Bicol University

College of Nursing
Legazpi City 2015-2016

Research Lecture:
All about Lipids

SUBMITTED TO:
DR. NOEMI R. MADRID

SUBMITTED BY:
PHOEBE GILLIAN N. MAGPAYO

Lipids
Lipid is the collective name for fats, oils, waxes and fat-like molecules (such as steroids) found in the body. Their roles
include:
components of cell membranes (phospholipids and cholesterol)
energy stores
chemical messengers (steroid 'hormones')
protection, waterproofing, insulation and buoyancy agents.

The basic unit of lipids is a triglyceride, synthesised from glycerol (propane-1,2,3-triol) and fatty acids.
Glycerol is a type of alcohol. Alcohols are organic compounds. Their molecules are characterisedbyhydroxyl groups, -OH.
Glycerol is a trihydric alcohol, which means each molecule has three hydroxyl groups.
Glycerol /lsrl/[4] (also called glycerine or glycerin; see spelling differences) is a simple polyol (sugar alcohol)
compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three
hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central
to all lipids known as triglycerides. Glycerol is sweet-tasting and is non-toxic.

Lipids are important constituent of of the diet because they are a source of high energy value. Lipids are also
important because of the fat-soluble vitamins, and essential fatty acids found in the fat of the natural food stuffs. Body fat
serves as a very good source of energy, it is stored in adipose tissues. They also act as insulating material in the
subcutaneous tissues and are also seen around certain organs. Lipids combined with proteins are important constituents
of the cell membranes and mitochondria of the cell. Lipids are not generally macromolecules.
Lipids are naturally occurring organic compounds, commonly known as oils and fats. Lipids occur through out the living
world in microorganisms, higher plants and animals and also in all cell types. Lipids contribute to cell structure, provide
stored fuel and also take part in many biological processes.

Lipids Definition
Lipids are naturally occurring hydrophobic molecules. They are heterogenous group of compounds related to fatty acids.
They include fats, oils, waxes, phospholipids, etc. They make up about 70% of the dry weight of the nervous system.
Lipids are crucial for the healthy functioning of the nerve cells. Lipids are greasy or oily organic substances; lipids are
sparingly soluble in water and are soluble in organic solvents like chloroform, ether and benzene.

Characteristics of Lipids
General characters of lipids are

Lipids are relatively insoluble in water.

They are soluble in non-polar solvents, like ether, chloroform, methanol.

Lipids have high energy content and are metabolized to release calories.

Lipids also act as electrical insulators, they insulate nerve axons.

Fats contain saturated fatty acids, they are solid at room temperatures. Example, animal fats.

Plant fats are unsaturated and are liquid at room temperatures.

Pure fats are colorless, they have extremely bland taste.

The fats are sparingly soluble in water and hence are described are hydrophobic substances.

They are freely soluble in organic solvents like ether, acetone and benzene.

The melting point of fats depends on the length of the chain of the constituent fatty acid and the degree of
unsaturation.

Geometric isomerism, the presence of double bond in the unsaturated fatty acid of the lipid molecule produces
geometric or cis-trans isomerism.

Fats have insulating capacity, they are bad conductors of heat.

Emulsification is the process by which a lipid mass is converted to a number of small lipid droplets. The process of
emulsification happens before the fats can be absorbed by the intestinal walls.

The fats are hydrolyzed by the enzyme lipases to yield fatty acids and glycerol.

The hydrolysis of fats by alkali is called saponification. This reaction results in the formation of glycerol and salts
of fatty acids called soaps.

Hydrolytic rancidity is caused by the growth of microorganisms which secrete enzymes like lipases. These split
fats into glycerol and free fatty acids.

Types of Lipids
In the year 1943 Bloor proposed the following classification of lipids based on their chemical composition.

Simple Lipids or Homolipids

oil is liquid.
Simple Triglycerides - Simple triglycerides are one in

Simple lipids are the esters of fatty acids with various

which three fatty acids radicles are similar or are of the

alcohols.

same type. Example: Tristearin, Triolein.

Fats and Oils (triglycerides and triacylglycerols) - These

Mixed Triglycerides are one in which the three fatty

are esters of fatty acids with a trihydroxy alcohol,

acids radicles are different from each other. Example:

glycerol. A fat is solid at ordinary room temperature, an

distearo-olein, dioleo-palmitin.

Waxes are the esters of fatty acids with high molecular

weight monohydroxy alcohols. Example: Beeswax,
Carnauba wax.

Compound Lipids or Heterolipids

Heterolipids are esters of fatty acids with alcohol and possess additional groups also.
Phospholipids or Phosphatids are compound containing fatty acids and glycerol in addition to a phosphoric acid,
nitrogen bases and other substituents. They usually possess one hydrophilic head and tow non-polar tails. They are called
polar lipids and are amphipathic in nautre.
Phospholipids can be phosphoglycerides, phosphoinositides and phosphosphingosides.
Phosphoglycerides are major phospholipids, they are found in membranes. It contains fatty acid molecules which are
esterified to hydroxyl groups of glycerol. The glycerol group also forms an ester linkage with phosphoric acid. Example:
Lecithin, Cephalins.
Phosphoinositides are said to occur in phospholipids of brain tissue and soybeans. The ply important role in transport
processes in cells.

Phosphosphingosides are commonly found in nerve tissue. Example: sphingomyelins.

Glycolipids are the compounds of fatty acids with carbohydrates and contain nitrogen but no phosphoric acid. The
glycolipids also include certain structurally related compounds comprising the groups gangliosides, sulpholipids and
sulfatids.

Derived Lipids
Derived lipids are the substances derived from simple and compound lipids by hydrolysis. These includes fatty acids,
alcohols, monoglycerides and diglycerides, steroids, terpenes, carotenoids.
The most common derived lipids are steroids, terpenes and carotenoids.
Steroids do not contain fatty acids, they are nonsaponifiable, and are not hydrolyzed on heating. They are widely
distributed in animals, where they are associated with physiological processes. Example: Estranes, androstranes, etc.

Terpenes in majority are found in plants. Example: Natural rubber. gernoil, etc.
Carotenoids are tetraterpenes. They are widely distributed in both plants and animals. They are exclusively of plant
origin. Due to the presence of many conjugated double bonds, they are colored red or yellow. Example: Lycopreene,
carotenes, Xanthophylls.
Essential fatty acids are those that cannot be constructed through any chemical pathways, known to happen in humans.
They must be obtained from the diet. Linoleic acid and linolenic acid are the essential fatty acids.
Non-essential fatty acids are those which are not necessary to be taken through diet, they are synthesized through
chemical pathways.
Unsaturated fatty acids have one or more double bonds between carbon atoms. The tow carbon atoms are bound to
each other through double bonds and can occur in cis or trans configuration.
Saturated fatty acids are long chain carboxylic acids and do not have double bonds. Example: Arachidic acid, Palmitic
acid, etc.

Structure of Lipids
Lipids has no single common structure. The most commonly occurring lipids are triglycerides and phospholipids.
Triglycerides are fats and oils. Triglycerides have a glycerol backbone bonded to three fatty acids. If the three fatty are
similar then the triglyceride is known as simple triglyceride. If the fatty acids are not similar then the fatty acids are known
as mixed triglyceride.

The second most common class of lipids are phospholipids. They are found in membranes of animal and plants.
Phospholipids contains glycerol and fatty acids, they also contain phosphoric acids and a low-molecular weight alcohol.
Common phospholipids are lecithins and cephalins.

Biological Functions of Lipids

Lipids perform several biological functions:

Lipids are storage compounds, triglycerides serve as reserve energy of the body.

Lipids are important component of cell membranes structure in eukaryotic cells.

Lipids regulate membrane permeability.

They serve as source for fat soluble vitamins like A, D, E, K.

They act electrical insulators to the nerve fibres, where the myelin sheath contains lipids.

Lipids are components of some enzyme systems.

Some lipids like prostaglandins and steroid hormones act as cellular metabolic regulators.

Cholesterol is found in cell membranes, blood, and bile of many organisms.

As lipids are small molecules and are insoluble in water, they act as signalling molecules.

Layers of fat in the subcutaneous layer, provides insulation and protection from cold. Body temperature
maintenance is done by brown fat.

Polyunsaturated phospholipids are important constituents of phospholipids, they provide fluidity and flexibility to
the cell membranes.

Lipoproteins that are complexes of lipids and proteins, occur in blood as plasma lipoprotein, they enable transport
of lipids in aqueous environment, and their transport throughout the body.

Cholesterol maintains fluidity of membranes by interacting with lipid complexes.

Cholesterol is the precursor of bile acids, Vitamin D and steroids.

Essential fatty acids like linoleic and linolenic acids are precursors of many different types of ecosanoids including
prostaglandins, thromboxanes. These play a important role in pain, fever, inflammation and blood clotting.
List of Lipids
Lipids are a diverse group of naturally occurring organic compounds. Below are the list of lipids:

Examples of Lipids
Few well known examples of lipids are as follows:
Fatty acids - Oleic acid, Linoleic acid, Palmitoleic acid, Arachidonic acid.
Fats and Oils - Animal fats - Butter, Lard, Human fat, Herring oil. Plant oils - Coconut oil, Corn, Palm, Peanut, Sunflower
oil.
Waxes - Spermacti, Beeswax, Carnauba wax.
Phospholipids - Lecithins, Cephalins, Plasmoalogens, Phosphatidylinositols, Sphingomyelins.
Glycolipids - Kerasin, Phrenosin, Nervon, Oxynervon.
Steroids - C 29, C 28, C 27, C 24, C 21 steroids.
Terpenes - Monoterpenes, Sesquiterpenes, Diterpenes, Triterpenes.
Carotenoids - Lycopene, Carotenes, Xanthophylls.

