Mechanisms of Gene Regulation by Fatty Acids1,2
Anastasia Georgiadi and Sander Kersten*
Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands
Consumption of specific dietary fatty acids has been shown to influence risk and progression of several chronic diseases, such as cardiovascular disease,
have provided the foundation for the emerging concept of fatty acid sensing, which can be interpreted as the property of fatty acids to influence
Here, we focus on fatty acid sensing via regulation of gene transcription and address the role of peroxisome proliferator–activated receptors, sterol
regulatory element binding protein 1, Toll-like receptor 4, G protein–coupled receptors, and other putative mediators. Adv. Nutr. 3: 127–134, 2012.
Consumption ofspecificdietary fatty acids has been shown to
affect the risk of a wide range of chronic diseases. What tra-
ditionally has been lacking is a clear mechanistic framework
that links uptake of specific lipids to a biological pathway
and disease process. Such a molecular framework should ac-
commodate the often differential effects of fatty acids differ-
ing in chain length and saturation on numerous biological
parameters. In recent years, insights into the mechanisms un-
derlying the biological effects of fatty acids have progressed
rapidly, in part because of the widespread use of in vivo
and invitro gene targeting, and have provided the foundation
for theemergingconceptoffattyacidsensing. Fattyacidsens-
ing can be interpreted as the property of fatty acids to influ-
ence biological processes by serving as signaling molecules.
Although it is well established that fatty acid derivatives
such as eicosanoids have a major signaling function, there is
convincing evidence that fatty acids themselves also carry
this property. Part of this regulation occurs via regulation of
gene transcription, which is the topic of this review.
Trafficking and cellular sensing of dietary fat
Everyday our body processes an amount of fat equivalent to al-
most one half cup. In the intestine, dietary triglycerides (TG)3
are first hydrolyzed into fatty acids and monoglycerides
that, together with bile acids, form into micelles in the intes-
tinal lumen. After being taken up by enterocytes, fatty acids
are re-esterified into TG and secreted as part of chylomicrons,
initially in the intestinal lymph vessels and from there in the
bloodstream. The increase in circulating chylomicrons after a
meal gives rise to the postprandial peak in plasma TG. The
time course and magnitude of the plasma TG peak may differ
among individuals and is increased in obese and diabetic in-
dividuals, giving rise to postprandial lipemia. Plasma chylo-
microns undergo rapid lipolytic processing via the action of
lipoprotein lipase (LPL) anchored to the capillary endothe-
lium, leading to the release of fatty acids and their subsequent
uptake by the underlying tissue (1).
One of the major sinks for meal-derived fatty acids is ad-
ipose tissue, which acquires most of the absorbed fatty acids
via increased local LPL activity. Other tissues that substan-
tially contribute to postprandial clearance of chylomicrons/
TGs are skeletal muscle, the heart, and, after conversion to
chylomicron remnants, the liver (2). In contrast to plasma
TG, circulating levels of adipose tissue–derived nonesterified
FFAs decrease rapidly after a mixed meal and again increase
at the end of the postprandial period. A considerable portion
of circulating FFA are taken up by the liver, where, together
with remnant-derived fatty acids and fatty acids produced
via de novo lipogenesis, they form the substrate for (re-)ester-
ification and subsequent secretion into plasma as VLDL/TG.
Depending on the tissue and feeding status, either plasma
FFA or TG-derived fatty acids comprise the major portion
of fatty acids for tissue uptake (2). Irrespective of the specific
route of delivery, it is evident that the rate of fatty acid uptake
by many tissues is very variable and influenced by numerous
1Studies supported by grants from the Netherlands Nutrigenomics Centre, the Netherlands
Organization for Scientific Research, the Dutch Diabetes Foundation, the Netherlands Heart
Foundation, and the European Foundation for the Study of Diabetes.
2Author disclosures: A. Georgiadi and S. Kersten, no conflicts of interest.
