Journal of Parenteral and Enteral

Nutrition http://pen.sagepub.com/

A Tutorial on Fatty Acid Biology

Brian T. Kalish, Erica M. Fallon and Mark Puder
JPEN J Parenter Enteral Nutr 2012 36: 380 originally published online 25 May 2012
DOI: 10.1177/0148607112449650

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50A Tutorial on Fatty Acid Biology / Kalish et al Journal
ion

Tutorial

A Tutorial on Fatty Acid Biology Journal of Parenteral and Enteral

Nutrition
Volume 36 Number 4
July 2012 380-388
2012 American Society
for Parenteral and Enteral Nutrition
Brian T. Kalish1,2; Erica M. Fallon, MD1, 2; DOI: 10.1177/0148607112449650
and Mark Puder, MD, PhD1, 2 http://jpen.sagepub.com
hosted at
http://online.sagepub.com

Abstract
Fatty acids are an extraordinarily diverse set of molecules that serve as sources of fuel, key components of cell structure, and parent
molecules for bioactive second messengers. The metabolism of fatty acids is part of a delicate homeostasis that is fundamental to normal
functioning and the response to pathophysiologic insult. The growing body of evidence on nutrition demonstrates that we truly are
what we eat, and the fatty acid content of our diets has far-reaching physiologic implications, many of which we are only beginning to
understand. As the gap between basic science and patient care becomes increasingly narrow, clinicians should have a working knowledge
of fatty acid biology. This tutorial provides an overview of fatty acid biology with the goal of increasing comfort in discussing how these
heterogeneous molecules are classified and metabolized, in addition to how fatty acid content influences basic cellular processes. (JPEN
J Parenter Enteral Nutr. 2012;36:380-388)

Keywords
fatty acids; gastroenterology; lipids; -3; -6

Fatty acids are a diverse set of molecules that act as essential
cellular building blocks and fuel sources. Early work in this
field focused on biochemistry and nutrition, but fatty acids
and their derivatives have since been implicated in countless
disease states, as well as targeted by numerous therapeutics.
Given their pervasive relevance and incorporation within the
field of medicine, it is important that clinicians have a work-
ing knowledge of fatty acid biology. The purpose of this
review is to provide a general background on fatty acid struc-
ture, terminology, metabolism, and function.
Structure
The structure of individual fatty acids determines their bio-
logic function. Fatty acids are hydrophobic (water-fearing)
molecules composed of a carboxylic acid group and a chain of
carbon and hydrogen atoms. Figure 1A depicts a prototypical
fatty acid with the methyl and carboxyl groups labeled. Fatty
acids differ structurally in 4 key ways: (1) the presence and
number of double bonds between carbon atoms, (2) the num-
ber of carbon atoms, (3) the location of double bonds, and (4)
the orientation of the double bond.
The type of bond between carbon atoms determines whether
the molecule is saturated or unsaturated (Figure 1B). Fatty
acids are considered saturated if there are no double bonds
between any of the carbon atoms. An unsaturated fatty acid can
become saturated if the double bond joining the carbon atoms
is eliminated with the addition of hydrogen atoms. Fatty acids
with a single double bond are termed monounsaturated fatty
acids (MUFAs), and fatty acids with more than 1 double bond
are classified as polyunsaturated fatty acids (PUFAs).
Saturated fatty acids can be divided into categories accord-
ing to the length of the carbon chain: short chain (37 carbon
atoms), medium chain (813 carbon atoms), long chain (14
20 carbon atoms), and very long chain (>21 carbon atoms).
Unsaturated fatty acids are typically divided into 3 classes
based on the length of the carbon chain: short chain (<19 car-
bon atoms), long chain (2024 carbon atoms), and very long
chain (>25 carbon atoms).
The terms cis and trans are used to denote the relative posi-
tion of the 2 carbon atoms connected to a double bond (Figure
1C). Atoms are cis if they lie on the same side of the double
bond, and atoms are trans if they lie on the opposite side of the
double bond. Nearly all naturally occurring unsaturated fatty
acids are cis, with the double bond most commonly in the
third, sixth, or ninth position from the terminal methyl group.
Most trans fatty acids are derived from hydrogenation, a manu-
facturing process used to stabilize oils from oxidation.
The degree of saturation alters the melting point of the fatty
acids. Unsaturated fatty acids have a lower melting point than
saturated fatty acids, due to the double bond(s) that creates a
From the 1Department of Surgery, Boston Childrens Hospital, Boston,
Massachusetts, and 2The Vascular Biology Program, Harvard Medical
School, Boston, Massachusetts.
Received for publication April 10, 2012; accepted for publication May 4,
2012.
Financial disclosure: none declared.
Corresponding Author: Mark Puder, MD, PhD, Boston Childrens
Hospital, 300 Longwood Ave, Fegan Building 3rd Floor, Boston, MA
02115; e-mail: Mark.puder@childrens.harvard.edu.

