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 (HMG-CoA 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.

Less than 200 Desirable

200 - 239 Borderline High

240 and above High

Less than 100 Optimal

00 - 129 Near optimal/above optimal

130 - 159 Borderline high

160 - 189 High

190 and above Very high

60 or more Desirable - helps to lower

risk of heart disease

Less than 40 Major risk factor --

increases the risk for

developing heart

disease

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