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By: James J. Neitzel, Ph.D. (The Evergreen State College) 2010 Nature Education
Citation: Neitzel, J. J. (2010) Fatty Acid Molecules: Fundamentals and Role in Signaling. Nature Education 3(9):57
Can eating fat be good for us? Some fatty acid molecules actually play a crucial role in maintaining our health and
cellular functions.
Plenty of news articles and advertisements all promote the beneficial effects of omega-3 and omega-6 fatty acids.
We know that fats provide caloric energy in our diet, but why should the particular kind of fat we eat make any
difference? Specific fatty acids are the starting material for many vital signal molecules in plants and animals.
Mammals cannot synthesize these fatty acid precursor molecules on their own, so a failure to obtain these fats
from the diet can have major negative consequences. How were these molecules discovered and what specific
features of their chemistry make them necessary? A fat-free diet for rats, hormonal secretions from the prostate
gland, aspirin, and innovative chemical syntheses, are all parts of this developing story that help us explain the
biological importance of these molecules.
By the early twentieth century, scientists and doctors widely agreed on the basic set of vitamins needed for human
health. But what about other nutrients? Working at the University of Minnesota, Burr & Burr (1929) examined the
effect of fat-free diets on rats. They fed rats a diet containing sufficient calories, with protein and all of the known
vitamins, but without fat. The control group of rats was fed the same diet, but containing fat. They carefully
observed the health of the rats over several months. Over that time, the rats on the fat-free diet failed to thrive,
developed severe skin and kidney problems, and often died within weeks. Interestingly, they could return the sickly
animals to good health by adding some dietary fats, or small amounts of liver, back to their food, but many other
fats had no beneficial effect. Why were these animals sick? Burr & Burr proposed several hypotheses. Perhaps the
strain on the animals caused by synthesizing all of their own fats was the cause. Could there be a new fat-soluble
vitamin (vitamin F), which was needed for animal health? Or were there specific features of the fat itself that were
necessary? They knew that there are several kinds of fatty acids in the human diet, so they decided to answer
some of these questions by systematically feeding the sick animals a selection of known fats to see if any of them
had an effect (Figure 1). They eventually discovered that adding back two particular purified fatty acids, linolenic
and linoleic acids, restored the sick animals to health, while the other fatty acids were unable to do so (Burr & Burr
1932). This led to the recognitions of linolenic and linoleic acids as essential fatty acids.
Figure 1: A quick introduction to fatty acids (A) This is the structure of stearic acid, an 18-carbon saturated fatty
acid. The normal numbering system, starting with the carboxylic acid, is shown in blue. The carbons and oxygens of
the carboxylic acid functional group are red. (B) This is the structure of oleic acid, an 18-carbon unsaturated fat.
The carbons of the alkene functional group, the site of unsaturation, are in the rounded rectangle. Since there is
only one double bond, oleic acid is an example of a monounsaturated fatty acid. This also illustrates the omega
labeling system, with the numbers in blue indicating the number from omega-1, the carbon farthest from the
carboxylic acid group, to the first carbon of the double bond. Since the first carbon in a double bond is carbon 9,
oleic acid is an omega-9 fatty acid. (C) This is linoleic acid. To simplify larger molecules scientists often use line-
angle drawings. In these drawings, every line is a bond and every bend is a carbon atom. Most hydrogen atoms are
not shown, and it is assumed each carbon has enough hydrogens so that each carbon has four bonds. Since linoleic
acid has more than one double bond (it has two), it is a polyunsaturated fatty acid. The omega numbering system
has been applied to this molecule. Here, counting in from the omega end, the first double bond encountered is on
carbon 6, so this is an example of an omega-6 fatty acid.
Through meticulous physiological experiments, scientists have tracked the metabolism of radioactively-labeled
fatty acids, and discovered that we have enzymes that can alter the structure of dietary fatty acids as needed.
These enzymes can add carbons, to increase the length of the fatty acid chain, or insert or delete carbon-carbon
double bonds. These conversions happen in the liver, brain and retina in our body. However, we are limited by the
enzymes we produce.
Our enzymes can only add new double bonds within 10 carbons of the carboxylic acid end of fatty acids, so we
cannot produce the carbon-carbon double bond at the omega-3 position of linolenic acid, or the double bond at
the omega-6 position of linoleic acid (Figure 2). It is the presence of these very crucial and specific double bonds
that allows these fatty acids to play important roles in our bodies. Any long chain omega-3 fatty acid has to
originate from an omega-3 fatty acid from our diet. Similarly, any omega-6 fatty acid had to arise from an omega-6
fat.
Some of these essential fatty acids, obtained in our diet, are converted into a 20-carbon fatty acid containing 4
carbon-carbon double bonds. This omega-6 fatty acid, arachidonic acid, is an important starting material for three
different types of signaling molecules (Figure 3). Similar research found pathways that converted fat from our diet
into the 22 carbon omega-3 fatty acid, docosahexaenoic acid (DHA). Identifying these different contributing
signaling molecules ultimately required work in multiple countries using a variety of experimental techniques.
Figure 3: Arachidonic acid, the key starting molecule for all eicosanoids. Arachidonic acid, the key starting molecule
for all eicosanoids
What Else Does the Body Make from the Fatty Acids We Consume?
Prostaglandins were discovered first, but they are not the only signaling molecules synthesized from these
essential fatty acids. Thromboxanes, which regulate blood clotting, and leukotrienes, which are important in
immune function, are also synthesized using arachidonic acid as a precursor. These diverse signaling molecules
derived from essential fatty acids are referred to as eicosanoids eicos is the Greek root for 20 since they all
originated as 20-carbon fatty acids. Thromboxane, produced in platelets, constricts blood vessels and promotes
platelet aggregation, an early step in blood clotting. Leukotrienes attract immune cells (such as neutrophils) to sites
of inflammation, constrict bronchioles in the lungs, and make capillary walls permeable. (Samuelsson 1983). Some
medical treatments interfere with these actions, as a way to improve health. As a common example, inhalers that
are widely used for asthma treatment deliver the drug montelukast, which blocks the interaction between
leukotriene molecules and their receptors to inhibit this process.