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A Tutorial on Fatty Acid Biology / Kalish et al 381

Figure 1. (A) Prototypical fatty acid structure, with the methyl and carboxyl group labeled. (B) Unsaturated fatty acids contain
double bonds between carbon atoms; the addition of hydrogen atoms to eliminate double bonds creates saturated fatty acids. (C) The
orientation of carbon atoms relative to a double bond can be cis (same side of a double bond) or trans (opposite side of a double bond).
(D) Skeleton structure of arachidonic acid, with omega () carbon labeled and systematic nomenclature noted.

kink in the molecule and thereby prevents tight packing as
commonly seen with saturated fatty acids. Less thermal
energy is required to disrupt these weaker interactions, result-
ing in the molecules typically assuming a liquid state near
room temperature.1
Fatty acids are the fundamental building blocks of more
structurally complex lipids, including esters, triglycerides,
phospholipids, and glycolipids. An ester molecule is formed
in the reaction between a carboxylic acid and an alcohol.
Three fatty acids in an ester linkage combined with a glycerol
form a triacylglycerol, or commonly termed a triglyceride
(Figure 2A). Phospholipids, the components of the lipid
bilayer of cell membranes (Figure 2B), are divided into glyc-
erophospholipids (phosphoglycerides) and sphingolipids. The
former is composed of a hydrophobic backbone of a glycerol
and fatty acids linked through a phosphodiester bond to a
polar head group of a phosphate and an alcohol. The latter is
composed of a backbone of sphingosine and a fatty acid linked
with a sugar. A glycolipid, another membrane lipid, similarly
has a sphingosine backbone, but the polar group is a sugar.
Nomenclature
Several systems of nomenclature are used to identify fatty
acids. The systematic name is defined according to the
International Union of Pure and Applied Chemists (IUPAC).
This system is based on the number of carbon atoms and the
position of double bonds, if any. The carbons are numbered
starting with the carboxyl group, and the double bond is
identified by the lower number of the 2 carbons it joins. The
systematic name for -linolenic acid, for example, is
cis,cis,cis-9,12,15-octadecatrienoic acid.
The systematic IUPAC terminology is often burdensome,
and therefore, common or trivial names are used. Shorthand

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382 Journal of Parenteral and Enteral Nutrition 36(4)

Figure 2. (A) A triglyceride is composed of 3 fatty acids joined by a glycerol backbone. (B) Schematic of the phospholipid bilayer
composition of a cell membrane. (C) Schematic of a chylomicron, which is a lipoprotein particle that transports dietary lipids from the
intestine.

