REVIEW

Mechanisms of Gene Regulation by Fatty Acids1,2

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Anastasia Georgiadi and Sander Kersten*
Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands

ABSTRACT

Consumption of specific dietary fatty acids has been shown to influence risk and progression of several chronic diseases, such as cardiovascular disease,
obesity, cancer, and arthritis. In recent years, insights into the mechanisms underlying the biological effects of fatty acids have improved considerably and
have provided the foundation for the emerging concept of fatty acid sensing, which can be interpreted as the property of fatty acids to influence
biological processes by serving as signaling molecules. An important mechanism of fatty acid sensing is via stimulation or inhibition of DNA transcription.
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.

Introduction are first hydrolyzed into fatty acids and monoglycerides

Consumption of specific dietary fatty acids has been shown to that, together with bile acids, form into micelles in the intes-
affect the risk of a wide range of chronic diseases. What tra- tinal lumen. After being taken up by enterocytes, fatty acids
ditionally has been lacking is a clear mechanistic framework are re-esterified into TG and secreted as part of chylomicrons,
that links uptake of specific lipids to a biological pathway initially in the intestinal lymph vessels and from there in the
and disease process. Such a molecular framework should ac- bloodstream. The increase in circulating chylomicrons after a
commodate the often differential effects of fatty acids differ- meal gives rise to the postprandial peak in plasma TG. The
ing in chain length and saturation on numerous biological time course and magnitude of the plasma TG peak may differ
parameters. In recent years, insights into the mechanisms un- among individuals and is increased in obese and diabetic in-
derlying the biological effects of fatty acids have progressed dividuals, giving rise to postprandial lipemia. Plasma chylo-
rapidly, in part because of the widespread use of in vivo microns undergo rapid lipolytic processing via the action of
and in vitro gene targeting, and have provided the foundation lipoprotein lipase (LPL) anchored to the capillary endothe-
for the emerging concept of fatty acid sensing. Fatty acid sens- lium, leading to the release of fatty acids and their subsequent
ing can be interpreted as the property of fatty acids to influ- uptake by the underlying tissue (1).
ence biological processes by serving as signaling molecules. One of the major sinks for meal-derived fatty acids is ad-
Although it is well established that fatty acid derivatives ipose tissue, which acquires most of the absorbed fatty acids
such as eicosanoids have a major signaling function, there is via increased local LPL activity. Other tissues that substan-
convincing evidence that fatty acids themselves also carry tially contribute to postprandial clearance of chylomicrons/
this property. Part of this regulation occurs via regulation of TGs are skeletal muscle, the heart, and, after conversion to
gene transcription, which is the topic of this review. chylomicron remnants, the liver (2). In contrast to plasma
TG, circulating levels of adipose tissue–derived nonesterified
Trafficking and cellular sensing of dietary fat FFAs decrease rapidly after a mixed meal and again increase
Every day our body processes an amount of fat equivalent to al- at the end of the postprandial period. A considerable portion
most one half cup. In the intestine, dietary triglycerides (TG)3 of circulating FFA are taken up by the liver, where, together
1
Studies supported by grants from the Netherlands Nutrigenomics Centre, the Netherlands with remnant-derived fatty acids and fatty acids produced
Organization for Scientific Research, the Dutch Diabetes Foundation, the Netherlands Heart via de novo lipogenesis, they form the substrate for (re-)ester-
Foundation, and the European Foundation for the Study of Diabetes. ification and subsequent secretion into plasma as VLDL/TG.
2
Author disclosures: A. Georgiadi and S. Kersten, no conflicts of interest.
3
Abbreviations used: ER, endoplasmic reticulum; FFAR, free fatty acid receptor; GPR, G Depending on the tissue and feeding status, either plasma
protein–coupled receptor; HNF4a, hepatocyte nuclear factor 4a; LPL, lipoprotein lipase; FFA or TG-derived fatty acids comprise the major portion
LXR, liver X receptor; MLX, MAX-like protein X; NRF2, nuclear factor (erythroid-derived 2)-like of fatty acids for tissue uptake (2). Irrespective of the specific
2; SREBP, sterol regulatory element binding protein; RXR, retinoid X receptor; TLR4, Toll-like
receptor 4; TG, triglyceride. route of delivery, it is evident that the rate of fatty acid uptake
* To whom correspondence should be addressed: [email protected]. by many tissues is very variable and influenced by numerous