3Abbreviations used: ER, endoplasmic reticulum; FFAR, free fatty acid receptor; GPR, G
protein–coupled receptor; HNF4a, hepatocyte nuclear factor 4a; LPL, lipoprotein lipase;
LXR, liver X receptor; MLX, MAX-like protein X; NRF2, nuclear factor (erythroid-derived 2)-like
2; SREBP, sterol regulatory element binding protein; RXR, retinoid X receptor; TLR4, Toll-like
receptor 4; TG, triglyceride.
*To whom correspondence should be addressed: firstname.lastname@example.org.
ã2012 American Society for Nutrition. Adv. Nutr. 3: 127–134, 2012; doi:10.3945/an.111.001602.
factors, including tissue metabolic activity, feeding status, fat
intake, and the intake of other nutrients, especially carbohy-
drates. Furthermore, circulating concentration and tissue
fluxesofFFAandTG-derivedfattyacidsare often altereddur-
ing obesity, type 2 diabetes, or other metabolic disturbances.
A number of proteins are involved in the cellular uptake
of FFA, including CD36 and various fatty acid transporters
(3). After uptake, fatty acids are bound by fatty acid–binding
proteins and can undergo a number of metabolic fates in-
cluding oxidation in mitochondria and esterification and
storage in lipid droplets. In addition, fatty acids can serve
as signaling molecules by affecting intra- and extracellular
receptor sensor systems either directly or after conversion
to specific fatty acid derivatives. An example of these lipid
sensors are the nuclear receptors that mediate activation of
gene transcription by a variety of hydrophobic compounds,
including retinoic acid, steroid hormones, oxysterols, and
bile acids (4). This review provides an overview of our cur-
rent knowledge of the various cellular receptor systems en-
abling the cell to sense the intra- or extracellular fatty acid
concentration and respond by altering gene transcription.
Peroxisome proliferator–activated receptors
The PPARs perhaps compose the best recognized sensor sys-
tem for fatty acids (Fig. 1). PPARs are transcription factors
that are members of the superfamily of nuclear hormone re-
ceptors, which also include receptors for fat-soluble vita-
mins A and D and steroid hormones (5). Nuclear
receptors function as ligand-activated transcription factors
by binding small lipophilic molecules. They share a modular
structure consisting of a DNA- and ligand-binding domain
and play a role in a numerous biological processes (6). Three
different PPAR subtypes have been cloned, each character-
ized by a unique tissue expression pattern. PPARa (Nr1c1)
is found in many tissues but is predominant in oxidative tis-
sues such as brown adipose tissue, cardiac muscle, skeletal
muscle, and liver. PPARd (Nr1c2) is found in many cell
types, whereas PPARg (Nr1c3) expression is more re-
stricted, with adipocytes and macrophages expressing the
highest level (7,8). Binding of ligand is thought to trigger
the physical association of PPARs to specific DNA se-
quences, called PPAR response elements, in and around tar-
get genes. Additionally, ligand binding leads to recruitment
of coactivator proteins and loss of corepressor proteins, re-
sulting in activation of DNA transcription (5). Similar to
many other nuclear receptors, PPARs bind to DNA as heter-
odimer with the nuclear receptor retinoid X receptor (RXR),
which binds the vitamin A derivative 9-cis retinoic acid.
PPARs serve as receptors for structurally diverse com-
pounds. Although substantial specificity for 1 particular
PPAR subtype has been achieved in the design of synthetic
PPAR agonists, there seems to be comparatively little sub-
type specificity among endogenous PPAR agonists. In sev-
eral landmark articles from the 1990s, it was demonstrated
that all 3 PPARs are able to bind fatty acids with a general
niques have firmly corroborated the direct physical association
between fatty acids and PPARs and have thus established
regulation by fatty acids (FA). The mechanisms
shown mainly apply to hepatocytes.
Polyunsaturated fatty acids (PUFA) reduce
expression of genes involved in fatty acid and
cholesterol synthesis by binding and
inactivating UBXD8, thereby inhibiting
proteolytic processing of sterol regulatory
element binding protein (SREBP) 1. PUFAs
reduce expression of L-type pyruvate kinase
(glycolysis) in liver, most likely by inhibiting
nuclear translocation of MAX-like protein X
(MLX)–carbohydrate responsive element
binding protein. Various fatty acids, but
especially PUFAs, act as ligands for peroxisome
proliferator–activated receptors (PPAR).