Table 1. Nomenclature of Selected Clinically Relevant Fatty Acids

Common Name IUPAC (Systematic) Name x Name C:D Name n-x Name Dietary Example
Palmitoleic acid (Z)-hexadec-9-enoic acid cis-9 16:1 n-7 Marine oils, macadamia oil
Oleic acid (OA) (Z)-octadec-9-enoic acid cis-9 18:1 n-9 Olive and canola oil; high-oleic
sunflower and safflower oils
Linoleic acid (LA) (9Z,12Z)-octadeca-9,12- cis-9, cis-12 18:2 n-6 Vegetable oils
dienoic acid
-Linolenic acid (ALA) (9Z,12Z,15Z)-octadeca- cis,cis,cis-9,12,15 18:3 n-3 Flaxseed, perilla, and canola oils
9,12,15-trienoic acid
Arachidonic acid (AA) (5Z,8Z,11Z,14Z)-icosa- cis,cis,cis,cis-5,8, 20:4 n-6 Animal fats, egg lipids, liver
5,8,11,14-tetraenoic acid 11,14
Eicosapentaenoic acid (5Z,8Z,11Z,14Z,17Z)-icosa- cis,cis,cis,cis,cis- 20:5 n-3 Oily fish (eg, salmon, herring,
(EPA) 5,8,11,14,17-pentaenoic acid 5,8,11,14,17 anchovy, mackerel)
Docosahexaenoic acid (4Z,7Z,10Z,13Z,16Z,19Z)- cis,cis,cis,cis,cis,cis- 22:6 n-3 Oily fish (eg, salmon, herring,
(DHA) docosa-4,7,10,13,16,19- 4,7,10,13, 16,19 anchovy, mackerel)
hexaenoic acid

notation of fatty acids is denoted in a C:D (n minus) format,
where C is the number of carbon atoms, D is the number of
double bonds, and n minus denotes the position of the closest
double bond relative to the terminal methyl group. For example,
-linolenic acid is abbreviated 18:3(n-3). The n is often replaced
with (omega), and therefore, the terms -3 and -6 indicate
that, from the methyl end, the double bond begins at the third
and sixth carbons, respectively. Saturated fatty acids are often
denoted in shorthand in the format C:0, where the zero reflects
the absence of double bonds. For example, palmitic acid is writ-
ten as 16:0 (16 carbon atoms, 0 double bonds). Finally, the delta
() classification system is based on the number of carbon atoms
between the carbon in the carboxyl group and the nearest double
bond; the orientation of the carbons around the double bond (cis/
trans) is also noted. For example, the notation for -linolenic
acid would be cis-9, cis-12, cis-15-18:3. Table 1 lists exam-
ples of nomenclature for selected clinically relevant fatty acids.
Figure 1D depicts the nomenclature and structure of arachidonic
acid (AA). The carbons preceding the double bonds are labeled
to correspond with the systematic nomenclature. The structure is
depicted as a carbon skeleton in which each inflection point
denotes a carbon atom.

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A Tutorial on Fatty Acid Biology / Kalish et al 383

Figure 3. The 3 main families of polyunsaturated fatty acids (-3, -6, and -9) are metabolized primarily through desaturation and
elongation to from physiologically relevant downstream molecules, including docosahexaenoic acid, eicosapentaenoic acid, arachidonic
acid, and mead acid. Of note, -linolenic acid and linoleic acid are considered the classical essential fatty acids.