ã2012 American Society for Nutrition. Adv. Nutr. 3: 127–134, 2012; doi:10.3945/an.111.001602. 127
factors, including tissue metabolic activity, feeding status, fat by binding small lipophilic molecules. They share a modular
intake, and the intake of other nutrients, especially carbohy- structure consisting of a DNA- and ligand-binding domain
drates. Furthermore, circulating concentration and tissue and play a role in a numerous biological processes (6). Three
fluxes of FFA and TG-derived fatty acids are often altered dur- different PPAR subtypes have been cloned, each character-
ing obesity, type 2 diabetes, or other metabolic disturbances. ized by a unique tissue expression pattern. PPARa (Nr1c1)
A number of proteins are involved in the cellular uptake is found in many tissues but is predominant in oxidative tis-
of FFA, including CD36 and various fatty acid transporters sues such as brown adipose tissue, cardiac muscle, skeletal
(3). After uptake, fatty acids are bound by fatty acid–binding muscle, and liver. PPARd (Nr1c2) is found in many cell
proteins and can undergo a number of metabolic fates in- types, whereas PPARg (Nr1c3) expression is more re-
cluding oxidation in mitochondria and esterification and stricted, with adipocytes and macrophages expressing the

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storage in lipid droplets. In addition, fatty acids can serve highest level (7,8). Binding of ligand is thought to trigger
as signaling molecules by affecting intra- and extracellular the physical association of PPARs to specific DNA se-
receptor sensor systems either directly or after conversion quences, called PPAR response elements, in and around tar-
to specific fatty acid derivatives. An example of these lipid get genes. Additionally, ligand binding leads to recruitment
sensors are the nuclear receptors that mediate activation of of coactivator proteins and loss of corepressor proteins, re-
gene transcription by a variety of hydrophobic compounds, sulting in activation of DNA transcription (5). Similar to
including retinoic acid, steroid hormones, oxysterols, and many other nuclear receptors, PPARs bind to DNA as heter-
bile acids (4). This review provides an overview of our cur- odimer with the nuclear receptor retinoid X receptor (RXR),
rent knowledge of the various cellular receptor systems en- which binds the vitamin A derivative 9-cis retinoic acid.
abling the cell to sense the intra- or extracellular fatty acid PPARs serve as receptors for structurally diverse com-
concentration and respond by altering gene transcription. 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-
Peroxisome proliferator–activated receptors type specificity among endogenous PPAR agonists. In sev-
The PPARs perhaps compose the best recognized sensor sys- eral landmark articles from the 1990s, it was demonstrated
tem for fatty acids (Fig. 1). PPARs are transcription factors that all 3 PPARs are able to bind fatty acids with a general
that are members of the superfamily of nuclear hormone re- preference for long- chain polyunsaturated fatty acids (PUFAs)
ceptors, which also include receptors for fat-soluble vita- (9–13). Subsequent studies using a variety of biochemical tech-
mins A and D and steroid hormones (5). Nuclear niques have firmly corroborated the direct physical association
receptors function as ligand-activated transcription factors between fatty acids and PPARs and have thus established

Figure 1 General mechanisms of gene

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.

128 Georgiadi and Kersten

fatty acids as bona fide PPAR ligands (14–18). In addition, nu- Interestingly, it was recently proposed that in the mouse
merous fatty acid–derived compounds and compounds showing heart, PPARa-mediated gene transcription requires the pre-
a structural resemblance to fatty acids, including acyl-CoAs, ox- vious esterification of fatty acids and subsequent hydrolysis
idized fatty acids (9(S)-HODE and 13(S)-HODE), eicosanoids, catalyzed by adipose TG lipase (39). Conversion to TGs and
endocannabinoids, and phytanic acid, have been shown to acti- subsequent lipolysis seems to be necessary for fatty acids to
vate PPARs (19–26). Whereas the eicosanoid 15-deoxy-delta- become active signaling lipids, but it is unclear whether the
12,14-prostaglandin J2 behaves as a specific high-affinity agonist specific routing of fatty acids leads to the formation of a spe-
for PPARg, (8S)-hydroxyeicosatetraenoic acid and prostacylin cific high-affinity ligand or feeds a distinct intracellular fatty
show preference for PPARa and PPARd, respectively (9,27– acid pool. In contrast, evidence was also provided that in the
29). Because the intracellular concentration of fatty acids (free liver, adipose TG lipase promotes PPARa activity indepen-