What Aspirin Taught us About Prostaglandins
What first suggested to scientists that these varied biological molecules might all come from a common precursor?
The answer came from aspirin, a drug many people began using in the early 1900s. Although aspirin and a wide
range of other non-steroidal anti-inflammatory drugs (NSAIDs) have been used for decades, the biological basis of
their actions was not understood. It was not until the mid 1970s that scientists discovered that aspirin influenced
prostaglandin production to reduce pain and inflammation.
Physicians observed that all these drugs had similar advantages as well as undesired side effects. They could relieve
pain and inflammation, but they also caused stomach ulcers and slowed blood clotting. Research by Jon Vane and
his lab indicated that aspirin blocked the synthesis of both prostaglandins and thromboxanes (Vane 1971, 1982).
This provided a logical explanation for aspirin's dual effect as both 1) a pain reliever and 2) an inhibitor of blood
clots. Cyclo-oygenase (COX) was the key enzyme that these drugs inhibited. Later, two forms of COX were
identified, and it was possible to selectively inhibit each of them. For a general summary overview, the major
branching pathways that lead from arachidonic acid to the eicosanoids are shown in Figure 5. Note that the COX
enzymes are positioned under one major branching pathway, the cyclo-oxygenase pathway. Next, we will
elaborate on this pathway.
What Systems Do These Signaling Molecules Activate?
The eicosenoids prostaglandins, thromboxanes, and leukotrienes are universally produced, and universally
active in the body. Virtually every type of cell (other than red blood cells) produces one or more of these signaling
molecules. Their very short half-lives means that they are very effective at signaling nearby cells, but fade fast
enough to not have global body effects. As these signaling molecules are so potent, their production is tightly
regulated.
What major molecules are involved? Normally, the precursor molecule arachidonic acid is stored as a component
of phospholipids on the cytoplasmic side of the plasma membrane. Specific phospholipase enzymes, such as
phospholipase A, cleave the arachidonic acid away from the phospholipid, which allows the COX enzymes to start
the conversion process. This cyclo-oxygenase pathway leads to a potential vairety of effects via the COX enzymes,
on many different tissues of the body (Figure 6).
We have already mentioned some drugs that interfere with eicosanoids or their precursors, the COX enzymes. In
addition, steroid drugs have a general effect on eicosanoid activity becuase they act at the root of the major
branching pathways. These drugs function by blocking synthesis of the enzymes used to release these fatty acids
from the cell membrane, preventing the synthesis of prostaglandins. Steroid drugs are commonly used to combat
inflammation and are longer acting than other drugs mentioned here.
How do these molecules activate signaling pathways in their target cells? They bind to cell-surface proteins of the
seven-helix-G protein-coupled receptors (GPCRs). These in turn activate either the cyclic AMP pathway or the
inositol phosphate-calcium pathway. Altogether, these cascading pathways can produce both immediate and long-
term changes in their target cells.
Figure 7. Anandamide
What is the Function of These Fatty Acid Derived Molecules in Non-Animal Life Forms?
These molecules have signaling functions in other species beyond the animal kingdom. Scientists have found a
number of small molecules that plants use as messengers. These molecules are synthesized when the plant is
stressed, say by bacterial or fungal infection, or by mechanical damage.
One such molecule is jasmonic acid and its volatile derivative, methyl jasmonate which are important
components of the plant's reaction to attack (Figure 8). Jasmonic acids are also made by starting with the carbon
skeleton of linolenic acid, in a pathway that is similar (but not identical) to the pathway that produces
prostaglandins in humans. (Turner et al. 2002) Plant cells exposed to jasmonic acid increase the production of
several antibacterial and antifungal proteins in their cells. In this case, plants have one important advantage over
animals as they contain the enzymes necessary to add the specific double bonds needed to produce linolenic,
arachidonic acid, and other long-chain polyunsaturated fatty acids. Unlike animals, however, plants synthesize all
of their essential molecules from carbon dioxide, minerals from soil, and sunlight. These observations do pose an
interesting question why were the same set of starting molecules, unsaturated fatty acids, chosen as the
starting point for signaling molecules in these widely divergent organisms?
Our Day-to-Day Diet How much of these fats do you need? Current recommendations suggest around 11.5g of
omega-3 fat (such as linoleic acid) and 1015g of omega-6 fats (such as linolenic acid) per day for adults (Food and
Nutrition Board 2002). Currently, there is a huge interest in the role of specific fats in human health, as they make
headline news nearly every day. Some of the most compelling hypotheses for how different types of dietary fat
could influence such diverse processes as asthma, cardiovascular disease, and brain development, suggest that
these diverse fats, from the long-chain unsaturated fats found in fish oil to the trans fats found in processed food,
work by altering these lipid based signaling systems. The amount and ratios of these fats in our diet could increase
or decrease the synthesis of prostaglandins, thromboxanes, and leukotrienes in our bodies. They could also
increase or decrease the effects of these signals on their normal target cells. The reactions that produce these
signaling molecules turn out to be those blocked by the action of drugs such as aspirin. Similar signaling molecules
derived from fatty acids are found in diverse organisms. How our diet influences these pathways, whether by
intake of trans fats or the ratio of omega-6 to omega-3 fatty acids, is currently the subject of great research
interest because of its possible impact on all aspects of human health, from the neural development of children to
cardiovascular disease in adults.