PUFA Metabolism
There are 3 families of PUFAs: (1) -3, derived from
-linolenic acid (ALA, 18:3n-3); (2) -6, derived from lin-
oleic acid (LA, 18:2n-6); and (3) -9, derived from oleic acid
(OA, 18:1n-9).
PUFAs are metabolized within a biochemical pathway
through a series of desaturation and elongation steps (Figure
3). In humans, there are 3 desaturase enzymes: 5, 6, and 9.
These enzymes function to insert double bonds at the fifth,
sixth, and ninth carbon atoms in a fatty acid chain, respec-
tively. LA is metabolized by the 6 to -linolenic acid (GLA),
which is then elongated to form dihomo--linolenic acid
(DGLA). DGLA is converted to AA, the most biologically rel-
evant molecule in the -6 pathway, via the 5 desaturase
enzyme. ALA is processed by the same enzymes to its biologi-
cally relevant metabolites: eicosapentaenoic acid (EPA; 20:5n-
3) and docosahexaenoic acid (DHA; 22:6n-3). ALA is
converted to EPA after 6 desaturation, elongation, and 5
desaturation. EPA is transformed through several intermedi-
ates (via elongation, desaturation, and -oxidation) to form
DHA. DHA can be retroconverted, or converted back to EPA,
as well. Finally, in the -9 pathway, OA undergoes desatura-
tion, elongation, and further desaturation to form mead acid
(MA; eicosatrienoic acid, 20:3n-9).
Of the 3 families of PUFAs, only OA can be synthesized de
novo in humans. Humans lack the necessary desaturase enzymes
to insert double bonds at positions-3 and -6, and therefore, ALA
and LA must be acquired from the diet.2 An increase in dietary
consumption of LA or ALA above the amount required by the
human body is not associated with a relative increase in the
membrane phospholipid levels of LA or ALA. Desaturation of
LA and ALA, therefore, may be regulated by the needs of mem-
brane recycling rather than dietary intake. In addition, the con-
version of ALA to DHA is highly inefficient such that increased
dietary intake of ALA does not lead to higher tissue levels of
DHA, although it may lead to higher tissue levels of EPA.3-6 The
overall rate of conversion of ALA to EPA and DHA has been
reported as 0.2% and 0.05%, respectively.7 However, increased
dietary intake of DHA or EPA is associated with relative
increases in the membrane phospholipid levels of these fatty
acids. DHA and EPA inhibit the desaturation of LA to AA, and
therefore, an increase in membrane levels of DHA and EPA is
associated with a decrease in membrane levels of AA. This has
important ramifications for cell signaling, especially in the con-
text of inflammation, as will be discussed later.
ALA, LA, and OA all compete for the same 5 and 6 desat-
urases and elongases, with the enzymes showing a preference
in the order of -3 > -6 > -9. Therefore, under normal