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and bound to fatty acid binding proteins) far exceeds the intra- dently of ligand-induced activation (40).
cellular concentration of eicosanoids and other endogenous PPARa acts as a master regulator of hepatic lipid catabo-
PPAR agonists and because fatty acids are able to bind PPARs lism by inducing the expression of numerous genes involved
with high affinity, the question can be raised to what extent in mitochondrial and peroxisomal fatty acid oxidation, as well
do eicosanoids and other fatty acid–derived compounds sub- as other lipid-related pathways, inflammatory pathways, and
stantially contribute to the activation of PPARs in vivo. Rather, glucose metabolism (41). Accordingly, it can be argued that
it can be argued that PPARs serve as general fatty acid sensors activation of PPARa by fatty acids in the liver and heart is
with comparatively limited ligand specificity. However, this con- part of a feed-forward mechanism aimed at promoting oxida-
cept is not universally embraced and has clearly not stopped the tion of incoming fuels and thereby preventing the intracellu-
quest to identify the potentially elusive single true endogenous lar accumulation and consequent lipotoxicity of fatty acids by
PPAR ligand. Recently, Chakravarthy et al. (30) identified the stimulating their oxidation. A similar role can be envisioned
phosphatidylcholine 1-palmitoyl-2-oleoyl-sn-glycerol-3-phos- for PPARd in skeletal muscle. In addition to stimulation of
phocholine as the lipid compound likely responsible for the ac- fatty acid oxidation and possibly by stimulating conversion
tivation of PPARa in mice carrying a targeted deletion of the of fatty acids into TGs (41), activation of PPAR by fatty acids
fatty acid synthase gene. Because phosphatidylcholines are may protect against lipotoxicity by inhibiting LPL-dependent
abundant in any cell, it is unclear how activation of PPARa hydrolysis of circulating TGs and consequent uptake of fatty
by 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine fits acids via induction of the LPL inhibitor Angptl4 (42).
into the notion of PPARa being a lipid sensor that responds The role of PPARs in gene regulation by fatty acids is less
to changes in metabolic status and lipid fluxes. clear in adipose tissue. Marine oil fatty acids have major ef-
As discussed earlier, dietary fatty acids mostly enter the liver fects on adipose tissue function and metabolism as well as
as TGs within chylomicron remnants and are liberated after on adipose tissue gene regulation (43). Although PUFAs are
degradation of the remnant particles by hepatic and lysosomal direct agonists for PPARg (12), it is unclear to what extent
lipase. It has been shown that PPARa is dominant in mediating the observed changes in adipose gene expression on chronic
the effects of dietary fatty acids on hepatic gene expression, in- PUFA feeding reflect direct ligand activation of PPARg or
cluding many genes involved in fatty acid catabolism, as re- other PPARs or are secondary effects conferred by specific ei-
vealed by experiments in which wild-type and PPARa2/2 cosanoids or other fatty acid–derived compounds. Activation
mice were provided with a single oral bolus of synthetic TG of PPARg by fatty acids may be aimed at promoting conver-
consisting of 1 type of fatty acid (17). Lipolysis of circulating sion of incoming fatty acids to TGs and stimulating overall
lipoproteins, whether hydrolysis of high-density lipoproteins TG storage capacity, thereby protecting against lipotoxicity.
by endothelial lipase or lipolysis of VLDL by LPL, was shown
to be an important mechanism for generating ligands for Sterol-regulatory element binding protein 1
PPARa in endothelial cells (31,32), whereas hydrolysis of Dietary PUFAs suppress hepatic expression of genes involved
VLDL by hepatic lipase and LPL was shown to provide ligands in fatty acid synthesis (Fig. 1). The underlying mechanism in-
for PPARd in hepatocytes and macrophages, respectively volves a member of the family of basic helix-loop-helix leucine
(33,34). zipper transcription factors named sterol regulatory element
In contrast and very surprisingly, circulating FFAs, which binding protein (SREBP) 1 (Srebf1). There are 2 SREBP iso-
primarily originate from adipose tissue lipolysis, do not seem forms, designated SREBP-1c and SREBP-2, which differ in
to be able to activate PPARa, at least in the liver (35,36). The their tissue-specific expression and their target genes selectiv-
precise mechanism behind the differential effect of circulating ity. Although SREBP-1c preferentially activates genes involved
FFAs (“old fat”) versus dietary and endogenously synthesized in de novo lipogenesis, SREBP-2 has a preference for genes in-
fatty acids (“new fat”) on hepatic PPARa activation remains un- volved in cholesterol synthesis and uptake, at least in the liver
clear but may be related to the existence of distinct intracellular (44). Together, SREBPs activate the expression of >30 genes
fatty acids pools with distinct metabolic and signaling properties involved in the synthesis and uptake of cholesterol, fatty acids,
(35). In contrast, hepatic PPARd can be activated by plasma TGs, and phospholipids.
FFAs (36), and likely the same is true in skeletal muscle, as re- Although SREBP1 and SREBP2 have both been suggested
vealed by the stimulatory effect of increased FFAs on expression to be inhibited by PUFAs, there is much more evidence impli-
of the PPARd target Angptl4 in skeletal muscle (37,38). cating SREBP1 in the down-regulation of gene expression by