Cholesterol, from the Ancient Greek chole- (bile) and stereos (solid) followed by the chemical suffix -ol for an
alcohol, is anorganic molecule. It is a sterol (or modified steroid),[4] a lipid molecule and is biosynthesized by all animal
cells because it is an essential structural component of all animal (not plant or bacterial) cell membranes that is required to
maintain both membrane structural integrity and fluidity. Cholesterol enables animal cells to not need a cell wall (like
plants and bacteria) to protect membrane integrity and cell viability, thus are able to change shape and move about (unlike
bacteria and plant cells which are restricted by their cell walls).
In addition to its importance within cells, cholesterol also serves as a precursor for the biosynthesis of steroid hormones,
bile acids, and vitamin D.[5] Cholesterol is the principal sterol synthesized by animals. All kinds of cells in animals can
produce it. Invertebrates the hepatic cells typically produce greater amounts than other cells. It is almost completely
absent amongprokaryotes (bacteria and archaea), although there are some exceptions such as Mycoplasma, which require
cholesterol for growth.[6]

Franois Poulletier de la Salle first identified cholesterol in solid form in gallstones in 1769. However, it was not until
1815 that chemist Michel EugneChevreul named the compound "cholesterine".[7][8]

Special treatment with cholesterol

Safe, effective treatment for high cholesterol isn't hard -- but it can be confusing. Get the facts.
By R. Morgan Griffin
WebMD Feature
Reviewed by Brunilda Nazario, MD
WebMD Feature Archive
If you've just been diagnosed with high cholesterol, you may be worried. After all, along with your age, genes, and other
factors, high cholesterol is a major contributor to cardiovascular disease, heart attack, and stroke. But while you can't turn
back the clock or yank out unhealthy genes from your DNA, you can change your cholesterol numbers. That's
because high cholesterol treatment works.
"We have good, safe treatments for high cholesterol," says Adolph Hutter, MD, a cardiologist at Massachusetts General
Hospital and a professor of medicine at Harvard Medical School. "They can directly lower your risks of heart
attack, stroke, and death. So why not take advantage of them?"
For many people, making changes to their lifestyle -- eating better,losing weight, and exercising -- will be enough to lower
cholesterol. Others may benefit from medicines. Often, a combination of these approaches is the right choice.
But where do you start? "People tend to be very confused about treating high cholesterol," says Nathan D. Wong, PhD,
director of theheart disease prevention program at the University of California, Irvine.
WebMD talked to experts to help reduce the confusion -- and help you sort through your high cholesterol
treatment options.
Tips for Lowering Your Cholesterol
art

Is it time to consider medication? Take this quiz for cholesterol-lowering tips.

Finding the Best High Cholesterol Treatment
There's a lot of variability in how high cholesterol treatments work in a given person. Treatment that did wonders for your
spouse may do nothing for you. Some of it depends on your genes. You and your doctor will need to come up with a
custom-tailored approach.
For most people, the first high cholesterol treatment to try is three lifestyle changes:

Eating better

Maintaining (or losing) weight

Exercising more
Some people, if they already have other risk factors -- such as diabetes-- may immediately start medication as well.
While lifestyle changes can really help bring your cholesterol down, Wong says that not enough people give them a real
chance.
"The problem is that both patients and their doctors like immediate results," he tells WebMD. "Lowering your cholesterol
with exercise and diet is just not like that."
So try to give high cholesterol lifestyle treatments time to work. If they do, you can avoid the hassle of being on a daily
medicine for the rest of your life.
Eating Right as a High Cholesterol Treatment
We've all heard that diet has an effect on cholesterol, but there's much confusion about what you should or shouldn't eat.
Here's a rundown of the current evidence.

Fat. If you have high cholesterol, you should cut down on saturated fat -- found in fatty meats and whole milk
dairy products like cheese, ice cream, and butter. You also need to reduce your intake of trans fats, a man-made fat found
in many processed foods, like stick margarine.
But the message isn't as simple as "fat is bad." There are a number of foods with healthy unsaturated fats that will actually
improve your cholesterol. They include fatty fish like tuna and salmon, walnuts, and almonds. Since even good fats are
high in calories, you should still eat them in moderation.

Calories. According to Wong, the importance of counting your calories is often overlooked by people with high
cholesterol. No matter how much or how little fat or cholesterol is in a food, its calories still add up. Eating too much of it
can lead to weight gain, and that increases your risk of high cholesterol.

High cholesterol foods. Experts have long urged people with high cholesterol to shun foods loaded with
cholesterol, like egg yolks, shrimp, and organ meats. While some recent evidence suggests eggs may not be quite as
harmful as once thought, experts still generally recommend you limit all high cholesterol foods. Also, don't assume that a
food labeled "cholesterol-free" is necessarily good for you.
So what sort of diet works as a high cholesterol treatment? Ask your doctor for specific recommendations. Some experts
recommend a Mediterranean-style diet, which cuts down on saturated and trans fats, while boosting intake of healthy
unsaturated fats from fish and nuts.
If an improved diet doesn't help your cholesterol, don't feel like a failure. Because of their genes, some people just don't
respond as well to this approach.
Weight Loss & Exercise as a High Cholesterol Treatment
Being overweight or obese ups your odds of having high LDL (bad cholesterol) and triglyceride levels and low HDL (good
cholesterol) levels. It can also lead to other serious risks like high blood pressure,diabetes, and heart disease. So it's
crucial to keep a healthy weight.
Weight Loss & Exercise as a High Cholesterol Treatment continued...
As a high cholesterol treatment, physical activity can have a modest effect. Exercise can lower your triglycerides (and
bad LDL cholesterolto a lesser extent) and boost your good HDL cholesterol. So you should aim to get some physical
activity -- even just a brisk walk -- for 30-60 minutes most days of the week.

But there are limits to what exercise can do. "For most people, exercise by itself wouldn't be an effective therapy to lower
cholesterol," says Laurence S. Sperling, MD, director of preventive cardiology at the Emory University School of Medicine,
Atlanta, Ga. But it can keep your weight down and reduce other cardiovascular risks.
Medications as High Cholesterol Treatments
If lifestyle changes haven't been enough as a high cholesterol treatment -- or if you're at high risk of cardiovascular
problems -- your doctor will likely turn to medications. In most cases, the first drug you will try is a statin.
Tatins like Crestor, Lescol, Lipitor, Mevacor, Pravachol, and Zocorwork by blocking the effects of an enzyme that helps
make cholesterol. They can lower bad LDL cholesterol by an impressive 20-55%. They have a modest effect
on triglycerides and give a mild boost to your good cholesterol, too.
But don't assume that taking a statin makes you invulnerable. They won't cancel out a diet of french fries and fondue.
"Statins are a complement to dietary changes," says Hutter, "not a replacement for them."
As with any drug, there are side effects. They can cause muscle aches, an increase in liver enzymes, and other issues.
But the risks are low and it's important to keep them in perspective.
"On one hand, statins can reduce your risk of death, heart attack,stroke by 30-35%," says Sperling. "On the other, they
pose a 1-2% risk of generally mild side effects." The benefits are often worth the small risk, Sperling says.
Although they tend to be overshadowed by statins, other medicines are also important high cholesterol treatments instead
of, or in addition to, statins. They include:

Bile acid resins like Colestid, Lo-Cholest, Prevalite, Questran, andWelChol. They stick to cholesterol in
the intestines and prevent it from being absorbed. They can lower LDL cholesterol by 15-30%.

Ezetimibe (Zetia) blocks some of the cholesterol from being absorbed by your body. It can lower LDL levels by
18-25%.

Fibric acid like Antara, Atromid, Lopid, and Tricor. They reduce your triglycerides and may give a mild boost to
your HDL.

Niacin , available as Niacor, Niaspan, and Nicolar. Niacinmodestly lowers LDL cholesterol and triglycerides and
can raise HDL cholesterol at low doses. LDL levels are usually cut by 5-15%.

A combination medicine like ezetimibe with simvastatin (Vytorin) which uses a statin to block production of
cholesterol and ezetimibe to prevent cholesterol from being absorbed.
Remember that medicines aren't right for everyone. Since they're often taken for life, you and your doctor need to
carefully discuss whether you should use them.
Do Alternative High Cholesterol Treatments Work?
While lifestyle changes and medicines have been shown to lower cholesterol and reduce your risk of cardiovascular
disease, the same can't always be said for many alternative treatments. Some of the various supplements and herbs that
have been touted as high cholesterol treatments are garlic, policosanol, and guggul.
While a few studies of garlic have found a modest benefit, a recent study of policosanol found no effect. However, none of
these studies have been large enough to be definitive, experts say.
Keep in mind that, unlike medications, herbal products are not regulated by the FDA. They are not evaluated to see if they
work. They could also interact with other medicines you use.
"You just don't know what you're getting when you buy these products," says Wong. So if you want to take an alternative
high cholesterol treatment, be sure to talk to your doctor.

Sticking to Your High Cholesterol Treatments

Many people find that their dedication to lowering their cholesterol fades over time. When they're first diagnosed, they're
gung ho. They go on a diet and train like marathon runners. But after a few months, they get complacent. Their lowcholesterol cookbooks gather dust and their gym membership card lies in a sock drawer.
It is very easy to forget about high cholesterol. Even though it may still be doing damage, you can't feel it.
So how can you make healthy changes stick? The experts have some advice.

Get tested regularly. All adults need to be tested at least once every five years. People with high cholesterol or
other risk factors may need to be tested once a year or more.

Know your numbers. "People need to know what the cholesterol numbers are and what their target numbers
should be," says Sperling.

If you've been prescribed medicine, take it. It's easy to get lax about taking a daily medicine. So do what you
can to remember. Use a weekly pill box or an alarm to help you remember.

Get help in making lifestyle changes. Changing the way you eat isn't easy -- you've probably developed some
bad habits over the decades. But, unfortunately, Wong says that many doctors -- because they are so busy -- just don't
give good guidance on this crucial part of treatment.
"Doctors might just tell a patient, 'Exercise more and eat less,'" Wong says. "But making these changes requires a lot
more than vague advice."
So ask specific questions about what to do. If you find you're having trouble making changes to your habits, check back in
with your doctor. If possible, Wong suggests having a few meetings with a dietician who can help guide you.

