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It's common knowledge that too much cholesterol and other fats can lead to disease, and that a
healthy diet involves watching how much fatty food we eat. However, our bodies need a certain
amount of fat to function²and we can't make it from scratch.

Triglycerides, cholesterol and other essential fatty acids²the scientific term for fats the body
can't make on its own²store energy, insulate us and protect our vital organs. They act as
messengers, helping proteins do their jobs. They also start chemical reactions that help control
growth, immune function, reproduction and other aspects of basic metabolism.

The cycle of making, breaking, storing and mobilizing fats is at the core of how humans and all
animals regulate their energy. An imbalance in any step can result in disease, including heart
disease and diabetes. For instance, having too many triglycerides in our bloodstream raises our
risk of clogged arteries, which can lead to heart attack and stroke.

Fats help the body stockpile certain nutrients as well. The so-called "fat-soluble" vitamins²A,
D, E and K²are stored in the liver and in fatty tissues.

Knowing that fats play such an important role in many basic functions in the body, researchers
funded by the National Institutes of Health study them in humans and other organisms to learn
more about normal and abnormal biology.

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These lipid droplets store fat in the cells of the tobacco hornworm, º. Courtesy:
Estela Arrese.

Despite fat's importance, no one yet understands exactly how humans store it and call it into
action. In search of insight, Oklahoma State University biochemist Estela Arrese studies
triglyceride metabolism in unexpected places: silkworms, fruit flies and mosquitoes.
The main type of fat we consume, triglycerides are especially suited for energy storage because
they pack more than twice as much energy as carbohydrates or proteins.

Once triglycerides have been broken down during digestion, they are shipped out to cells through
the bloodstream. Some of the fat gets used for energy right away. The rest is stored inside cells in
blobs called lipid droplets.

When we need extra energyrfor instance, when we run a marathonrour bodies use enzymes
called lipases to break down the stored triglycerides. The cell's power plants, mitochondria, can
then create more of the body's main energy source: adenosine triphosphate, or ATP.

Arrese works to identify, purify and determine the roles of individual proteins involved in
triglyceride metabolism. Her lab was the first to purify the main fat regulation protein in insects,
TGL, and now she is trying to learn what it does. She also discovered the function of a key lipid
droplet protein called Lsd1, and she is investigating its sister, Lsd2.

Arresers work could teach us more about disorders like diabetes, obesity and heart disease.
Plus, by understanding how insects use fat when they metamorphose and lay eggs and by
hypothesizing how to disrupt those processes, her discoveries could lead to new ways for farmers
to protect their crops from pests and for health officials to combat mosquito-borne diseases like
malaria and West Nile virus.

But before any of that can happen, says Arrese, "We need to study a lot and have information at
the molecular level."

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The plasma membrane is a perfect example of the rule that oil and water don't mix.

One of Arresers challenges is trying to get oily substances like fat to work in lab tests, which
tend to be water-based. However, our cells couldnrt function without fat and waterrs mutual
dislike.

Cell membranes encase our cells and the organelles inside them. Fat²specifically, cholesterol²
makes these membranes possible. The fatty ends of membrane molecules veer away from the
water inside and outside cells, while the non-fatty ends gravitate toward it. The molecules
spontaneously line up to form a semi-permeable membrane. The result: flexible protective
barriers that, like bouncers at a club, only allow the appropriate molecules to cross into and out
of cells.




Eating healthy means that you need to be careful about the amount of fat in your diet. But a
certain amount of fat is really necessary: All humans need lipids, called essential fatty acids,
from food because our bodies can't make them from scratch. Some body fat is also necessary as
insulation to prevent heat loss and to protect vital organs from the strain of routine activities.

The body stores excess fat in fat cells, or lipocytes, which expand in size until the fat is used for
fuel.

Lipids in adipose tissue (fat cells) are a major form of energy storage in animals and people. The
"fat-soluble" vitamins (A, D, E and K) are essential nutrients stored in the liver and in fatty
tissues. Triglycerides, another type of lipid, are especially suited for stockpiling energy because
of their high caloric content. When we need energy, our bodies use enzymes called lipases to
break down stored triglycerides into smaller pieces that participate directly in metabolism.

The mitochondria in our cells ultimately create energy from these reactions by generating
adenosine triphosphate, or ATP, the main currency of metabolism.

In addition to providing and storing energy, lipids do many other things. They act as messengers,
helping proteins come together in a lock-and-key fashion. They also start chemical reactions that
help control growth, immune function, reproduction and other aspects of basic metabolism.

The lipid molecule cholesterol is a key part of the plasma membrane, a coating that wraps around
every cell in the human body.

Although it does act as a protective barrier, the plasma membrane is less like a rigid wall and
more like a pliable blanket. In addition to lipids, the plasma membrane contains sugars that stick
out from its surface and proteins that thread through it.

It is an orderly arrangement of ball-and-stick molecules called glycolipids (lipid chains with

sugars attached) and phospholipids (lipids marked with cellular tags called phosphates). When
aligned "tail-to-tail," these fat-containing molecular assemblies resemble a double array of
matchsticks lined up perfectly end-to-end.

The plasma membrane is a perfect example of the rule that oil and water don't mix.

The membrane forms more or less automatically when the lipid end of each glycolipid or
phospholipid matchstick is attracted to oily substances: other lipids. The other matchstick end,
containing a sugar or phosphate molecule, drifts naturally toward the watery environment typical
of the areas inside or between cells.

Membranes are a hallmark of how organisms evolved the ability to multitask. Membranes allow
cells to keep proteins and other molecules in different compartments so that more than one set of
reactions can occur at the same time.

In addition to the plasma membranes around cells, organelles inside cells are wrapped by similar,
lipid-containing membranes that encase specialized contents.

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In chemistry, a polymer is a substance that contains repeating units: Polyester and many plastics
are examples of synthetic polymers. Proteins, nucleic acids and carbohydrates are natural
"biopolymers" that consist of chains of amino acids, DNA, RNA or sugar molecules.

How do our bodies make biopolymers? You guessed it: enzymes. Scientists can also make some
biopolymers in the lab. DNA, RNA and proteins are fairly simple to construct²so simple that
scientists today routinely synthesize thousands of different versions at once on wafer-like chips
similar in size to those used in computers.
Amino acids link head-to-tail to make proteins (top). Simple sugars link in many orientations to
make oligosaccharides (bottom).

But complex carbohydrates²chains of sugars²are a different story.

Why is making sugar chains so hard? The answer lies in their fundamental structure.

Proteins are strings of amino acids that can only fit together one way, head-to-tail. In contrast,
long, branched chains of sugars called oligosaccharides can fit together in dozens of different
ways. Chemists have a tough time forcing them to connect one way instead of another.

One reason chemists want to make sugars from scratch is to design vaccines that target the
surfaces of bacteria and viruses.

Glycan "arrays" enable scientists to test which proteins attach to thousands of different human
glycans. Credit: Ola Blixt

Sugars attached to proteins, called glycoproteins, are an important part of cell membranes.
Jutting out from the surface of nearly all cells, these sugary signposts are a cell's identification.
They are sort of like cellular address labels.
Also called glycans, these branched molecules serve as specialized receptors that act as docking
stations for proteins on other cells. Each organ and tissue has its own special glycans, which
grant access only to those molecules that know the proper molecular "code."

Every type of virus we encounter can only grip the glycans that have the right connections at
their tips. In this manner, the types of glycans that a virus latches onto can determine how it will
make you sick. Some viruses prefer glycans in the lungs, some like the intestines or the throat,
and so on.