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384 Journal of Parenteral and Enteral Nutrition 36(4)
conditions, very little OA is metabolized to MA (Figure 3). An
increase in the concentration of MA indicates that there is little
ALA and LA as a substrate for desaturation, and the production
of MA is a compensatory mechanism to maintain the same
number of double bonds in membrane-bound fatty acids.
Essential fatty acid deficiency (EFAD) is defined by the rela-
tive decrease in AA levels and increase in MA levels.
Structurally, AA, a tetraene, contains 4 double bonds, whereas
MA, a triene, contains 3 double bonds, so the ratio of MA to
AA is often referred to as the triene-tetraene ratio. A triene-
tetraene ratio >0.2 biochemically defines EFAD, with clinical
symptoms (eg, dermatitis, alopecia, coagulopathy, impaired
growth) typically manifested when the ratio exceeds 0.4.8,9
All downstream fatty acids can be synthesized from LA and
ALA. For these reasons, ALA and LA are classically consid-
ered the essential fatty acids. Burr and Burr10 were the first
to describe the essentiality of ALA and LA in 1929, when
they demonstrated that AA and ALA alone could reverse
symptoms of EFAD in rats fed a fat-free diet. However, other
fatty acidsnotably AA, DHA, and EPAare necessary for
normal development and function throughout the life cycle and
are hence referred to as conditionally essential fatty acids.
There is emerging evidence from animal studies that the sup-
plementation of DHA and AA alonewithout ALA and LA
is sufficient to prevent EFAD.11 Research has shown that
EFAD can develop when less than 1%2% of total calories are
provided by ALA and LA. Premature infants, in particular,
have a higher requirement for ALA and LA due to their limited
fat stores and hence require at least 3% of calories from essen-
tial fatty acids.12
Physiologic Functions of Fatty Acids
Fatty acids serve 3 basic biologic functions: (1) sources of
fuel, in the form of uncharged esters with glycerol called tria-
cylglycerols; (2) components of cell membranes, in the form
of phospholipids and glycolipids; and (3) second messengers.
Fuel
Fats as sources of fuel are derived from 3 sources: the diet,
storage depots, and exportation from one organ to another.
Triglycerides from the enteral diet are emulsified by bile salts
to form micelles in the intestine. Pancreatic lipases cleave the
triacyglycerols into free fatty acids and 2-monoacylglycerols.
These are incorporated into micelles, along with unesterified
cholesterol and fat-soluble vitamins (A, D, E, and K). These
components are smaller and can therefore diffuse across the
intestinal epithelium, where they are reassembled to triacyg-
lycerols and incorporated into lipoprotein molecules called
chylomicrons (Figure 2C). Chylomicrons enter the lymphatic
system, then the blood, and are finally transported to muscle
and adipose tissue. Endothelial lipoprotein lipase digests the
triglycerides within chylomicrons to fatty acids and glycerol,
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which can be absorbed into the cell and either oxidized for
energy or stored as triacyglycerols.
Gastrointestinal hormones (eg, epinephrine and glucagon)
signal the need for metabolic energy and the mobilization of
fat from intracellular stores. Once mobilized, fatty acids are
transported to tissues, where they undergo degradation in the
form of -oxidation. Long-chain fatty acids must undergo a
carnitine-mediated, 3-step process to move from the cytosol to
the mitochondria where -oxidation occurs. During this pro-
cess, 2-carbon units of acetyl-CoA are successively removed
from the carboxyl end of the fatty acid chain. This degradation
occurs in 4 steps: dehydrogenation to introduce a double bond,
hydration to introduce oxygen, dehydrogenation of the alcohol
to a ketone, and cleavage by coenzyme A. Acetyl-CoA then
enters the citric acid cycle in the mitrochondrial matrix, where
it is oxidized to water and carbon dioxide. The electrons
extracted from fatty acids enter the electron transport chain to
generate energy, or adenosine triphosphate (ATP). The oxida-
tive yield of 1 g of fatty acid is 9 kilocalories (kcal), as com-
pared with 4 kcal from protein or carbohydrates. Fatty acids
have a greater energy yield because of their reduced and nearly
anhydrous form.
Fatty acid synthesis is most active in the liver and the lactat-
ing mammary gland. Malonyl-CoA is the donor of the 2-carbon
units, and formation of malonyl-CoA by the carboxylation
of acetyl-CoA is the rate-limiting step of fatty acid synthesis.
Fatty acids are synthesized in a stepwise fashion with the
sequential addition of 2-carbon units. Fatty acid synthase cata-