Activation of PPARa by PUFAs in the liver leads
to stimulation of fatty acid (FA) catabolism.
Docosahexanoic acid has been reported as a
ligand for retinoid X receptor. G protein–
coupled receptors (GPR) 40–43 and GPR120 are
expressed by enterocytes, enteroendocrine
cells, and other cell types and serve as
membrane receptors for various types of fatty
acids including short-chain fatty acids. It is uncertain whether they are involved in the effects of fatty acids on gene expression. Toll-like
receptor 4 (TLR4) is present in macrophages and other cell types and has been proposed to be activated by saturated fatty acids (SFA).
bHLH, basic helix-loop-helix; ChREBP, carbohydrate-responsive element binding protein; FXR, farnesoid X receptor; HNF4a, hepatocyte
nuclear factor 4a; INSIG, insulin induced gene; LXR, liver X receptor; PXR, pregnane X receptor; SCAP, SREBP cleavage activating protein.
General mechanisms of gene
128Georgiadi and Kersten
fatty acids as bona fide PPAR ligands (14–18). In addition, nu-
a structural resemblance to fatty acids, including acyl-CoAs, ox-
idized fatty acids (9(S)-HODE and 13(S)-HODE), eicosanoids,
endocannabinoids, and phytanic acid, have been shown to acti-
vate PPARs (19–26). Whereas the eicosanoid 15-deoxy-delta-
12,14-prostaglandin J2 behaves as a specific high-affinity agonist
for PPARg, (8S)-hydroxyeicosatetraenoic acid and prostacylin
show preference for PPARa and PPARd, respectively (9,27–
29). Because the intracellular concentration of fatty acids (free
and bound to fatty acid binding proteins) far exceeds the intra-
cellular concentration of eicosanoids and other endogenous
PPAR agonists and because fatty acids are able to bind PPARs
with high affinity, the question can be raised to what extent
do eicosanoids and other fatty acid–derived compounds sub-
stantially contribute to the activation of PPARs in vivo. Rather,
it can be argued that PPARs serve as general fatty acid sensors
cept is notuniversallyembraced and has clearly not stopped the
quest to identify the potentially elusive single true endogenous
PPAR ligand. Recently, Chakravarthy et al. (30) identified the
phocholine as the lipid compound likely responsible for the ac-
tivation of PPARa in mice carrying a targeted deletion of the
fatty acid synthase gene. Because phosphatidylcholines are
abundant in any cell, it is unclear how activation of PPARa
by 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine fits
into the notion of PPARa being a lipid sensor that responds
to changes in metabolic status and lipid fluxes.
As discussed earlier, dietary fatty acids mostly enter the liver
as TGs within chylomicron remnants and are liberated after
degradation of the remnant particles by hepatic and lysosomal
lipase. It has been shownthat PPARa is dominant in mediating
the effects of dietary fatty acids on hepatic gene expression, in-
cluding many genes involved in fatty acid catabolism, as re-
vealed by experiments in which wild-type and PPARa2/2
mice were provided with a single oral bolus of synthetic TG
consisting of 1 type of fatty acid (17). Lipolysis of circulating
lipoproteins, whether hydrolysis of high-density lipoproteins
by endothelial lipase or lipolysis of VLDL by LPL, was shown
to be an important mechanism for generating ligands for
PPARa in endothelial cells (31,32), whereas hydrolysis of
VLDL by hepatic lipase and LPL was shown to provide ligands
for PPARd in hepatocytes and macrophages, respectively
In contrast and very surprisingly, circulating FFAs, which
primarily originate from adipose tissue lipolysis, do not seem
to be able to activate PPARa, at least in the liver (35,36). The
precise mechanism behind the differential effect of circulating
FFAs (“old fat”) versus dietary and endogenously synthesized
clear but may be related to the existence of distinct intracellular
(35). In contrast, hepatic PPARd can be activated by plasma
FFAs (36), and likely the same is true in skeletal muscle, as re-
vealed by the stimulatoryeffect of increased FFAs on expression
of the PPARd target Angptl4 in skeletal muscle (37,38).