Physicochemical properties of lipids

Fatty acid bioavailability can be managed through the physicochemical properties of lipid such as lipid-droplet
size, lipid-droplet ultrastructure (lipids organization between core and surface), structure of triglycerides and of
phospholipids. The lipid-droplet size exhibits a major effect on lipase activity during lipid digestion. The lipiddroplet ultrastructure is a dynamic factor controlling lipase interaction at the lipid interface via the surface
phospholipid layer, and also lipase activity via the proportion of triglyceride molecules able to locate at the
surface. Triglyceride structure affects in a strong manner digestion, absorption and fatty acid metabolism.
Finally,optimal fatty acid transport to specific tissues is dependent on the vehicle molecule (triglyceride or ethyl
ester or phospholipid). All these aspects provide convincing support for the possibility of using
biotechnologically remodeled lipids with specific physicochemical properties for health benefits.

Physical properties of lipids

Water is the substance that makes life possible, which is why most organic molecules are
soluble in water. Lipids are an exception, with the unique physical property of being

hydrophobic, or insoluble in water. The physical properties of lipids give them an

essential role in influencing the texture, appearance and healthfulness of the foods we
eat. Thus, the food science industry has developed a number of criteria by which to
measure and evaluate the physical properties of lipids.
The Facts

Lipids are one of the four major groups of organic macromolecules, along with
proteins, carbohydrates and nucleic acids. All of these large molecules share the
properties of being carbon-based and essential for life as we know it. Lipids are a diverse
group of molecules that include fats, oils, waxes, phospholipids and steroids.
Structure

Like all organic molecules, lipids are composed of a chain of carbon atoms
attached to other functional groups of atoms. Fats are composed of a glycerol (a three
carbon alcohol) joined to three fatty acids.
Significance

Lipids are important in the food science industry, as lipids are a major source of
dietary energy and affect the nutritional value, taste and texture of foods.
Criteria important in food science include the solid fat content of the lipid, the cloud point
and the smoke/fire/flash point.

Solid Fat Content

The solid fat content is the ratio of the lipid volume that is solid mass compared to
the total mass of the lipid. Solid fat content affects spreadability, firmness, texture and
stability of the lipid. Food manufacturers are interested in the solid fat content of
products like butter and margarine.
Cloud Point

The cloud point is a measure of the temperature at which crystallization begins in

an oil when cooled. Producing oils that don't form crystals at cool temperatures is of
practical importance as it may increase the ability of some oils to be stored for prolonged
periods.
Smoke/Fire/Flash Point

Understanding the smoke and fire points for particular lipids is important for
selecting lipids that can be used at high temperatures. These points measure the effects
of heating on the physical properties of the lipid and are an indicator of the amount of
volatile organic material present in the lipid.
Saturated and Unsaturated Fats

Carbon's ability to form a maximum of four bonds with other atoms is important for
understanding the difference between saturated and unsaturated fats.
Saturated fats, like lard or butter, are solid at room temperature. This is due to the
physical properties of the fatty acid tails in the lipid molecules. In a saturated fat, each
carbon atom forms a single bond with hydrogen and other atoms in the molecule. This
creates a fatty acid with a straight "tail," which allows many saturated fat molecules to
be packed tightly together in a relatively small space.
Unsaturated fats, like olive oil, are liquid at room temperature. In these fats, carbon
atoms form double bonds that create a kink in the tail of the fatty acid. Kinks prevent
tight packing of unsaturated molecules.

CHEMICAL PROPERTIES OF LIPIDS :

CHEMICAL PROPERTIES OF LIPIDS Stephy Maria Sebastian s1FST MACFAST

ACID NUMBER :
ACID NUMBER It is defined as the mg of KOH necessary to neutralize the free fatty acids present in 1g of fat or oil. The acid
number thus,tells us of the quantity of free fatty acid present in a fat. A high acid value indicates a state oil or fat stored under
improper conditions. Acid value is important because it measures hydrolytic rancidity. FFA=ml alkali * N of alkali * 28.2
mg/sample wt

2.SAPONIFICATION NUMBER :
2.SAPONIFICATION NUMBER Saponification is the process of breaking down or degrading a neutral fat into glycerol and fatty
acids by treatment of with alkali. Saponification number is defined as the mg of KOH required to saponify 1g of fat.
Saponification number=(S-B) *N*56.1/sample weight.

3.IODINE NUMBER :
3.IODINE NUMBER Iodine value is a measure of degree of unsaturation, the number of carbon-carbon double bonds in relation
to the amount of fat or oil. It is defined as the g iodine absorbed per 100g of sample. Iodine number=(B-S)*N*12.69/sample
weight

.PEROXIDE VALUE :
4.PEROXIDE VALUE Peroxide value measures the degree of lipid oxidation in fats and oils but not their stability. It is defined as
the number of milli equivalents of peroxide per kg fat. It is a measure of the formation of peroxide or hydroxide groups that are
initial products of the lipid oxidation. Peroxide value=(S-B)*N*1000/sample weight.

RIECHERT MESSEL VALUE :

5.RIECHERT MESSEL VALUE The RiechertMessel Number is a measure of the amount of H2O soluble volatile fatty acids. It is
defined as the number of milliliters of 0.1 N alkali necessary to neutralize the volatile H2O soluble fatty acids in a 5g sample of
fat.

.POLENSKEE NUMBER :
6.POLENSKEE NUMBER Polenkee number measures the amount of volatile insoluble fatty acids. It can be defined as the no: of
millilites of 0.1N alkali necessary to neutralize the volatile H2O insoluble fatty acids which are present in 5g sample.

.HYDROLYSIS :
7.HYDROLYSIS It is the reaction of water with a substance such as fats. This results in the splitting of some of the fatty acids
from the oil or fat, yielding some free fatty acids,monoglycerides and diglycerides. This reaction takes place at the junction of the
fatty acids and glycerol portion of the molecule. It is accelerated by high temperatures & pressures & an excessive amount of
water.

.HYDROGENATION :
8.HYDROGENATION Hydrogenation is a reaction used to optimize the properties of fats and oils prepared for specific uses. The
rate of hydrogenation depends on the following factors:- Nature of substance to be hydrogenated Nature and concentraction of
the catalyst Concentraction of hydrogen Reaction temperature Pressure Agitation

.ISOMERIZATION :
9.ISOMERIZATION Isomers are two or more substances that are composed of same elements combined in the same
proportions,hence having the same molecular formula. The two important types of isomerism are: Geometric & Positional
isomerism.
Geometrical Isomerism :
1. Geometrical Isomerism A double bond can have two configurations;- Cis or Trans If the H2 atoms are on the same side of the
carbon chain, the arrangement is called cis & If the H2 atoms are on opposite sides of the carbon chain, the arrangement is
called trans. Natural fats & oils contain cis form.
. Positional Isomerism :
2. Positional Isomerism Unsaturated fatty acid can be isomerised in acid or alkaline conditions or by high temperatures, with the
double bond migrating from one position to another. Hydrogenation process can cause shifts in the location of double bonds in
the fatty acid chains as well as cis - transisomerisation. Cis isomers occur in food fats & oils &trans isomers occur in fats from
reminats. Most Trans isomers results from the partial hydrogenation of fats & oils.

. ESTERIFICATION :
10. ESTERIFICATION Reverse of hydrolysis. It is the combining or recombining of free fatty acids with glycerol to form
triglycerides. Mono &diglycerides are produced by esterification.Monoglycerides are important emulfying agents in food
products. Emulsifiers are made either by alcoholysis or by direct esterification. In direct esterification, fatty acids & polyalcohol
are reacted together under controlled conditions to form esters.

. INTERESTERIFICATION :

11. INTERESTERIFICATION It refers to the fats & oil reaction in which fatty acid esters react with the other esters of fatty acid to
form new esters by an interchange of fatty acid groups. This process is also referred to as Randomization, rearrangement or
modification. This process is utilized for processing edible fats & oils to produce confectionary or coating fats, margarine
oils,cooking fats, frying fats, shortenings & other special application products.

OXIDATION :
13. OXIDATION It is the reaction of an oil or fat with O2 in the air, and with the food. It occurs at the double bonds or points of
unsaturation. This reaction is not desirable because it will adversely affect the flavour of the fat . The rate of oxidation increases
with increase in temperature, exposure to O2 in the air, the presence of light &condact with materials that are classified as prooxidants. Eg: Metal Cu. Oxidation induced by air at room temperature is referred to as Autoxidation.

.POLYMERIZATION :
14.POLYMERIZATION Excessive oxidation is accompanied by polymerization. It may occur either at the points of unsaturation
of fatty acid chains or at the juncture of the fatty acid & glycerol molecule. It also occur in deep frying of foods at temperatures
ranging from 325o F -375o F. Heat stress, oxidation & presence of the radical & polar catalyst leads to polymerization of
unsaturated fatty acid in lipids. Rate of polymerization increases with the amount of unsaturation & viscosity of fat or oil.

.HALOGENATION :
15.HALOGENATION The halogens include Chlorine, Bromine & Iodine. They can readily add to the double bonds of unsaturated
fatty acids. Measured quantities of iodine monosaccharide may be added to measured quantities of fats or oils to determine the
average degree of unsaturation of this fat or oil. This results in iodine number, an important analytical measurement.

Importance of Cholesterol
Cholesterol, a substance required for the normal function of cells, is present in every cell of the human body. It is
also found in the bloodstream. The soft waxy substance is produced in the body and is essential for the production
of vitamin D, bile salts and hormones.

Sources
75% of cholesterol is created in the body. Photo Credit Warren Goldswain/iStock/Getty Images

The body creates most of the cholesterol found in the cells and blood, although some comes from food. According to the
American Heart Association, about 75 percent of cholesterol is created in the body.

The Liver
The liver is responsible for producing the cholesterol in the body. Photo CreditCatherineYeulet/iStock/Getty Images

The liver is responsible for producing the cholesterol in the body. Alone, this organ can synthesize enough cholesterol to keep
the cells healthy and hormones at the appropriate levels.

Cell Membranes
Cholesterol is critical for cell membranes to function efficiently. Photo Creditmonkeybusinessimages/iStock/Getty Images

The membranes of the cells need to allow needed elements such as oxygen and nutrients to enter. This semi-permeable state also
allows unwanted materials to be eliminated. Cholesterol is critical for cell membranes to function efficiently.