Gene regulation by fatty acids 129

PUFAs. Studies over the past decade indicated that PUFAs of a fatty acid that appeared to be constitutively bound
potently lower SREBP-1 mRNA levels and inhibit proteolytic (64,65). More recently, it was shown using affinity isola-
processing of SREBP-1 (45–49). The latter process is required tion/mass-spectrometry that HNF4a is occupied by linoleic
for maturation of precursor membrane-bound SREBP-1 to acid in COS-7 cells as well as in the liver of fed but not fasted
the mature SREBP-1, which moves to the nucleus and serves mice, suggesting fatty acid binding is exchangeable. How-
as the actual transcription factor. Recently, the target of PUFAs ever, no induction of HNF4a targets by linoleic acid was ob-
was identified as Ubxd8, an endoplasmic reticulum (ER) mem- served in a human colon cancer cell line, raising questions
brane–bound protein that facilitates the degradation of Insig-1, about the purpose of binding of linoleic acid to HNF4a
which normally sequesters the SCAP-SREBP complex in the (66). Overall, the binding and especially the activation of
ER and prevents its activation (50). Specifically, it was shown HNF4a by fatty acids or acyl-CoAs remains controversial.

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that PUFAs inhibit the activity of Ubxd8, thus causing the Indeed, there is only very limited evidence that changes in
SCAP-SREBP complex to stay in the ER. In addition to the the concentration of fatty acids or acyl-CoA lead to activa-
mechanism described above, evidence has been provided that tion of HNF4a targets.
docosahexanoic acid (DHA) but not other PUFAs stimulate In addition to PPARs and HNF4a, the nuclear receptors
the removal of mature nuclear SREBP-1 via a mechanism de- LXR, FXR, and RXR have been proposed to serve as medi-
pendent on 26S-proteosome and extracellular signal–regulated ators of the effects of fatty acids on gene transcription.
kinase (51). Down-regulation of SREBP-1 mRNA by PUFAs has With respect to LXR, it was suggested that unsaturated fatty
been proposed to be mediated by stimulation of SREBP- acids suppress Srebp1c gene expression by inhibiting LXR
1 mRNA decay (52), or by antagonizing the activity of the nu- (53). However, another study found that unsaturated fatty
clear receptor liver X receptor (LXR) a, a potent inducer of acids do not influence LXR-dependent gene regulation in
SREBP-1 gene transcription (53,54). Because a role of LXR in primary rat hepatocytes or in the liver (55).
mediating effects of PUFAs is debatable (55), the reduction in DHA was originally identified as a ligand for RXR when
SREBP-1 mRNA by PUFA is more likely to be secondary to in- looking for a factor in brain tissue that activates RXR in a
hibition of SREBP-1 maturation, which, via autoregulation of cell-based assay (67). Subsequent experiments showed the
SREBP-1 transcriptional activation, leads to reduced SREBP- direct binding of PUFAs to RXR, with strongest RXR activa-
1 mRNA levels (56). tion observed for DHA and arachidonic acid, followed by
PUFAs have also been shown to reduce expression of the linolenic, linoleic, and oleic acids (68). Recent studies con-
glycolytic gene pyruvate kinase via a mechanism independent firmed the direct binding of DHA to RXR, although with
of PPARa (57). This effect may be mediated by inhibiting nu- much lower affinity compared with 9cRA (69). In as much
clear translocation of either carbohydrate-responsive element as DHA also binds PPARs and PPARs form permissive het-
binding protein (MLXIPL) or MAX-like protein X (MLX) erodimers with RXR, it is technically challenging to distin-
(Fig. 1) (58,59). ChREBP and MLX form a heterodimer func- guish between DHA gene signaling via PPAR versus RXR.
tioning as glucose-responsive transcription factor that in- Interestingly, using RXR and PPARg antagonists, it was
duces expression of genes involved in glycolysis and found that DHA induces expression of adipocyte differenti-
lipogenesis, including pyruvate kinase, acetyl-CoA carboxyl- ation-related protein (Plin2) in human choriocarcinoma
ase 1, and fatty acid synthase. However, additional data cells via activation of RXR (70). Recently, effect of DHA
need to be collected to more precisely define how PUFAs in- on despair behaviors and working memory could be attrib-
fluence ChREBP or MLX nuclear translocation and what the uted to activation of RXRg (71).
direct molecular target of PUFAs is.
NF-E2–related factor-2 (NRF2)
Hepatocyte nuclear factor 4a and other nuclear An oral lipid load with PUFAs causes rapid up-regulation of
receptors numerous oxidative stress genes in several organs, likely
The hepatocyte nuclear factor 4a (HNF4a, Nr2a1) is a nu- representing an adaptive mechanism aimed at preventing
clear receptor that is exclusively expressed in the gastrointes- cellular lipotoxicity (72). Increased levels of reactive oxygen
tinal tract, liver, and kidney (7). Targeted disruption of species and derivatives of fatty acid peroxidation activate the
HNF4a leads to early embryonic lethality related to defects transcription factor NRF2 (NFE2L2), which governs the ex-
in the expression of visceral endoderm proteins required for pression of multiple genes involved in the oxidative stress re-
maintaining gastrulation (60). Using liver-specific HNF4a2/2 sponse. Compounds that activate NRF2, ranging from
mice, it was shown that liver HNF4a is important for hepa- diphenols to hydroperoxides and heavy metals, are thought
tocyte differentiation and for governing the expression of to modulate the sulfhydryl group of cysteine residues with
genes involved in lipid homeostasis (61). In 1998, evidence KEAP1, which serves as an NRF2-specific adaptor protein
was provided that saturated fatty acyl-CoAs may be able to for the Cullin-3 ubiquitin ligase complex (73). As a result,
serve as agonists for HNF4a, whereas unsaturated fatty these compounds cause the dissociation of Cullin-3 and
acyl-CoAs were proposed to serve as an antagonistic ligand thereby inhibit NRF2 ubiquitination, leading to stabilization
(62). These data have been contested experimentally and are and nuclear translocation of NRF2 and subsequent induc-
not widely accepted (63). Elucidation of the molecular tion of NRF2 target genes. Studies have shown that oxida-
structure using X-ray crystallography revealed the presence tion products of linoleic acid, eicosapentanoic acid, and