Interestingly, it was recently proposed that in the mouse
heart, PPARa-mediated gene transcription requires the pre-
vious esterification of fatty acids and subsequent hydrolysis
catalyzed by adipose TG lipase (39). Conversion to TGs and
subsequent lipolysis seems to be necessary for fatty acids to
become active signaling lipids, but it is unclear whether the
specific routing of fatty acids leads to the formation of a spe-
cific high-affinity ligand or feeds a distinct intracellular fatty
acid pool. In contrast, evidence was also provided that in the
liver, adipose TG lipase promotes PPARa activity indepen-
dently of ligand-induced activation (40).
PPARa acts as a master regulator of hepatic lipid catabo-
lism by inducing the expression of numerous genes involved
as other lipid-related pathways, inflammatory pathways, and
glucose metabolism (41). Accordingly, it can be argued that
activation of PPARa by fatty acids in the liver and heart is
part ofa feed-forward mechanism aimedatpromoting oxida-
tion of incoming fuels and thereby preventing the intracellu-
lar accumulation and consequent lipotoxicity of fatty acids by
stimulating their oxidation. A similar role can be envisioned
for PPARd in skeletal muscle. In addition to stimulation of
fatty acid oxidation and possibly by stimulating conversion
of fatty acids into TGs (41), activation of PPAR by fatty acids
may protect against lipotoxicity by inhibiting LPL-dependent
hydrolysis of circulating TGs and consequent uptake of fatty
acids via induction of the LPL inhibitor Angptl4 (42).
The role of PPARs in gene regulation by fatty acids is less
clear in adipose tissue. Marine oil fatty acids have major ef-
fects on adipose tissue function and metabolism as well as
on adipose tissue gene regulation (43). Although PUFAs are
direct agonists for PPARg (12), it is unclear to what extent
the observed changes in adipose gene expression on chronic
PUFA feeding reflect direct ligand activation of PPARg or
other PPARs or are secondary effects conferred by specific ei-
cosanoids or other fatty acid–derived compounds. Activation
of PPARg by fatty acids may be aimed at promoting conver-
sion of incoming fatty acids to TGs and stimulating overall
TG storage capacity, thereby protecting against lipotoxicity.
Sterol-regulatory element binding protein 1
Dietary PUFAs suppress hepatic expression of genes involved
in fatty acid synthesis (Fig. 1). The underlying mechanism in-
zipper transcription factors named sterol regulatory element
binding protein (SREBP) 1 (Srebf1). There are 2 SREBP iso-
forms, designated SREBP-1c and SREBP-2, which differ in
their tissue-specific expression and their target genes selectiv-
ity. Although SREBP-1c preferentially activates genes involved
in de novo lipogenesis, SREBP-2 has a preference for genes in-
volved in cholesterol synthesis and uptake, at least in the liver
(44). Together, SREBPs activate the expression of >30 genes
involved in the synthesis and uptake of cholesterol, fatty acids,
TGs, and phospholipids.
Although SREBP1 and SREBP2 have both been suggested
to beinhibited by PUFAs,there ismuchmoreevidenceimpli-
cating SREBP1 in the down-regulation of gene expression by
Gene regulation by fatty acids129
PUFAs. Studies over the past decade indicated that PUFAs
potently lower SREBP-1 mRNA levels and inhibit proteolytic
processing of SREBP-1 (45–49). The latter process is required
for maturation of precursor membrane-bound SREBP-1 to
the mature SREBP-1, which moves to the nucleus and serves
as the actualtranscription factor. Recently, the target ofPUFAs
brane–bound proteinthatfacilitatesthe degradationof Insig-1,
which normally sequesters the SCAP-SREBP complex in the
ER and prevents its activation (50). Specifically, it was shown
that PUFAs inhibit the activity of Ubxd8, thus causing the
SCAP-SREBP complex to stay in the ER. In addition to the
mechanism described above, evidence has been provided that
docosahexanoic acid (DHA) but not other PUFAs stimulate
the removal of mature nuclear SREBP-1 via a mechanism de-
pendent on 26S-proteosome and extracellular signal–regulated
been proposed to be mediated by stimulation of SREBP-
1 mRNA decay (52), or by antagonizing the activity of the nu-
clear receptor liver X receptor (LXR) a, a potent inducer of
SREBP-1 gene transcription (53,54). Because a role of LXR in
mediating effects of PUFAs is debatable (55), the reduction in
SREBP-1 mRNA by PUFA is more likely to be secondary to in-
hibition of SREBP-1 maturation, which, via autoregulation of
SREBP-1 transcriptional activation, leads to reduced SREBP-
1 mRNA levels (56).