lyzes a 7-step cycle to add 2-carbon units to the growing fatty
acid chain until palmitate, C16:0, is typically produced.
Palmitate may be elongated to form other long-chain fatty
acids or alternatively desaturated to form MUFAs.
PUFAs exert powerful effects on the genes that regulate
fatty acid metabolism. The net effect of this influence is to shift
metabolism toward fatty acid oxidation and away from de
novo lipogenesis and lipid storage. PUFAs regulate at least 4
families of transcription factors that influence fatty acid syn-
thesis and oxidation, as well as cholesterol and bile acid
metabolism: peroxisome proliferator-activated receptor
(PPAR; , , and ), liver X receptors (LXRs; and ), hepatic
nuclear factor-4 (HNF-4) , and sterol regulatory element
binding proteins (SREBPs) 1 and 2.13 PUFAs activate PPARs,
thereby promoting fatty acid oxidation, whereas PUFAs also
antagonize SREBPs and LXRs, thereby inhibiting de novo
lipogenesis. In addition, PUFAs inhibit transcription of the
leptin gene; decreased leptin levels are associated with
decreased adiposity.
Cell Membranes
Fatty acidderived phospholipids and glycolipids are the pri-
mary constituents of the lipid bilayer of cell membranes
(Figure 2A). After adipose tissue, the brain has the second
highest level of lipid in the body, and most of this lipid is
A Tutorial on Fatty Acid Biology / Kalish et al 385
Figure 4. Eiconsaoids are signaling molecules derived from 20-carbon precursors. This schematic outlines the 3 pathways for formation
of eicosanoids: cyclooxygenase, lipoxygenase, and cytochrome P450.
membrane bound.14 AA and DHA, in particular, are found in
high concentration in excitable membranes of the brain and
retina. Large quantities of DHA and AA are deposited in the
brain during central nervous system development, and there-
fore, dietary deficiencies of these fatty acids are associated
with impaired neurodevelopment.15-18
Fatty acid structure modulates membrane fluidity and the
behavior of membrane-bound receptors. Higher saturated fatty
acid content decreases membrane fluidity, whereas higher
unsaturated fatty acid content increases fluidity. Membrane
fluidity has a direct impact on the number and affinity of cell
surface receptors. For instance, membranes with lower unsatu-
rated fatty acid content (more rigid) show a reduction in insulin
receptors, which may contribute to insulin resistance.19
Second Messengers
Membrane-bound PUFAs serve as the precursors to a variety
of second messengers. These lipid mediators are both pro- and
anti-inflammatory, and therefore, the physiologic state can
vary dramatically depending on this equilibrium. Eicosanoids
are a class of signaling molecules derived from 20-carbon
PUFAs (the term eicosanoids comes from the Greek word for
twenty, eikosi) that actively regulate a variety of biologic
functions, including host defense, vasoactivity, and reproduc-
tion.20 The eicosanoids have receptors on diverse cell types
throughout the body, and therefore, they exert control over a
broad array of physiologic functions. Classically, 4 classes of
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eicosanoidsprostaglandins, prostacyclins, thromboxanes,
and leukotrienesact locally through G-protein-coupled
receptors. Prostaglandins regulate cellular growth and smooth
muscle tone, along with pain sensitization, thrombus forma-
tion, parturition, and cellular growth.21 Prostacyclins inhibit
platelet aggregation and promote vasodilation, whereas throm-
boxanes promote hemostasis through platelet aggregation.
Leukotrienes act as potent chemotactic agents for inflamma-
tory cells, induce bronchoconstriction, and increase vascular
permeability.22
Eicosanoids are not stored in cells; rather, they are synthe-
sized in response to extracellular stimuli, such as growth fac-
tors and hormones. Phospholipase A2 (PLA2) is an enzyme that
releases 20-carbon PUFAs from the middle carbon of glycerol.
Due to the relative excess of AA in the cell membrane com-
pared with other PUFAs such as DHA and EPA, AA is the pri-
mary substrate for eicosanoid synthesis. There are 3 key
pathways in eicosanoid production: cyclooxygenase, lipoxy-
genase, and cytochrome P450 (Figure 4). Each of these will be
reviewed below.
The cyclooxygenase (COX) pathway is responsible for the
production of the prostanoids: prostaglandins, prostacyclins,
and thromboxanes. COX metabolizes AA, EPA, and DGLA
to produce the 2-series prostaglandins and thromboxanes, the
3-series prostaglandins and thromboxanes, and the 1-series
prostaglandins, respectively. There are 2 main enzymes in the
human COX pathway: COX-1 and COX-2. The traditional
teaching is that the COX-1 enzyme is constitutively expressed
386 Journal of Parenteral and Enteral Nutrition 36(4)