130 Georgiadi and Kersten

DHA can react with KEAP1, whereas the intact fatty acids importance of GPRs in fatty acid sensing in a variety of tis-
cannot (74–76). Thus, the effects of (dietary) PUFAs on sues, some discussion of GPRs is warranted.
the expression of genes involved in the oxidative stress re- In addition to being activated by short-chain fatty acids
sponse are likely mediated by specific fatty acid oxidation (SCFAs) such as acetate, propionate, butyrate, and pentanoate,
products via NRF2-dependent 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,
Toll-like receptor 4
GPR41 is expressed in numerous immune cells and adipose
Numerous studies have investigated the impact of fatty acids
tissue, where it was shown to be involved in the regulation
on the inflammatory response in a great variety of cell types
and tissues. These studies overwhelmingly point to a proin- of leptin production (90). The relative role of GPR41 versus

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GPR43 as a sensor for SCFAs in the enteroendocrine system
flammatory effect of saturated fatty acids, whereas (n-3)
is not clear. Recently, it was proposed that GPR41 mediates
PUFA exhibit mostly anti-inflammatory properties (77).
the effect of gut microbiota on fat mass (91), whereas stimu-
Most of the modulatory effect of fatty acids on inflammation
lation of GPR43 by SCFAs was shown to be necessary for the
can probably be attributed to fatty acid metabolites, includ-
normal resolution of certain inflammatory responses (92).
ing prostaglandins, leukotoxins, resolvins, endocannabi-
In contrast to GPR41 and GPR43, GPR40 is activated by
noids, ceramides, and diacylglycerols (77). However, there
medium- and long-chain fatty acids, which include satu-
is accumulating evidence that fatty acids may be able to di-
rectly activate or suppress inflammatory pathways. rated and unsaturated fatty acids. GPR40 is expressed at
high levels in pancreatic b cells, where it mediates the stim-
Most of the biological activity of lipopolysaccharides is me-
ulatory effect of fatty acids on glucose-stimulated insulin se-
diated via its lipid A moiety. It is well established that the fatty
cretion (93,94). Apart from the pancreatic b cells, GPR40 is
acids that are part of lipid A play an important role in ligand
known to be expressed in various other cell types such as en-
recognition and receptor activation of Toll-like receptor 4
teroendocrine cells. In these cells, GPR40 is involved in the
(TLR4), leading to the suggestion that saturated fatty acids
stimulation of production of glucagon-like peptide 1 and
may promote inflammation by direct activation of TLR4
gastric inhibitory peptide by fatty acids (95).
(Fig. 1). Subsequent studies provided compelling evidence
that saturated fatty acids activate nuclear factor-kB and stim- Other relevant members of the GPR family are GPR84,
GPR119, and GPR120. GPR84 is well expressed in bone
ulate expression of nuclear factor-kB targets such as cycloox-
marrow–derived macrophages and has been proposed as re-
ygenase 2, inducible nitric oxide synthase, and interleukin-
ceptor for medium-chain fatty acids (96). GPR119 has an
1a in macrophages by activating TLR4 signaling in a
expression pattern similar to that of GPR40, but the recep-
MyD88-, IRAK-1-, and TRAF6-dependent manner (78–80).
tors shares only little homology. Endogenous ligands of
In contrast, unsaturated fatty acids are ineffective or may
GPR119 have been identified and include the fatty acid de-
even act as antagonists. It was reported that saturated fatty
rivatives monoacyl glycerol, lysophosphatidylcholine, and
acids activate TLR4 by promoting its recruitment to lipid rafts
via a mechanism involving reactive oxygen species (81). Data oleoylethanolamide (97,98). GPR120 is activated by satu-
rated and unsaturated fatty acids with $12 carbons.
