes in the amount and activity of
3-hydroxy-3-methylglutaryl CoA reductase.
The Absence of the LDL Receptor Leads to
Hypercholesteremia and
Atherosclerosis
The results of Brown and Goldstein's pioneering studies
of familial hypercholesterolemia revealed the
physiologic importance of the LDL receptor. The total
concentration of cholesterol and LDL in the plasma is
markedly elevated in this genetic disorder, which
results from a mutation at a single autosomal locus.
The cholesterol level in the plasma of homozygotes is
typically 680 mg /dl, compared with 300 mg /dl in
heterozygotes.
How Does High Cholesterol Cause Heart Disease?
When there is too much cholesterol in your blood, it
builds up in the walls of your arteries, causing a
process called atherosclerosis, a form of heart
disease. The arteries become narrowed & blood flow
to the heart muscle is slowed down or blocked. The
blood carries oxygen to the heart, and if not enough
blood and oxygen reach your heart, you may suffer
chest pain. If the blood supply to a portion of the
heart is completely cut off by a blockage, the result is
a heart attack.
Total Cholesterol
Category
Less than 200
Desirable
200 - 239
Borderline High
240 and above
High
LDL Cholesterol
Category
Less than 100
Optimal
00 - 129
Near optimal/above optimal
130 - 159
Borderline high
160 - 189
High
190 and above
Very high
HDL*
Category
60 or more
Desirable - helps to lower
risk of heart disease
Less than 40
Major risk factor -increases the risk for
developing heart
disease
Triglycerides
Category
Less than 150
Normal (desirable)
heart disease
150-199
Borderline high
200-499
>500
High
Very high
In addition, the following tests can give you a far better
assessment of your heart disease risk than your total
cholesterol alone:
•HDL/Cholesterol ratio: HDL percentage is a very potent heart disease
risk factor. Just divide your HDL level by your total cholesterol. That
percentage should ideally be above 24 percent.
•Triglyceride/HDL ratios: You can also do the same thing with your
triglycerides and HDL ratio. That percentage should be below 2.
•Your fasting blood sugar level: Studies have shown that people with
a fasting blood sugar level of 100-125 mg/dl had a nearly 300
percent increased higher risk of having coronary heart disease than
people with a level below 79 mg/dl.
•Your iron level: Iron can be a very potent oxidative stress, so if you
have excess iron levels you can damage your blood vessels and
increase your risk of heart disease. Ideally, you should monitor your
ferritin levels and make sure they are not much above 80 ng/ml.
• What Affects Cholesterol Levels ?
• Diet. Saturated fat, trans fat, carbohydrates, and
cholesterol in the food you eat increase cholesterol
levels. Reducing the amount of saturated fat, trans
fats and sugars in your diet helps lower your blood
cholesterol level. Increasing the amount of fiber and
plant-derived sterols can also help lower LDL
cholesterol.
• Weight In addition to being a risk factor for heart
disease, being overweight can also increase your
cholesterol. Losing weight can help lower your LDL,
total cholesterol levels, and triglyceride levels, as
well as raise your HDL.
• Exercise. Regular exercise can lower LDL cholesterol
and raise HDL cholesterol. You should try to be
physically active for 30 minutes every day.
• Age and Gender. As we get older, cholesterol levels
rise. Before menopause, women tend to have lower
total cholesterol levels than men of the same age.
After menopause, however, women's LDL levels tend
to rise.
• Heredity. Your genes partly determine how much
cholesterol your body makes. High blood cholesterol
can run in families.
• Medical conditions. Occasionally, a medical
condition may cause an elevation of cholesterol
levels in the blood. These
include hypothyroidism , liver disease and kidney
disease.
• Medications. Some medicines, like steroids and
progestins, may increase "bad" cholesterol and
decrease the "good" cholesterol.
Lovastatin
A Competitive Inhibitor of HMG-CoA Reductase. The
part of the structure that resembles
the 3-hydroxy-3-methylglutaryl moiety is shown in red.
Niacin
• Niacin is a B-complex vitamin. It's found in
food, but is also available at high doses by
prescription. It lowers LDL cholesterol and
raises HDL cholesterol. These drugs also lower
elevated triglycerides.
Bile Acid Sequestrants
• These drugs work inside the intestine, where they
bind to bile and prevent it from being reabsorbed
into the circulatory system. Bile is made largely
from cholesterol, so these drugs work by
reducing the body's supply of cholesterol, thus
lowering total and LDL cholesterol.
• Examples : Cholestyramine
Colestipol