PUFAs have also been shown to reduce expression of the
glycolytic gene pyruvate kinase via a mechanism independent
of PPARa (57).Thiseffect may be mediated by inhibiting nu-
clear translocation of either carbohydrate-responsive element
binding protein (MLXIPL) or MAX-like protein X (MLX)
(Fig. 1) (58,59). ChREBPand MLX form a heterodimer func-
tioning as glucose-responsive transcription factor that in-
duces expression of genes involved in glycolysis and
lipogenesis, including pyruvate kinase, acetyl-CoA carboxyl-
ase 1, and fatty acid synthase. However, additional data
need to be collected to more precisely define how PUFAs in-
fluence ChREBP or MLX nuclear translocation and what the
direct molecular target of PUFAs is.
Hepatocyte nuclear factor 4a and other nuclear
The hepatocyte nuclear factor 4a (HNF4a, Nr2a1) is a nu-
clear receptor that is exclusively expressed in the gastrointes-
tinal tract, liver, and kidney (7). Targeted disruption of
HNF4a leads to early embryonic lethality related to defects
in the expression of visceral endoderm proteins required for
mice, it was shown that liver HNF4a is important for hepa-
tocyte differentiation and for governing the expression of
genes involved in lipid homeostasis (61). In 1998, evidence
was provided that saturated fatty acyl-CoAs may be able to
serve as agonists for HNF4a, whereas unsaturated fatty
acyl-CoAs were proposed to serve as an antagonistic ligand
(62). These data have been contested experimentally and are
not widely accepted (63). Elucidation of the molecular
structure using X-ray crystallography revealed the presence
of a fatty acid that appeared to be constitutively bound
(64,65). More recently, it was shown using affinity isola-
tion/mass-spectrometry that HNF4a is occupied by linoleic
acid in COS-7 cells as well as in the liver of fed but not fasted
mice, suggesting fatty acid binding is exchangeable. How-
ever, no induction of HNF4a targets by linoleic acid was ob-
served in a human colon cancer cell line, raising questions
about the purpose of binding of linoleic acid to HNF4a
(66). Overall, the binding and especially the activation of
HNF4a by fatty acids or acyl-CoAs remains controversial.
Indeed, there is only very limited evidence that changes in
the concentration of fatty acids or acyl-CoA lead to activa-
tion of HNF4a targets.
In addition to PPARs and HNF4a, the nuclear receptors
LXR, FXR, and RXR have been proposed to serve as medi-
ators of the effects of fatty acids on gene transcription.
With respect to LXR, it was suggested that unsaturated fatty
acids suppress Srebp1c gene expression by inhibiting LXR
(53). However, another study found that unsaturated fatty
acids do not influence LXR-dependent gene regulation in
primary rat hepatocytes or in the liver (55).
DHA was originally identified as a ligand for RXR when
looking for a factor in brain tissue that activates RXR in a
cell-based assay (67). Subsequent experiments showed the
direct binding of PUFAs to RXR, with strongest RXR activa-
tion observed for DHA and arachidonic acid, followed by
linolenic, linoleic, and oleic acids (68). Recent studies con-
firmed the direct binding of DHA to RXR, although with
much lower affinity compared with 9cRA (69). In as much
as DHA also binds PPARs and PPARs form permissive het-
erodimers with RXR, it is technically challenging to distin-
guish between DHA gene signaling via PPAR versus RXR.