showing direct physical binding of saturated fatty acids to
GPR120 is most abundant in mouse large intestine, lung,
TLR4 are still lacking, leaving open the mechanism of TLR4
and adipose tissue, but is also expressed in enteroendocrine
activation (82). Others have argued against TLR4 activation
cells where it mediates the effect of fatty acids on release of
by saturated fatty acids (83). Using TLR42/2 macrophages,
glucagon-like peptide 1 and cholecystokinin (99–101). Re-
the role of TLR4 in mediating the inflammatory effects of sat-
markably, GPR120 was recently proposed to serve as a spe-
urated fatty acids was convincingly demonstrated (84,85). Loss
cific sensor for (n-3) fatty acids in macrophages that may
of TLR4 was also shown to partially protect against diet-in-
duced obesity and insulin resistance, suggesting that TLR4 mediate the putative insulin-sensitizing and antidiabetic ef-
fects of (n-3) fatty acids in vivo by repressing macrophage-
may be involved in mediating the detrimental effects of
induced tissue inflammation (102). So far, evidence is lack-
chronic high saturated fat consumption (84,86,87).
ing that shows that activation of these receptors is directly
linked to the regulation of gene expression.
G protein–coupled receptors
Members of the G protein–coupled receptor (GPR) family Conclusion
are involved in mediating the stimulatory effects of fatty Although the importance of dietary fatty acids as determi-
acids on insulin secretion by pancreatic b cells and on secre- nants of the risk of numerous chronic diseases has been
tion of various gastrointestinal hormones in the gut (88,89). well recognized, only recently have we started to gain appre-
These receptors, which include GPR40 (FFA receptor ciation for the vast regulatory functions of dietary fatty acids
[FFAR]1), GPR41 (FFAR3), GPR43 (FFAR2), GPR84, and in the human body. It is now evident that fatty acids, either
GPR120, each exhibit a preference for a specific set of fatty directly or via its metabolites, act via a great variety of signal-
acids. To what extent activation of GPRs by fatty acids di- ing pathways to influence numerous metabolic, inflammatory,
rectly influences gene transcription remains to be deter- and other biological processes. In the past decade, nutrigenomics
mined (Fig. 1). Nevertheless, because of the emerging has provided the ideal conceptual framework and the necessary

Gene regulation by fatty acids 131

technological tools to address the global effects of dietary fatty 15. Malapaka RR, Khoo SK, Zhang J, Choi JH, Zhou XE, Xu Y, Gong Y, Li
acids and has greatly contributed to a major advancement in J, Yong EL, Chalmers MJ, et al. Identification and mechanism of a ten
carbon fatty acid as a modulating ligand of peroxisome proliferator
our understanding of the molecular action of dietary fatty acids. activated receptors. J Biol Chem. Epub 2011 Oct 28.
So far, the focus has been on the molecular characterization of 16. Murakami K, Ide T, Suzuki M, Mochizuki T, Kadowaki T. Evidence for
specific signaling routes, coupled with the description of the direct binding of fatty acids and eicosanoids to human peroxisome
whole genome effects of dietary fatty acids. In the future, greater proliferators-activated receptor alpha. Biochem Biophys Res Com-
emphasis will have to be placed on the functional consequences mun. 1999;260:609–13.
17. Sanderson LM, de Groot PJ, Hooiveld GJ, Koppen A, Kalkhoven E,
of specific target gene regulation to fully understand the func- Muller M, Kersten S. Effect of synthetic dietary triglycerides: a novel
tional impact of dietary fatty acids and their potentially preven- research paradigm for nutrigenomics. PLoS ONE. 2008;3:e1681.
tive effect in specific disease conditions. It can be foreseen that 18. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown

Downloaded from advances.nutrition.org at UNIVERSITY OF TENNESSEE JOHN C HODGES LIBRARY on November 19, 2012
nutrigenomics will continue to make a push toward a more PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, et al. Mo-
mechanistic and genomics-driven approach within the domain lecular recognition of fatty acids by peroxisome proliferator-activated
receptors. Mol Cell. 1999;3:397–403.
of nutritional sciences and further promote the implementation 19. Fang X, Hu S, Xu B, Snyder GD, Harmon S, Yao J, Liu Y, Sangras B,
of high-throughput technologies. Falck JR, Weintraub NL, et al. 14,15-Dihydroxyeicosatrienoic acid ac-
tivates peroxisome proliferator-activated receptor-alpha. Am J Physiol
Heart Circ Physiol. 2006;290:H55–63.
Acknowledgments 20. Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, Rodriguez De Fonseca
Both authors have read and approved the final manuscript. F, Rosengarth A, Luecke H, Di Giacomo B, Tarzia G, et al. Oleylethano-
lamide regulates feeding and body weight through activation of the nu-
Literature Cited clear receptor PPAR-alpha. Nature. 2003;425:90–3.
1. Wang H, Eckel RH. Lipoprotein lipase: from gene to obesity. Am J 21. Hostetler HA, Petrescu AD, Kier AB, Schroeder F. Peroxisome prolif-
Physiol Endocrinol Metab. 2009;297:E271–88. erator-activated receptor alpha interacts with high affinity and is con-
2. Teusink B, Voshol PJ, Dahlmans VE, Rensen PC, Pijl H, Romijn JA, formationally responsive to endogenous ligands. J Biol Chem. 2005;
Havekes LM. Contribution of fatty acids released from lipolysis of 280:18667–82.
plasma triglycerides to total plasma fatty acid flux and tissue-specific 22. Itoh T, Fairall L, Amin K, Inaba Y, Szanto A, Balint BL, Nagy L, Yamamoto
fatty acid uptake. Diabetes. 2003;52:614–20. K, Schwabe JW. Structural basis for the activation of PPARgamma by ox-
3. Glatz JF, Luiken JJ, Bonen A. Membrane fatty acid transporters as reg- idized fatty acids. Nat Struct Mol Biol. 2008;15:924–31.
ulators of lipid metabolism: implications for metabolic disease. Phys- 23. Li Y, Zhang J, Schopfer FJ, Martynowski D, Garcia-Barrio MT, Kovach
iol Rev. 2010;90:367–417. A, Suino-Powell K, Baker PR, Freeman BA, Chen YE, et al. Molecular
4. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and recognition of nitrated fatty acids by PPAR gamma. Nat Struct Mol
lipid physiology: opening the X-files. Science. 2001;294:1866–70. Biol. 2008;15:865–7.
5. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and dis- 24. Moya-Camarena SY, Vanden Heuvel JP, Blanchard SG, Leesnitzer LA,
ease. Nature. 2000;405:421–4. Belury MA. Conjugated linoleic acid is a potent naturally occurring
6. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono ligand and activator of PPARalpha. J Lipid Res. 1999;40:1426–33.
K, Blumberg B, Kastner P, Mark M, et al. The nuclear receptor super- 25. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL
family: the second decade. Cell. 1995;83:835–9. regulates macrophage gene expression through ligand activation of
7. Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ. PPARgamma. Cell. 1998;93:229–40.
Anatomical profiling of nuclear receptor expression reveals a hierar- 26. Zomer AW, van Der Burg B, Jansen GA, Wanders RJ, Poll-The BT, van
chical transcriptional network. Cell. 2006;126:789–99. Der Saag PT. Pristanic acid and phytanic acid: naturally occurring lig-
8. Escher P, Braissant O, Basu-Modak S, Michalik L, Wahli W, Desvergne ands for the nuclear receptor peroxisome proliferator-activated recep-
B. Rat PPARs: quantitative analysis in adult rat tissues and regulation tor alpha. J Lipid Res. 2000;41:1801–7.
in fasting and refeeding. Endocrinology. 2001;142:4195–202. 27. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A
9. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans prostaglandin J2 metabolite binds peroxisome proliferator-activated recep-
RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipo- tor gamma and promotes adipocyte differentiation. Cell. 1995;83:813–9.
cyte determination factor PPAR gamma. Cell. 1995;83:803–12. 28. Lim H, Gupta RA, Ma WG, Paria BC, Moller DE, Morrow JD, DuBois
10. Göttlicher M, Widmark E, Li Q, Gustafsson JA. Fatty acids activate a RN, Trzaskos JM, Dey SK. Cyclo-oxygenase-2-derived prostacyclin
chimera of the clofibric acid-activated receptor and the glucocorticoid mediates embryo implantation in the mouse via PPARdelta. Genes
receptor. Proc Natl Acad Sci U S A. 1992;89:4653–7. Dev. 1999;13:1561–74.
11. Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W. Fatty 29. Muga SJ, Thuillier P, Pavone A, Rundhaug JE, Boeglin WE, Jisaka M,
acids and retinoids control lipid metabolism through activation of Brash AR, Fischer SM. 8S-lipoxygenase products activate peroxisome
peroxisome proliferator-activated receptor-retinoid X receptor hetero- proliferator-activated receptor alpha and induce differentiation in
dimers. Proc Natl Acad Sci U S A. 1993;90:2160–4. murine keratinocytes. Cell Growth Differ. 2000;11:447–54.
12. Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, 30. Chakravarthy MV, Lodhi IJ, Yin L, Malapaka RR, Xu HE, Turk J,
Devchand P, Wahli W, Willson TM, Lenhard JM, et al. Fatty acids and Semenkovich CF. Identification of a physiologically relevant endoge-
eicosanoids regulate gene expression through direct interactions with nous ligand for PPARalpha in liver. Cell. 2009;138:476–88.
peroxisome proliferator-activated receptors alpha and gamma. Proc 31. Ahmed W, Orasanu G, Nehra V, Asatryan L, Rader DJ, Ziouzenkova
Natl Acad Sci U S A. 1997;94:4318–23. O, Plutzky J. High-density lipoprotein hydrolysis by endothelial lipase
13. Krey G, Braissant O, L’Horset F, Kalkhoven E, Perroud M, Parker activates PPARalpha: a candidate mechanism for high-density lipo-
MG, Wahli W. Fatty acids, eicosanoids, and hypolipidemic agents protein-mediated repression of leukocyte adhesion. Circ Res. 2006;
identified as ligands of peroxisome proliferator-activated receptors 98:490–8.
by coactivator-dependent receptor ligand assay. Mol Endocrinol. 32. Ziouzenkova O, Perrey S, Asatryan L, Hwang J, MacNaul KL, Moller
1997;11:779–91. DE, Rader DJ, Sevanian A, Zechner R, et al. Lipolysis of triglyceride-
14. Lin Q, Ruuska SE, Shaw NS, Dong D, Noy N. Ligand selectivity of the rich lipoproteins generates PPAR ligands: evidence for an antiinflam-
peroxisome proliferator-activated receptor alpha. Biochemistry. 1999; matory role for lipoprotein lipase. Proc Natl Acad Sci U S A. 2003;100:
38:185–90. 2730–5.