Vitamin D
Vitamin D is created in the body when sunlight hits the skin. Photo Creditgyn9038/iStock/Getty Images

Vitamin D is created in the body when sunlight hits the skin. If cholesterol is not present in the body, this will not occur.

Metabolism of Cholesterol
Cholesterol is an extremely important biological
molecule that has roles in membrane structure as well as
being a precursor for the synthesis of the steroid
hormones, the bile acids, and vitamin D. Both dietary
cholesterol, and that synthesized de novo, are
transported through the circulation in lipoprotein
particles. The same is true of cholesteryl esters, the form
in which cholesterol is stored in cells. Due to its
important role in membrane function, all cells express
the enzymes of cholesterol biosynthesis.
The synthesis and utilization of cholesterol must be
tightly regulated in order to prevent over-accumulation
and abnormal deposition within the body. Of particular
clinical importance is the abnormal deposition of
cholesterol and cholesterol-rich lipoproteins in the
coronary arteries. Such deposition, eventually leading to
atherosclerosis, is the leading contributory factor in
diseases of the coronary arteries.

Cholesterol

Biosynthesis of Cholesterol
Slightly less than half of the cholesterol in the body
derives from biosynthesis de novo. Biosynthesis in the
liver accounts for approximately 10%, and in the
intestines approximately 15%, of the amount produced
each day. The cholesterol biosynthesis pathway involves
enzymes that are in the cytoplasm, microsomes (ER),
and peroxisomes. Synthesis of cholesterol, like that of
most biological lipids, begins from the two-carbon
acetate group of acetyl-CoA.
The acetyl-CoA utilized for cholesterol biosynthesis is
derived from an oxidation reaction (e.g., fatty acids or
pyruvate) in the mitochondria and is transported to the
cytoplasm by the same process as that described for fatty
acid synthesis (see the Figure below). Acetyl-CoA can
also be synthesized from cytosolic acetate derived from
cytoplasmic oxidation of ethanol which is initiated by
cytoplasmic alcohol dehydrogenase (ADH). All the
reduction reactions of cholesterol biosynthesis use
NADPH as a cofactor. The isoprenoid intermediates of
cholesterol biosynthesis can be diverted to other
synthesis reactions, such as those for dolichol (used in
the synthesis of N-linked glycoproteins, coenzyme Q (of
the oxidative phosphorylation pathway) or the side chain
of heme-a. Additionally, these intermediates are used in
the lipid modification of some proteins.

Pathway for the movement of acetyl-CoA units from

within the mitochondrion to the cytoplasm. Note that the
cytoplasmic malic enzyme catalyzed reaction generates
NADPH which can be used for reductive biosynthetic
reactions such as those of fatty acid and cholesterol
synthesis. SLC25A1 is the citrate transporter (also called
the dicarboxylic acid transporter). Transport of pyruvate
across the plasma membrane is catalyzed by the
SLC16A1 protein (also called the monocarboxylic acid
transporter 1, MCT1) and transport across the outer
mitochondrial membrane involves a voltage-dependent
porin transporter. Pyruvate transport across the inner
mitochondrial membrane requires a heterotetrameric
transport complex (mitochondrial pyruvate carrier)
consisting of the MPC1 gene and MPC2 gene encoded
proteins.

The process of cholesterol synthesis can be considered to

be composed of five major steps:
1. Acetyl-CoAs are converted to 3-hydroxy-3methylglutaryl-CoA (HMG-CoA)
2. HMG-CoA is converted to mevalonate
3. Mevalonate is converted to the isoprene based
molecule, isopentenyl pyrophosphate (IPP), with the
concomitant loss of CO2
4. IPP is converted to squalene
5. Squalene is converted to cholesterol.

Pathway of cholesterol biosynthesis. Synthesis of

cholesterol begins with the transport of acetyl-CoA from
within the mitochondria to the cytosol. The rate limiting
step in cholesterol synthesis occurs at the 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) reducatase, HMGR,
catalyzed step. The phosphorylation reactions are
required to solubilize the isoprenoid intermediates in the
pathway. Intermediates in the pathway are used for the
synthesis of prenylated proteins, dolichol, coenzyme Q
and the side chain of heme a. The abbreviation "PP" (e.g.
isopentenyl-PP) stands for pyrophosphate. ACAT2:
acetyl-CoA acetyltransferase 2. HMGCS1: HMG-CoA
synthase 1 (cytosolic). HMGCR: HMG-CoA reductase.
MVK: mevalonate kinase. PMVK: phosphomevalonate
kinase. MVD: diphosphomevalonate decarboxylase.
IDI1/IDI2: isopentenyl-diphosphate delta isomerase 1
and 2. FDPS: farnesyl diphosphate synthase. GGPS1:
geranylgeranyl diphosphate synthase 1. FDFT1:
farnesyl-diphosphate farnesyltransferase 1 (more
commonly called squalene synthase). SQLE: squalene
epoxidase (also called squalene monooxygenase). LSS:

lanosterol synthase (2,3-oxidosqualene-lanosterol

cyclase). DHCR7: 7-dehydrocholesterol reductase.

Acetyl-CoA units are converted to mevalonate by a

series of reactions that begins with the formation of
HMG-CoA. Unlike the HMG-CoA formed during
ketone body synthesis in the mitochondria, this form is
synthesized in the cytoplasm. However, the pathway and
the necessary enzymes are similar to those in the
mitochondria. Two moles of acetyl-CoA are condensed
in a reversal of the thiolase reaction, forming
acetoacetyl-CoA. The cytoplasmic thiolase enzyme
involved in cholesterol biosynthesis is acetoacetyl-CoA
thiolase (acetyl-CoA acetyltransferase 2) encoded by the
ACAT2 gene. Although the bulk of acetoacetyl-CoA is
derived via this process, it is possible for some
acetoacetate, generated during ketogenesis, to diffuse out
of the mitochondria and be converted to acetoacetylCoA in the cytosol via the action of acetoacetyl-CoA

synthetase (AACS). Acetoacetyl-CoA and a third mole

of acetyl-CoA are converted to HMG-CoA by the action
of the cytosolic version of HMG-CoA synthase encoded
by the HMGCS1 gene. The HMGCS1 gene is located on
chromosome 5p14p13 and is composed of 12 exons
that generate two alternatively spliced mRNAs, both of
which encode the same 520 amino acid protein.
HMG-CoA is then converted to mevalonate by HMGCoA reductase, HMGR (this enzyme is bound in the
endoplasmic reticulum, ER). HMGR absolutely requires
NADPH as a cofactor and two moles of NADPH are
consumed during the conversion of HMG-CoA to
mevalonate. The reaction catalyzed by HMGR is the rate
limiting step of cholesterol biosynthesis, and this
enzyme is subject to complex regulatory controls as
discussed below. HMGR is derived from the HMGCR
gene which is located on chromosome 5q13.3q14 and
is composed of 22 exons that generate two alternatively
spliced mRNAs that encode HMGR isoform 1 (888
amino acids) and HMGR isoform 2 (835 amino acids).

isopentenylpyrophosphate isomerase). Humans express

two isopentenyl-diphosphate delta isomerase genes, IDI1
and IDI2. The IDI1 gene is located on chromosome
10p15.3 and is composed of 7 exons that encode a 284
amino acid protein that is localized to the peroxisomes.
The IDI2 gene is located on the same chromosomal
region as the IDI1 gene but is composed of only 5 exons
and encodes a 227 amino acid protein.
One molecule of IPP condenses with one molecule of
DMPP to generate geranyl pyrophosphate, GPP. GPP
further condenses with another IPP molecule to yield
farnesyl pyrophosphate, FPP. Synthesis of both GPP and
FPP is catalyzed by the enzyme, farnesyl diphosphate
synthase. Farnesyl diphosphate synthase is derived from
the FDPS gene which is located on chromosome1q22
and is composed of 11 exons that generate five
alternatively spliced mRNAs that, together, encode three
different isoforms of the enzyme.

Mevalonate is then activated by two successive

phosphorylations (catalyzed by mevalonate kinase, and
phosphomevalonate kinase) yielding, sequentially,
mevalonate 5-phosphate and then mevalonate 5diphosphate (the latter compound is also called 5pyrophosphomevalonate or mevalonate 5pyrophosphate). In humans, mevalonate kinase is a
peroxisome localized enzyme encoded by the MVK
gene. The MVK gene is located on chromosome 12q24
and is composed of 12 exons that generate three
alternatively spliced mRNAs. Phosphomevalonate
kinase is also a peroxisomal enzyme and it is derived
from the PMVK gene. The PMVK gene is located on
chromosome 1q22 and is composed of 6 exons that
encode a 192 amino acid protein.

The synthesis of squalene, from FPP, represents the first

cholesterol-specific step in the cholesterol synthesis
pathway. This is due to the fact that, as depicted in the
pathway Figure above, several intermediates in the
pathway can be diverted to the production of other
biologically relevant molecules. The synthesis of
squalene is catalyzed by the NADPH-requiring enzyme,
farnesyl-diphosphate farnesyltransferase 1 (commonly
called squalene synthase). Farnesyl-diphosphate
farnesyltransferase 1 (encoded by the FDFT1 gene)
catalyzes the two-step head-to-head condensation of two
molecules of FPP, yielding squalene. The FDFT1 gene is
located on chromosome 8p23.1p22 and is composed of
14 exons that generate 11 alternatively spliced mRNAs.
These 11 different FDFT1-encoded mRNAs collectively
synthesize five different isoforms of farnesyldiphosphate farnesyltransferase 1.