Figure 5. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) serve as parent molecules in the formation of specialized pro-
resolving mediators that serve to actively reduce cellular inflammation. LOX, lipoxygenase.

throughout the body, whereas COX-2 is inducible under inflam-
matory stress. However, recent evidence suggests that expres-
sion of both enzymes is present under both normal and
pathologic conditions.23 Classical nonsteroidal anti-inflam-
matory drugs (NSAIDs) inhibit both enzymes, thereby
decreasing prostaglandin and thromboxane synthesis, which
in turn has an anti-inflammatory, antipyretic, antithrombotic,
and analgesic effect. However, classical NSAIDs may cause
gastrointestinal complications because the inhibition of
COX-1 specifically decreases the production of prostaglan-
dins that are protective in the gastric mucosa. Selective COX-2
inhibitors that preserve the production of physiologic prosta-
glandins in the stomach have reduced gastrointestinal side
effects.24
The lipoxygenase pathway produces leukotrienes and
lipoxins. Lipoxins are nonclassical eicosanoids that are potent
anti-inflammatory mediators and act as counterregulators of
leukocyte trafficking.25 To date, 2 lipoxins have been identi-
fied: lipoxin A4 and lipoxin B4. At least 6 lipoxygenase
enzymes produce leukotrienes and lipoxins; many of these
enzymes have been implicated in the pathogenesis of cardiovas-
cular disease, cancer, rheumatologic conditions, and allergy.22
The first 2 steps in leukotriene synthesis are catalyzed by
5-lipoxygenase (5-LO). 12/15-Lipoxygenase (12/15-LO) is
highly expressed in eosinophils and in the airway epithelium,
and it has been studied extensively in the setting of atheroscle-
rosis.26,27 12/15-LO is also responsible for the production of
lipoxins. Lipoxins are synthesized through 15-lipoxygenase
(15-LO), which converts AA to 15-hydroxyeicosatetraenoic
acid (15-HETE); 15-HETE is further processed by 5-lipoxy-
genase and other epoxide hydrolases.
The cytochrome P450 pathwaythe third pathway in AA
metabolismhas 2 components: -hydroxylases which con-
vert AA to hydroxyeicosatetraenoic acids (HETEs), and epox-
ygenases, which convert AA to epoxyeicosatrienoic acids
(EETs). The HETEs are proinflammatory and proangiogenic
and are known to regulate vascular tone. The EETs are anti-
inflammatory, vasodilatory, and proangiogenic and have thus
generated significant interest in the fields of cardiovascular
and oncologic medicine.28,29
The beneficial effects of -3 fatty acids are suggested to
occur due to suppression of the production of AA-derived
prostaglandins and leukotrienes. As stated previously, -3-
derived PUFAs competitively inhibit the desaturation of LA
to AA.30,31 Increased intake of DHA and EPA raises the level
of these -3 fatty acids in inflammatory cells and decreases
the amount of AA available for eicosanoid synthesis.32,33
Furthermore, DGLA and EPA can compete with AA for
access to COX and lipoxygenase, therefore limiting
AA-derived eicosanoid synthesis. More recently, the para-
digm for understanding the anti-inflammatory effects of -3
fatty acids has shifted with the discovery of a novel class of
lipid molecules termed specialized pro-resolving mediators.
These molecules are short-lived endogenous mediators of
cellular programs to restore tissue homeostasis and resolve
inflammation. This novel class includes the lipoxins, as pre-
viously described, as well as lipid autocoids derived from -3
fatty acids: resolvins, protectins, and maresins (Figure 5).
DHA gives rise to the D-series resolvins and protectins, as
well as maresins, whereas EPA gives rise to the E-series
resolvins. These molecules have protective effects in a vari-
ety of animal models of inflammatory disease, including

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A Tutorial on Fatty Acid Biology / Kalish et al 387
colitis, ischemia-reperfusion, pain, sepsis, and acute lung
injury.34-37
Free Fatty Acid Receptors
Recently, a number of G-protein-coupled receptors (GPRs) for
free fatty acids have been identified. FFAR2 (free fatty acid
receptor; GPR43) and FFAR3 (GPR41) are both receptors for
short-chain fatty acids.38,39 FFAR1 (GPR40) is a receptor for
medium- and long-chain fatty acids, particularly in pancreatic
cells and enteroendocrine cells. Activation of FFAR1
enhances glucose-stimulated insulin release, and FFAR1
knockout mice have been shown to be resistant to hyperglyce-
mia, hepatic steatosis, and obesity-induced hyperinsulinemia.40
GPR120 functions as an -3 fatty acid receptor/sensor in
proinflammatory macrophages and mature adipocytes. The
activation of this receptor by DHA leads to the inhibition of
tumor necrosis factor (TNF-), Toll-like receptor 4 (TLR-
4), and lipopolysaccharide (LPS)mediated inflammatory
cascades. GPR120 expression has been found to be higher in
adipose tissue of obese individuals than in lean controls.41 In
addition, a mutation that inhibits GPR120 signaling has been
shown to increase the risk of obesity in European popula-
tions.41 Because of the roles these molecules play in energy
homeostasis, there is significant interest in pharmacologically
targeting both GPR40 and GPR120.
Conclusions
The world of fatty acid biology is incredibly complex. There
is an ever-expanding literature on the role of fatty acids in
maintaining nutrition homeostasis, driving and resolving
inflammation, and influencing the risk and severity of diseases
ranging from atherosclerosis to schizophrenia to cancer. The
physiologic effects of altering the consumption and metabo-
lism of fatty acids are only beginning to be unraveled, and the
fundamentals of fatty acid biology will be critical to translat-
ing these advancements.
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