Interestingly, using RXR and PPARg antagonists, it was
found that DHA induces expression of adipocyte differenti-
ation-related protein (Plin2) in human choriocarcinoma
cells via activation of RXR (70). Recently, effect of DHA
on despair behaviors and working memory could be attrib-
uted to activation of RXRg (71).
NF-E2–related factor-2 (NRF2)
An oral lipid load with PUFAs causes rapid up-regulation of
numerous oxidative stress genes in several organs, likely
representing an adaptive mechanism aimed at preventing
cellular lipotoxicity (72). Increased levels of reactive oxygen
species and derivatives of fatty acid peroxidation activate the
transcription factor NRF2 (NFE2L2), which governs the ex-
pression of multiple genes involved in the oxidative stress re-
sponse. Compounds that activate NRF2, ranging from
diphenols to hydroperoxides and heavy metals, are thought
to modulate the sulfhydryl group of cysteine residues with
KEAP1, which serves as an NRF2-specific adaptor protein
for the Cullin-3 ubiquitin ligase complex (73). As a result,
these compounds cause the dissociation of Cullin-3 and
thereby inhibit NRF2 ubiquitination, leading to stabilization
and nuclear translocation of NRF2 and subsequent induc-
tion of NRF2 target genes. Studies have shown that oxida-
tion products of linoleic acid, eicosapentanoic acid, and
130 Georgiadi and Kersten
DHA can react with KEAP1, whereas the intact fatty acids
cannot (74–76). Thus, the effects of (dietary) PUFAs on
the expression of genes involved in the oxidative stress re-
sponse are likely mediated by specific fatty acid oxidation
products via NRF2-dependent
Toll-like receptor 4
Numerous studies have investigated the impact of fatty acids
on the inflammatory response in a great variety of cell types
and tissues. These studies overwhelmingly point to a proin-
flammatory effect of saturated fatty acids, whereas (n-3)
PUFA exhibit mostly anti-inflammatory properties (77).
Most of the modulatory effect of fatty acids on inflammation
can probably be attributed to fatty acid metabolites, includ-
ing prostaglandins, leukotoxins, resolvins, endocannabi-
noids, ceramides, and diacylglycerols (77). However, there
is accumulating evidence that fatty acids may be able to di-
rectly activate or suppress inflammatory pathways.
Most of the biological activityof lipopolysaccharides is me-
diated via its lipid A moiety. It is well established that the fatty
acids that are part of lipid A play an important role in ligand
recognition and receptor activation of Toll-like receptor 4
(TLR4), leading to the suggestion that saturated fatty acids
may promote inflammation by direct activation of TLR4
(Fig. 1). Subsequent studies provided compelling evidence
that saturated fatty acids activate nuclear factor-kB and stim-
ulate expression of nuclear factor-kB targets such as cycloox-
ygenase 2, inducible nitric oxide synthase, and interleukin-
1a in macrophages by activating TLR4 signaling in a
MyD88-, IRAK-1-, and TRAF6-dependent manner (78–80).
In contrast, unsaturated fatty acids are ineffective or may
even act as antagonists. It was reported that saturated fatty
acids activate TLR4 by promoting its recruitment to lipid rafts
via a mechanism involving reactive oxygen species (81). Data
showing direct physical binding of saturated fatty acids to
TLR4 are still lacking, leaving open the mechanism of TLR4
activation (82). Others have argued against TLR4 activation
by saturated fatty acids (83). Using TLR42/2macrophages,
the role of TLR4 in mediating the inflammatory effects of sat-
of TLR4 was also shown to partially protect against diet-in-
duced obesity and insulin resistance, suggesting that TLR4
may be involved in mediating the detrimental effects of
chronic high saturated fat consumption (84,86,87).
G protein–coupled receptors
Members of the G protein–coupled receptor (GPR) family
are involved in mediating the stimulatory effects of fatty
acids on insulin secretion by pancreatic b cells and on secre-
tion of various gastrointestinal hormones in the gut (88,89).