Following the formation of mevalonate 5-diphosphate,

an ATP-dependent decarboxylation yields isopentenyl
pyrophosphate (IPP) which is an activated isoprenoid
molecule. The synthesis of IPP is catalyzed by
diphosphomevalonate decarboxylase (also called
mevalonate-5-pyrophosphate decarboxylase) derived
from the MVD gene. The MVD gene is located on
chromosome 16q24.3 and is composed of 14 exons that
encode a 400 amino acid protein. Isopentenyl
pyrophosphate is in equilibrium with its isomer,
dimethylallyl pyrophosphate (DMPP) via the action of
isopentenyl-diphosphate delta isomerase (also called

Squalene then undergoes a two step cyclization to yield

lanosterol. This first reaction in this two-step cyclization
is catalyzed by the enzyme, squalene epoxidase (also
called squalene monooxygenase). This enzyme uses
NADPH as a cofactor to introduce molecular oxygen as
an epoxide at the 2,3 position of squalene forming the
intermediate, 2,3-oxidosqualene. In the second step, this
epoxide intermediate is converted to lanosterol through
the action of the enzyme lanosterol synthase (2,3oxidosqualene-lanosterol cyclase). Squalene epoxidase
is derived from the SQLE gene which is located on
chromosome 8q24.1 and is composed of 12 exons that

encode a protein of 574 amino acids. Lanosterol

synthase is derived from the LSS gene which is located
on chromosome 21q22.3 and is composed of 25 exons
that generate four alternatively spliced mRNAs which
together generate three distinct isoforms of the enzyme.
Through a series of 19 additional reactions, lanosterol is
converted to cholesterol. These 19 reaction steps are
catalyzed by nine different enzymes that are localized
either to the ER or to the peroxisomes. The terminal
reaction in cholesterol biosynthesis is catalyzed by the
enzyme 7-dehydrocholesterol reductase encoded by the
DHCR7 gene. Functional DHCR7 protein is a 55.5 kDa
NADPH-requiring integral membrane protein localized
to the microsomal (ER) membrane. Deficiency in
DHCR7 (due to gene mutations) results in the disorder
calledSmith-Lemli-Opitz syndrome, SLOS. SLOS is
characterized by increased levels of 7dehydrocholesterol and reduced levels (15% to 27% of
normal) of cholesterol resulting in multiple
developmental malformations and behavioral problems.
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 (150200 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 cellular supply of cholesterol is maintained at a
steady level by three distinct mechanisms:
1. Regulation of HMGR activity and levels
2. Regulation of excess intracellular free cholesterol
through the activity of sterol O-acyltransferases, SOAT1
and SOAT2 with SOAT2 being the predominant activity
in liver. The original designation for these enzymes was
ACAT for acyl-CoA: cholesterol acyltranferase.
However, this conflicts with the official ACAT enzymes,
ACAT1 and ACAT2 which are acetyl-CoA
acetyltransferases 1 and 2. These latter two enzymes are

thiolases discussed in the Lipolysis and Fatty Acid

Oxidation page.
3. Regulation of plasma cholesterol levels via LDL
receptor-mediated uptake and HDL-mediated reverse
transport.
Regulation of HMGR activity is the primary means for
controlling the level of cholesterol biosynthesis. The
enzyme is controlled by four distinct mechanisms: feedback inhibition, control of gene expression, rate of
enzyme degradation and phosphorylationdephosphorylation.
The first three control mechanisms are exerted by
cholesterol itself. Cholesterol acts as a feed-back
inhibitor of pre-existing HMGR as well as inducing
rapid degradation of the enzyme. The latter is the result
of cholesterol-induced polyubiquitination of HMGR and
its degradation in the proteosome (see proteolytic
degradation below). This ability of cholesterol is a
consequence of the sterol sensing domain, SSD of
HMGR. In addition, when cholesterol is in excess the
amount of mRNA for HMGR is reduced as a result of
decreased expression of the gene. The mechanism by
which cholesterol (and other sterols) affect the
transcription of the HMGR gene is described below
under regulation of sterol content.
Regulation of HMGR through covalent modification
occurs as a result of phosphorylation and
dephosphorylation. The enzyme is most active in its
unmodified form. Phosphorylation of the enzyme
decreases its activity. HMGR is phosphorylated by
AMP-activated protein kinase, AMPK (this is not the
same as cAMP-dependent protein kinase, PKA). AMPK
itself is activated via phosphorylation. Phosphorylation
of AMPK is catalyzed by at least 2 enzymes. The
primary kinase sensitive to rising AMP levels is LKB1.
LKB1 was first identified as a gene in humans carrying
an autosomal dominant mutation in Peutz-Jeghers
syndrome, PJS. LKB1 is also found mutated in lung
adenocarcinomas. The second AMPK phosphorylating
enzyme is calmodulin-dependent protein kinase kinasebeta (CaMKK). CaMKK induces phosphorylation of
AMPK in response to increases in intracellular Ca2+ as
a result of muscle contraction. Visit AMPK: The Master
Metabolic Regulator for more detailed information on
the role of AMPK in regulating metabolism.

Regulation of HMGR by covalent modification. HMGR

is most active in the dephosphorylated state.
Phosphorylation is catalyzed by AMP-activated protein
kinase (AMPK) an enzyme whose activity is also
regulated by phosphorylation. Phosphorylation of
AMPK is catalyzed by at least 2 enzymes: LKB1 and
CaMKK. Hormones such as glucagon and epinephrine
negatively affect cholesterol biosynthesis by increasing
the activity of the inhibitor of phosphoprotein
phosphatase inhibitor-1, PPI-1. Conversely, insulin
stimulates the removal of phosphates and, thereby,
activates HMGR activity. Additional regulation of
HMGR occurs through an inhibition of its' activity as
well as of its' synthesis by elevation in intracellular
cholesterol levels. This latter phenomenon involves the
transcription factor SREBP described below.
The activity of HMGR is additionally controlled by the
cAMP signaling pathway. Increases in cAMP lead to
activation of cAMP-dependent protein kinase, PKA. In
the context of HMGR regulation, PKA phosphorylates
phosphoprotein phosphatase inhibitor-1 (PPI-1) leading
to an increase in its' activity. PPI-1 can inhibit the
activity of numerous phosphatases including protein
phosphatase 2C (PP2C) and PP2A (also called HMGR
phosphatase) which remove phosphates from AMPK and
HMGR, respectively. This maintains AMPK in the
phosphorylated and active state, and HMGR in the
phosphorylated and inactive state. As the stimulus

leading to increased cAMP production is removed, the

level of phosphorylations decreases and that of
dephosphorylations increases. The net result is a return
to a higher level of HMGR activity.
Since the intracellular level of cAMP is regulated by
hormonal stimuli, regulation of cholesterol biosynthesis
is hormonally controlled. Insulin leads to a decrease in
cAMP, which in turn activates cholesterol synthesis.
Alternatively, glucagon and epinephrine, which increase
the level of cAMP, inhibit cholesterol synthesis.
The ability of insulin to stimulate, and glucagon to
inhibit, HMGR activity is consistent with the effects of
these hormones on other metabolic pathways. The basic
function of these two hormones is to control the
availability and delivery of energy to all cells of the
body.
Long-term control of HMGR activity is exerted
primarily through control over the synthesis and
degradation of the enzyme. When levels of cholesterol
are high, the level of expression of the HMGR gene is
reduced. Conversely, reduced levels of cholesterol
activate expression of the gene. Insulin also brings about
long-term regulation of cholesterol metabolism by
increasing the level of HMGR synthesis.
Proteolytic Regulation of HMG-CoA Reductase

The stability of HMGR is regulated as the rate of flux

through the mevalonate synthesis pathway changes.
When the flux is high the rate of HMGR degradation is
also high. When the flux is low, degradation of HMGR
decreases. This phenomenon can easily be observed in
the presence of the statin drugs as discussed below.
HMGR is localized to the ER and like SREBP (see
below) contains a sterol-sensing domain, SSD. When
sterol levels increase in cells there is a concomitant
increase in the rate of HMGR degradation. The
degradation of HMGR occurs within the proteosome, a
multiprotein complex dedicated to protein degradation.
The primary signal directing proteins to the proteosome
is ubiquitination. Ubiquitin is a 7.6kDa protein that is
covalently attached to proteins targeted for degradation
by ubiquitin ligases. These enzymes attach multiple
copies of ubiquitin allowing for recognition by the
proteosome. HMGR has been shown to be ubiquitinated
prior to its degradation. The primary sterol regulating
HMGR degradation is cholesterol itself. As the levels of
free cholesterol increase in cells, the rate of HMGR
degradation increases.
The Utilization of Cholesterol
Cholesterol is transported in the plasma predominantly
as cholesteryl esters associated with lipoproteins.
Dietary cholesterol is transported from the small
intestine to the liver within chylomicrons. Cholesterol
synthesized by the liver, as well as any dietary
cholesterol in the liver that exceeds hepatic needs, is
transported in the serum within LDLs. The liver
synthesizes VLDLs and these are converted to LDLs
through the action of endothelial cell-associated
lipoprotein lipase. Cholesterol found in plasma
membranes can be extracted by HDLs and esterified by
the HDL-associated enzyme lecithin-cholesterol
acyltransferase, LCAT. The cholesterol acquired from
peripheral tissues by HDLs can then be transferred to
VLDLs and LDLs via the action of cholesteryl ester
transfer protein (CETP) which is associated with HDLs.
Reverse cholesterol transport allows peripheral
cholesterol to be returned to the liver in LDLs.
Ultimately, cholesterol is excreted in the bile as free
cholesterol or as bile salts following conversion to bile
acids in the liver.
Cytochrome P450 Enzymes in Cholesterol Metabolism

Cytochrome P450 enzymes are involved in a diverse

array of biological processes that includes lipid,
cholesterol, and steroid metabolism as well as the
metabolism of xenobiotics. The now common
nomenclature used to designate P450 enzymes is CYP.
There are at least 57 CYP enzymes in human tissues
with eight being involved in cholesterol biosynthesis and
metabolism, which includes conversion of cholesterol to
bile acids. CYP metabolism of cholesterol yields several
oxysterols that function as biologically active molecules
such as in the activation of the liver X receptors (LXRs)
and SREBP (see the next section).
CYP3A4: CYP3A4 is also known as glucocorticoidinducible P450 and nifedipine oxidase. Nifedipine is a
member of the calcium channel blocker drugs used to
treat hypertension. CYP3A4 is a major hepatic P450
enzyme and is responsible for the biotransformation of
nearly 60% of all commercially available drugs. With
respect to cholesterol metabolism, CYP3A4 catabolizes
cholesterol to 4-hydroxycholesterol. This cholesterol
derivative is one of the major circulating oxysterols and
is seen at elevated levels in patients treated with antiseizure medications such as carbamazepine,
phenobarbitol, and phenytoin. The nuclear receptor,
pregnane X receptor (PXR), is known to be an inducer
of the CYP3A4 gene.
CYP7A1: CYP7A1 is also known as cholesterol 7hydroxylase and is the rate limiting enzyme in the
primary pathway of bile acid synthesis referred to as the
classic pathway. This reaction of bile acid synthesis
plays a major role in hepatic regulation of overall
cholesterol balance. Deficiency in CYP7A1 manifests
with markedly elevated total cholesterol as well as LDL,
premature gallstones, premature coronary and peripheral
vascular disease. Treatment of this disorder with
members of the statin drug family do not alleviated the
elevated serum cholesterol due to the defect in hepatic
diversion of cholesterol into bile acids.
CYP7B1: CYP7B1 is also known as oxysterol 7hydroxylase and is involved in the synthesis of bile acids
via the less active secondary pathway referred to as the
acidic pathway. A small percentage (1%) of individuals
suffering from autosomal recessive hereditary spastic
paraplegia 5A (SPG5A) have been shown to harbor
mutations in the CYP7B1 gene.
CYP8B1: CYP8B1 is also known as sterol 12ahydroxylase and is involved in the conversion of 7-

hydroxycholesterol (CYP7A1 product) to cholic acid

which is one of two primary bile acids and is derived
from the classic pathway of bile acid synthesis. The
activity of CYP8B1 controls the ratio of cholic acid over
chenodeoxycholic acid in the bile.
CYP27A1: CYP27A1 is also known as sterol 27hydroxylase and is localized to the mitochondria.
CYP27A1 functions with two cofactor proteins called
adrenodoxin and adrenodoxin reductase to hydroxylate a
variety of sterols at the 27 position. CYP27A1 is also
involved in the diversion of cholesterol into bile acids
via the less active secondary pathway referred to as the
acidic pathway. Deficiencies in CYP27A1 result in
progressive neurological dysfunction, neonatal
cholestasis, bilateral cataracts, and chronic diarrhea.
CYP39A1: CYP39A1 is also known as oxysterol 7hydroxylase 2. This P450 enzyme was originally
identified in mice in which the CYP7B1 gene had been
knocked out. The preferential substrate for CYP39A1 is
24-hydroxycholesterol, which is a major product of
CYP46A1, which via CYP39A1 action is diverted into
bile acid synthesis.
CYP46A1: CYP46A1 is also known as cholesterol 24hydroxylase. This enzyme is expressed primarily in
neurons of the central nervous system where it plays an
important role in metabolism of cholesterol in the brain.
The product of CYP46A1 action if 24Shydroxycholesterol which can readily traverse the bloodbrain-barrier to enter the systemic circulation. This
pathway of cholesterol metabolism in the brain is a part
of the reverse cholesterol transport process and serves as
a major route of cholesterol turnover in the brain. 24Shydroxycholesterol is a known potent activator of LXR
and as such serves as an activator of the expression of
LXR target genes and thus, can effect regulation of
overall cholesterol metabolism not only in the brain but
many other tissues as well.
CYP51A1: CYP51A1 is also referred to as lanosterol14-demethylase. This P450 enzyme is the only one of
the eight that is involved in de novo cholesterol
biosynthesis and it catalyzes the removal of the 14methyl group from lanosterol resulting in the generation
of at least two oxysterols that, in mammalian tissues, are
efficiently converted into cholesterol as well as more
polar sterols and steryl esters. The oxysterols derived
through the action of CYP51A1 inhibit HMGR and are
also known to inhibit sterol synthesis. Knock-out of the

mouse CYP51A1 homolog results in a phenotype similar

to that seen in the human disorder known as AntleyBixler syndrome (ABS). ABS represents a group of
heterogeneous disorders characterized by skeletal,
cardiac, and urogenital abnormalities that have
frequently been associated with mutations in the
fibroblast growth factor receptor 2 (FGFR2) gene.
Regulation of Cellular Sterol Content
The continual alteration of the intracellular sterol content
occurs through the regulation of key sterol synthetic
enzymes as well as by altering the levels of cell-surface
LDL receptors. As cells need more sterol they will
induce their synthesis and uptake, conversely when the
need declines synthesis and uptake are decreased.
Regulation of these events is brought about primarily by
sterol-regulated transcription of key rate limiting
enzymes and by the regulated degradation of HMGR.
Activation of transcriptional control occurs through the
regulated cleavage of the membrane-bound transcription
factor sterol regulated element binding protein, SREBP.
As discussed above, degradation of HMGR is controlled
by the ubiquitin-mediated pathway for proteolysis.
Sterol control of transcription affects more than 30 genes
involved in the biosynthesis of cholesterol,
triacylglycerols, phospholipids and fatty acids.
Transcriptional control requires the presence of an
octamer sequence in the gene termed the sterol
regulatory element, SRE-1. It has been shown that
SREBP is the transcription factor that binds to SRE-1
elements. Humans express two distinct SREBP genes.
These genes are identified as sterol regulatory element
binding transcription factor 1 (SREBF1) and sterol
regulatory element binding transcription factor 2
(SREBF2). In addition, mammalian SREBF1 encodes
two major proteins identified as SREBP-1a and SREBP1c/ADD1 (ADD1 is adipocyte differentiation-1) as a
consequence of alternative transcriptional start sites
resulting in the utilization of different first exons that are
spliced to a common exon 2. The SREBF1 gene is
located on chromosome 17p11.2 and is composed of 21
exons. The human SREBP-1a protein (1147 amino
acids) predominates in the spleen and intestines while
the SREBP-1c protein (1123 amino acids) predominates
in liver, adipose tissue, and muscle. The SREBF2 gene is
located on chromosome 22q13 and is composed 23
exons that encode a 1141 amino acid protein.

SREBP-1a regulates all SREBP-responsive genes in

both the cholesterol and fatty acid biosynthetic
pathways. SREBP-1c controls the expression of genes
involved in fatty acid synthesis and is involved in the
differentiation of adipocytes. SREBP-1c is also an
essential transcription factor downstream of the actions
of insulin at the level of carbohydrate and lipid
metabolism. SREBP-2 is the predominant form of this
transcription factor in the liver and it exhibits preference
at controlling the expression of genes involved in
cholesterol homeostasis, including all of the genes
encoding the sterol biosynthetic enzymes. In addition
SREBP-2 controls expression of the LDL receptor
(LDLR) gene.

controlled within the ER by the interaction of SCAP

with insulin-induced protein-1 and -2 (Insig-1 and Insig2: see next paragraph). When cells have sufficient sterol
content SREBP and SCAP are retained in the ER via the
SCAP-Insig interaction. The N-terminus of SCAP,
including membrane spans 26, resembles HMGR
which itself is subject to sterol-stimulated degradation
(see above). This shared motif is called the sterol sensing
domain (SSD) and as a consequence of this domain
SCAP functions as the cholesterol sensor in the protein
complex. When cells have sufficient levels of sterols,
SCAP will bind cholesterol which promotes the
interaction with Insig and the entire complex will be
maintained in the ER.

Regulated expression of the SREBPs is complex in that

the effects of sterols are different on the SREBP-1 gene
versus the SREBP-2 gene. High sterols activate
expression of the SREBP-1 gene but do not exert this
effect on the SREBP-2 gene. The sterol-mediated
activation of the SREBP-1 gene occurs via the action of
theliver X receptors (LXRs). The LXRs are members of
the steroid/thyroid hormone superfamily of cytosolic
ligand binding receptors that migrate to the nucleus upon
ligand binding and regulate gene expression by binding
to specific target sequences. There are two forms of the
LXRs: LXR and LXR. The LXRs form heterodimers
with the retinoid X receptors (RXRs) and as such can
regulate gene expression either upon binding oxysterols
(e.g. 22R-hydroxycholesterol) or 9-cis-retinoic acid.

There are two Insig encoding genes identified as INSIG1

and INSIG2. The INSIG1 gene is located on
chromosome 7q36 and is composed of 7 exons that
generate three alternatively spliced mRNAs encoding
three isoforms of Insig-1. The INSIG2 gene is located on
chromosome 2q14.2 and is composed of 7 exons that
encode a 225 amino acid protein. The Insig-1 protein
was originally isolated in experiments examining
regenerating liver and was subsequently shown to be
dramatically induced in fat tissue in experimental
animals at the onset of diet-induced obesity. INSIG1
gene expression is highest in human liver while INSIG2
gene expression is ubiquitous. The Insig proteins bind to
oxysterols which in turn affects their interactions with
SCAP. The major form of human Insig-1 is a 277 amino
acids protein and, as indicated, Insig-2 is a 225 amino
acid protein. These two proteins share 59% amino acid
identity with the greatest differences being found in the
N- and C-terminal regions. Insig-2 also lacks the 50
amino acids that are found in the N-terminus of Insig-1.
Both Insig proteins can cause ER retention of the
SREBP/SCAP complex. The Insig proteins span the ER
membrane six times. It has been shown that a critical
aspartate (D) residue in Insig-1 and Insig-2, found in the
cytosolic loop between membrane spans 4 and 5, is
critical for interaction with SCAP as mutation of this
amino acid causes loss of SCAP binding. The third and
fourth transmembrane spans in both Insig proteins are
required for interaction with oxysterols. The Insig-1
gene has been shown to be transcriptionally regulated by
SREBP with the SRE in the Insig-1 gene residing
approximately 380bp upstream of the transcriptional
start site. Expression of Insig-1 has also been shown to
be regulated by several members of the nuclear receptor
family including PPAR, PXR and CAR. The Insig-2