These receptors, which include GPR40 (FFA receptor
[FFAR]1), GPR41 (FFAR3), GPR43 (FFAR2), GPR84, and
GPR120, each exhibit a preference for a specific set of fatty
acids. To what extent activation of GPRs by fatty acids di-
rectly influences gene transcription remains to be deter-
mined (Fig. 1). Nevertheless, because of the emerging
importance of GPRs in fatty acid sensing in a variety of tis-
sues, some discussion of GPRs is warranted.
In addition to being activated by short-chain fatty acids
GPR41 and GPR43 have in common that they are well ex-
pressed in the colon, which is exposed to elevated concentra-
tions of SCFAs via bacterial fermentation (88). Furthermore,
GPR41 is expressed in numerous immune cells and adipose
tissue, where it was shown to be involved in the regulation
of leptin production (90). The relative role of GPR41 versus
GPR43 as a sensor for SCFAs in the enteroendocrine system
is not clear. Recently, it was proposed that GPR41 mediates
the effect of gut microbiota on fat mass (91), whereas stimu-
lation of GPR43 by SCFAs was shown to be necessary for the
normal resolution of certain inflammatory responses (92).
In contrast to GPR41 and GPR43, GPR40 is activated by
medium- and long-chain fatty acids, which include satu-
rated and unsaturated fatty acids. GPR40 is expressed at
high levels in pancreatic b cells, where it mediates the stim-
ulatory effect of fatty acids on glucose-stimulated insulin se-
cretion (93,94). Apart from the pancreatic b cells, GPR40 is
known to be expressed invarious other cell types such as en-
teroendocrine cells. In these cells, GPR40 is involved in the
stimulation of production of glucagon-like peptide 1 and
gastric inhibitory peptide by fatty acids (95).
Other relevant members of the GPR family are GPR84,
GPR119, and GPR120. GPR84 is well expressed in bone
marrow–derived macrophages and has been proposed as re-
ceptor for medium-chain fatty acids (96). GPR119 has an
expression pattern similar to that of GPR40, but the recep-
tors shares only little homology. Endogenous ligands of
GPR119 have been identified and include the fatty acid de-
rivatives monoacyl glycerol, lysophosphatidylcholine, and
oleoylethanolamide (97,98). GPR120 is activated by satu-
rated and unsaturated fatty acids with $12 carbons.
GPR120 is most abundant in mouse large intestine, lung,
and adipose tissue, but is also expressed in enteroendocrine
cells where it mediates the effect of fatty acids on release of
glucagon-like peptide 1 and cholecystokinin (99–101). Re-
markably, GPR120 was recently proposed to serve as a spe-
cific sensor for (n-3) fatty acids in macrophages that may
mediate the putative insulin-sensitizing and antidiabetic ef-
fects of (n-3) fatty acids in vivo by repressing macrophage-
induced tissue inflammation (102). So far, evidence is lack-
ing that shows that activation of these receptors is directly
linked to the regulation of gene expression.
Although the importance of dietary fatty acids as determi-
nants of the risk of numerous chronic diseases has been
well recognized, only recently have we started to gain appre-
ciation for the vast regulatory functions of dietary fatty acids
in the human body. It is now evident that fatty acids, either
directly or via its metabolites, act via a great variety of signal-
ing pathwaystoinfluence numerous metabolic,inflammatory,
has provided the ideal conceptual framework and the necessary
Gene regulation by fatty acids131
technological tools to address the global effects of dietary fatty
acids and has greatly contributed to a major advancement in
our understanding of the molecular action of dietary fatty acids.
So far, the focus has been on the molecular characterization of
specific signaling routes, coupled with the description of the
whole genome effects of dietary fatty acids. In the future, greater
emphasis will have to be placed on the functional consequences
of specific target gene regulation to fully understand the func-
tional impact of dietary fatty acids and their potentially preven-
tive effect in specific disease conditions. It can be foreseen that
nutrigenomics will continue to make a push toward a more
mechanistic and genomics-driven approach within the domain
of nutritional sciences and further promote the implementation
of high-throughput technologies.
Both authors have read and approved the final manuscript.
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