All three SREBPs are proteolytically activated and the

proteolysis is controlled by the level of sterols in the
cell. Full-length SREBPs have several domains and are
embedded in the membrane of the endoplasmic
reticulum (ER). The N-terminal domain contains a
transcription factor motif of the basic helix-loop-helix
(bHLH) type that is exposed to the cytoplasmic side of
the ER. There are two transmembrane spanning domains
followed by a large C-terminal domain also exposed to
the cytosolic side. The C-terminal domain (CTD)
interacts with a protein called SREBP cleavageactivating protein (SCAP). SCAP is a large protein also
found in the ER membrane and contains at least eight
transmembrane spans. The C-terminal portion, which
extends into the cytosol, has been shown to interact with
the C-terminal domain of SREBP. This C-terminal
region of SCAP contains 4 motifs called WD40 repeats.
The WD40 repeats are required for interaction of SCAP
with SREBP. The regulation of SREBP activity is further

promoter is activated in response to signals downstream

of insulin receptor activation. Nuclear receptors also
regulate the expression of the Insig-2 gene which has
been shown to contain two FXR response elements.
In addition to their role in regulating sterol-dependent
gene regulation, both Insig proteins activate steroldependent degradation of HMGR. In the presence of the
cholesterol-derived oxysterol, 24,25-dihydrolanosterol,
Insig binds to the transmembrane domain of HMGR.
The oxysterol-induced interaction between Insig and
HMGR within the ER membrane allows Insig to recruit
the ubiquitin ligase, gp78, to HMGR resulting in
ubiquitination of HMGR and its resultant proteasomal
degradation as described above.
When sterols are scarce, SCAP does not interact with
Insig. Under these conditions the SREBP-SCAP
complex migrates to the Golgi where SREBP is
subjected to proteolysis. The cleavage of SREBP is
carried out by two distinct enzymes. The regulated
cleavage occurs in the lumenal loop between the 2
transmembrane domains. This cleavage is catalyzed by
site-1 protease, S1P (also known as subtilisin/kexinisozyme 1, SKI-1). S1P is officially called membranebound transcription factor peptidase, site 1, MBTPS1.
The MBTPS1 gene is located on chromosome 16q24 and
is composed of 23 exns that encode a 1052 amino acid
preproprotein. MBTPS1 is a member of the subtilisinlike proprotein convertase 2 family of serine proteases.
This family of proteases are responsible for the

processing of proteins that are in the regulated or

constitutive branches of the secretory pathway. The
subtilisin-like proprotein convertase 2 family of enzymes
are encoded by nine different genes in humans one of
which is the proprotein convertase subtilisin/kexin type
9 (PCSK9) gene whose encoded enzyme is a recent
target in the treatment of hypercholesteremia (see next
section). The function of SCAP is to positively stimulate
S1P-mediated cleavage of SREBP.
The second cleavage, catalyzed by site-2 protease, S2P,
occurs in the first transmembrane span, leading to
release of active SREBP. The official name for S2P is
membrane-bound trasncription factor peptidase, site 2
(MBTPS2). The MBTPS2 gene is located on the X
chromosome (Xp22.12-p22.11) and is composed of 11
exons that encode a 519 amino acid protein. S2P is an
intramembrane zinc metalloprotease. In order for S2P to
act on SREBP, site-1 must already have been cleaved.
The result of the S2P cleavage is the release of the Nterminal bHLH motif into the cytosol. The bHLH
domain then migrates to the nucleus where it will
dimerize and form complexes with transcriptional
coactivators leading to the activation of genes containing
the SRE motif. To control the level of SREBP-mediated
transcription, the soluble bHLH domain is itself subject
to rapid proteolysis. In addition to the cleavageactivation of SREBP transcriptional activity, S2P is
involved in pathways that regulate cellular responses to
endoplasmic reticulum stress, primarily the unfolded
protein response, UPR.

Protease-mediated regulation of SREBP

activation.Diagramatic representation of the interactions
between SREBP, SCAP and Insig in the membrane of
the ER when sterols are high. When sterols are low,
SCAP does not interact with Insig and the SREBP-SCAP
complex migrates to the Golgi where the proteases, S1P
and S2P reside. bHLH = basic helix-loop-helix domain.
CTD = C-terminal domain. WD = WD40 domain.
Several proteins whose functions involve sterols also
contain the SSD. These include patched, an important
development regulating receptor whose ligand,
hedgehog, is modified by attachment of cholesterol and
theNiemann-Pick disease type C1 (NPC1) protein which
is involved in cholesterol transport in the secretory
pathway. NPC1 is one of several genes whose activities,
when disrupted, lead to severe neurological dysfunction.

Treatment of Hypercholesterolemia
Reductions in circulating cholesterol levels can have
profound positive impacts on cardiovascular disease,
particularly on atherosclerosis, as well as other
metabolic disruptions of the vasculature. Control of
dietary intake is one of the easiest and least cost
intensive means to achieve reductions in cholesterol.
Recent studies in laboratory rats has demonstrated an
additional benefit of reductions in dietary cholesterol

intake. In these animals it was observed that reductions

in dietary cholesterol not only resulted in decreased
serum VLDLs and LDLs, and increased HDLs but DNA
synthesis was also shown to be increased in the thymus
and spleen. Upon histological examination of the spleen,
thymus and lymph nodes it was found that there was an
increased number of immature cells and enhanced
mitotic activity indicative of enhanced proliferation.
These results suggest that a marked reduction in serum
LDLs, induced by reduced cholesterol intake, stimulates
enhanced DNA synthesis and cell proliferation.
Drug treatment to lower plasma lipoproteins and/or
cholesterol is primarily aimed at reducing the risk of
atherosclerosis and subsequent coronary artery disease
that exists in patients with elevated circulating lipids.
Drug therapy usually is considered as an option only if
non-pharmacologic interventions (altered diet and
exercise) have failed to lower plasma lipids.
Alirocumab (Praluent), Evolcumab (Repatha): These
drugs are the newest type of anti-hypercholesterolemia
drugs recently approved by the FDA for use in the US.
Both drugs are injectible antibodies that block the
function of proprotein convertase subtilisin/kexin type 9,
PCSK9. PCSK9 is serine protease of the subtilisin-like
proprotein convertase 2 family. A major function of
PCSK9 is the endosomal degradation of the LDL
receptor (LDLR), thereby reducing the recyling of the
LDLR to the plasma membrane. This effect of PCSK9

leads to a reduced ability of the liver to remove IDL and

LDL from the blood contributing to the potential for
hypercholesterolemia. The potential for the
pharmaceutical benefits of the interference in the activity
PCSK9 was recognized by a confluence of several
studies. Patients with a specific form of familial
hypercholesterolemia not due to mutations in the LDLR
gene were shown to have severe hypercholesterolemia
due to mutations in the PCSK9 gene resulting in
hyperactivity of the enzyme. In addition, it was found
that in certain individuals with low serum LDL levels
there was an association with the inheritance of nonsense
mutations in the PCSK9 gene which result in loss of
PCSK9 activity. Hypercholesterolemic patients taking
another cholesterol-lowering drug while simultaneously
utilizing either of these new PCSK9 inhibitors saw
further reductions in serum LDL levels of betweeen 55%
and 77%.
Atorvastatin (Lipitor), Simvastatin (Zocor),
Lovastatin (Mevacor): These drugs are fungal HMGCoA reductase (HMGR) inhibitors and are members of
the family of drugs referred to as the statins. The net
result of treatment is an increased cellular uptake of
LDLs, since the intracellular synthesis of cholesterol is
inhibited and cells are therefore dependent on
extracellular sources of cholesterol. However, since
mevalonate (the product of the HMG-CoA reductase
reaction) is required for the synthesis of other important
isoprenoid compounds besides cholesterol, long-term
treatments carry some risk of toxicity. A component of
the natural cholesterol lowering supplement, red yeast
rice, is in fact a statin-like compound.
The statins have become recognized as a class of drugs
capable of more pharmacologic benefits than just
lowering blood cholesterol levels via their actions on
HMGR. Part of the cardiac benefit of the statins relates
to their ability to regulate the production of Snitrosylated COX-2. COX-2 is an inducible enzyme
involved in the synthesis of the prostaglandins and
thromboxanes as well as the lipoxins and resolvins. The
latter two classes of compounds are anti-inflammatory
lipids discussed in the Lipid-Derived Inflammatory
Modulators page. Evidence has shown that statins
activate inducible nitric oxide synthase (iNOS) leading
to nitrosylation of COX-2. The S-nitrosylated COX-2
enzyme produces the lipid compound 15Rhydroxyeicosatetraenoic acid (15R-HETE) which is then
converted via the action of 5-lipoxygenase (5-LOX) to

the epimericlipoxin, 15-epi-LXA4. This latter compound

is the same as the aspirin-triggered lipoxin (ATL) that
results from the aspirin-induced acetylation of COX-2.
Therefore, part of the beneficial effects of the statins is
exerted via the actions of the lipoxin family of antiinflammatory lipids.
Additional anti-inflammatory actions of the statins result
from a reduction in the prenylation of numerous proinflammatory modulators. Prenylation refers to the
addition of the 15 carbon farnesyl group or the 20 carbon
geranylgeranyl group to acceptor proteins. The
isoprenoid groups are attached to cysteine residues at the
carboxy terminus of proteins in a thioether linkage (C-SC). A common consensus sequence at the C-terminus of
prenylated proteins has been identified and is composed
of CAAX, where C is cysteine, A is any aliphatic amino
acid (except alanine) and X is the C-terminal amino acid.
In addition to numerous prenylated proteins that contain
the CAAX consensus, prenylation is known to occur on
proteins of the RAB family of RAS-related G-proteins.
There are at least 60 proteins in this family that are
prenylated at either a CC or CXC element in their Ctermini. The RAB family of proteins are involved in
signaling pathways that control intracellular membrane
trafficking. The prenylation of proteins allows them to
be anchored to cell membranes. In addition to cell
membrane attachment, prenylation is known to be
important for protein-protein interactions. Thus,
inhibition of this post-translational modification by the
statins interferes with the important functions of many
signaling proteins which is manifest by inhibition of
inflammatory responses.
Some of the effects on immune function that have been
attributed to the statins are attenuation of autoimmune
disease, inhibition of T-cell proliferation, inhibition of
inflammatory co-stimulatory molecule expression,
decreases in leukocyte infiltration, and promotion of a
shift in cytokine profiles of helper T-cell types from Th1
to Th2. Th1 cells are involved in cell-mediated immunity
processes, whereas, Th2 cells are involved in humoral
immunity process. The cytokines produced by Th2 cells
include IL-4, IL-5, IL-10 and IL-13 and these trigger B
cells to switch to IgE production and to activate
eosinophils.
Nicotinic acid (Niacor and Niaspan): Nicotinic acid
reduces the plasma levels of both VLDLs and LDLs by
inhibiting hepatic VLDL secretion, as well as

suppressing the flux of FFA release from adipose tissue

by inhibiting lipolysis. In addition, nicotinic
administration strongly increases the circulating levels of
HDLs. Patient compliance with nicotinic acid
administration is sometimes compromised because of the
unpleasant side-effect of flushing (strong cutaneous
vasodilation). Recent evidence has shown that nicotinic
acid binds to and activates the G-protein coupled
receptor identified as GPR109A (also called HM74A or
PUMA-G). For more detailed information on the normal
biological function of GPR109A go to the Bioactive
Lipids page. The identity of a receptor to which nicotinic
acid binds allows for the development of new drug
therapies that activate the same receptor but that may
lack the negative side-effect of flushing associated with
nicotinic acid. Because of its ability to cause large
reductions in circulating levels of cholesterol, nicotinic
acid is used to treat Type II, III, IV and V
hyperlipoproteinemias.

Signaling events initiated in response to hydroxybutyrate or nicotinic acid binding to GPR109A

on adipocytes or macrophages. During periods of
fasting, hepatic ketone synthesis increases and the
released -hydroxybutyrate binds to GPR109A on
adipocytes triggering activation of the receptorassociated Gi-type G-protein which then inhibits the
activity of adenylate cyclase (AC). Inhibition of AC
leads to reduced HSL-mediated release of fatty acids
from diacylglycerides. Nicotinic acid binding to
GPR109A on adipocytes also leads to reduced fatty acid
release. The reduced release of adipose tissue fatty acids
leads to decreased synthesis and release of VLDL by the
liver. It is this effect of nicotinic acid that contributes to
the antidyslipidemic action of this drug. The GPR109A
receptor on macrophages is also activated by nicotinic
acid but this effect contributes to the undesired sideeffets of nicotinic acid therapy. Within macrophages,
GPR109A activation results in increased activation of
PLA2 leading to increased arachidonic acid delivery to
COX and increased production of the pro-inflammatory
eicosanoids PGE2 and PGD2. The release of these
eicosanoids causes increased cutaneous vasodilation
resulting in the typical flushing and burning pain
response to nicotinic acid therapy.
Gemfibrozil (Lopid), Fenofibrate (TriCor): These
compounds (called fibrates) are derivatives of fibric acid

and although used clinically since the 1930's were only

recently discovered to exert some of their lipid-lowering
effects via the activation of peroxisome proliferation.
Specifically, the fibrates were found to be activators of
the peroxisome proliferator-activated receptor-
(PPAR) class of proteins that are classified as nuclear
receptor co-activators. The naturally occurring ligands
for PPAR are leukotriene B4 (LTB4, see the Lipid
Synthesis page), unsaturated fatty acids and oxidized
components of VLDLs and LDLs. The PPARs interact
with another receptor family called the retinoid X
receptors (RXRs) that bind 9-cis-retinoic acid.
Activation of PPARs results in modulation of the
expression of genes involved in lipid metabolism. In
addition the PPARs modulate carbohydrate metabolism
and adipose tissue differentiation. Fibrates result in the
activation of PPAR in liver and muscle. In the liver this
leads to increased -oxidation of fatty acids, thereby
decreasing the liver's secretion of triacylglycerol- and
cholesterol-rich VLDLs, as well as increased clearance
of chylomicron remnants, increased levels of HDLs and
increased lipoprotein lipase activity which in turn
promotes rapid VLDL turnover.
Cholestyramine or colestipol (resins): These compounds
are nonabsorbable resins that bind bile acids which are
then not reabsorbed by the liver but excreted. The drop
in hepatic reabsorption of bile acids releases a feedback
inhibitory mechanism that had been inhibiting bile acid
synthesis. As a result, a greater amount of cholesterol is
converted to bile acids to maintain a steady level in
circulation. Additionally, the synthesis of LDL receptors
increases to allow increased cholesterol uptake for bile
acid synthesis, and the overall effect is a reduction in
plasma cholesterol. This treatment is ineffective in
homozygous FH patients, since they are completely
deficient in LDL receptors.
Ezetimibe: This drug is sold under the trade names
Zetia or Ezetrol and is also combined with the statin
drug simvastatin and sold as Vytorin or Inegy.
Ezetimibe functions to reduce intestinal absorption of
cholesterol, thus effecting a reduction in circulating
cholesterol. The drug functions by inhibiting the
intestinal brush border transporter involved in absorption
of cholesterol. This transporter is known as NiemannPick type C1-like 1 (NPC1L1). NPC1L1 is also highly
expressed in human liver. The hepatic function of
NPC1L1 is presumed to limit excessive biliary
cholesterol loss. NPC1L1-dependent sterol uptake is

regulated by cellular cholesterol content. In addition to

the cholesterol lowering effects that result from
inhibition of NPC1L1, its' inhibition has been shown to
have beneficial effects on components of the metabolic
syndrome, such as obesity, insulin resistance, and fatty
liver, in addition to atherosclerosis. Ezetimibe is usually
prescribed for patients who cannot tolerate a statin drug
or a high dose statin regimen. There is some controversy
as to the efficacy of ezetimibe at lowering serum
cholesterol and reducing the production of fatty plaques
on arterial walls. The combination drug of ezetimibe and
simvastatin has shown efficacy equal to or slightly
greater than atorvastatin (Lipitor) alone at reducing
circulating cholesterol levels.
New Approaches: Numerous epidemiological and
clinical studies over the past 10 years have demonstrated
a direct correlation between the circulating levels of
HDL cholesterol (most often abbreviated HDL-c) and a
reduction in the potential for atherosclerosis and
coronary heart disease (CHD). Individuals with levels of
HDL above 50mg/dL are several time less likely to
experience CHD than individuals with levels below
40mg/dL. In addition, clinical studies in which
apolipoprotein A-I (apoA-I), the predominant protein
component of HDL-c) or reconstituted HDLs are infused
into patients raises circulating HDL levels and reduces
the incidence of CHD. Thus, there is precedence for
therapies aimed at raising HDL levels in the treatment
and prevention of atherosclerosis and CHD.
Unfortunately current therapies only modestly elevate
HDL levels. Both the statins and the fibrates have only
been shown to increase HDL levels between 520% and

niacin is poorly tolerated in many patients. Therefore,

alternative strategies aimed at increasing HDL levels are
being tested. Cholesterol ester transfer protein (CETP) is
secreted primarily from the liver and plays a critical role
in HDL metabolism by facilitating the exchange of
cholesteryl esters (CE) from HDL for triglycerides (TG)
in apoB containing lipoproteins, such as LDL and
VLDL. The activity of CETP directly lowers the
cholesterol levels of HDLs and enhances HDL
catabolism by providing HDLs with the TG substrate of
hepatic lipase. Thus, CETP plays a critical role in the
regulation of circulating levels of HDL, LDL, and apoAI. It has also been shown that in mice naturally lacking
CETP most of their cholesterol is found in HDL and
these mice are relatively resistant to atherosclerosis. The
potential for the therapeutic use of CETP inhibitors in
humans was first suggested when it was discovered in
1985 that a small population of Japanese had an inborn
error in the CETP gene leading to
hyperalphalipoproteinemia and very high HDL levels. To
date three CETP inhibitors have been used in clinical
trials. These compounds are anacetrapib, torcetrapib, and
dalcetrapib. Although torcetrapib is a potent inhibitor of
CETP, its' use has been discontinued due to increased
negative cardiovascular events and death rates in test
subjects. Treatment with dalcetrapib results in increases
in HDL (1937%) and a modest decrease (6%) in LDL
levels. Treatment with anacetrapib results in a significant
increase in both HDL (130%) and LDL (40%).
Anacetrapib is currently in phase III clinical studies.

The Structure of Cholesterol

Cholesterol has a molecular formula of C27H45OH. This molecule is composed of three regions (shown in
the picture above): a hydrocarbon tail (shown in blue), a ring structure region with 4 hydrocarbon rings
(shown in green), and a hydroxyl group (shown in red.).
The hydroxyl (OH) group is polar, which makes it soluble in water. This small 2-atom structure makes
cholesterol an alcohol. The alcohol that we drink, ethanol, is a much smaller alcohol that also has a
hydroxyl group (C2H5OH).
The 4-ring region of cholesterol is the signature of all steroid hormones (such as testosterone and
estrogen). All steroids are made from cholesterol. The rings are called "hydrocarbon" rings because each
corner of the ring is composed of a carbon atom, with two hydrogen atoms extending off the ring.
The combination of the steroid ring structure and the hydroxyl (alcohol) group classifies cholesterol as a
"sterol." Cholesterol is the animal sterol. Plants only make trace amounts of cholesterol, but make other
sterols in larger amounts.
The last region is the hydrocarbon tail. Like the steroid ring region, this region is composed of carbon and
hydrogen atoms. Both the ring region and tail region are non-polar, which means they dissolve in fatty and
oily substances but will not mix with water.
Because cholesterol contains both a water-soluble region and a fat-soluble region, it is
calledamphipathic.
Cholesterol, however, is not water-soluble enough to dissolve in the blood. Along with fats and fat-soluble
nutrients, therefore, it travels in the blood through lipoproteins such as LDL and HDL.

http://www.rsc.org/Education/Teachers/Resources/cfb/lipids.htm

Read more : http://www.ehow.com/about_5456474_physical-properties-lipids.html

http://www.authorstream.com/Presentation/stephymaria-1474206-chemical-properties-lipids/
http://www.livestrong.com/article/29614-importance-cholesterol/
http://www.newhealthguide.org/Function-Of-Cholesterol.html
http://biology.tutorvista.com/biomolecules/lipids.html
http://www.cholesterol-and-health.com/cholesterol_structure.html
http://www.webmd.com/cholesterol-management/features/high-cholesterol-treatment-what-works?page=5