132 Georgiadi and Kersten

33. Brown JD, Oligino E, Rader DJ, Saghatelian A, Plutzky J. VLDL hy- 51. Botolin D, Wang Y, Christian B, Jump DB. Docosahexaneoic acid (22:
drolysis by hepatic lipase regulates PPARdelta transcriptional re- 6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk-
sponses. PLoS ONE. 2011;6:e21209. and 26S proteasome-dependent pathways. J Lipid Res. 2006;47:181–
34. Chawla A, Lee CH, Barak Y, He W, Rosenfeld J, Liao D, Han J, Kang 92.
H, Evans RM. PPARdelta is a very low-density lipoprotein sensor in 52. Xu J, Teran-Garcia M, Park JH, Nakamura MT, Clarke SD. Polyunsat-
macrophages. Proc Natl Acad Sci U S A. 2003;100:1268–73. urated fatty acids suppress hepatic sterol regulatory element-binding
35. Chakravarthy MV, Pan Z, Zhu Y, Tordjman K, Schneider JG, Coleman protein-1 expression by accelerating transcript decay. J Biol Chem.
T, Turk J, Semenkovich CF. "New" hepatic fat activates PPARalpha to 2001;276:9800–7.
maintain glucose, lipid, and cholesterol homeostasis. Cell Metab. 53. Ou J, Tu H, Shan B, Luk A, DeBose-Boyd RA, Bashmakov Y, Goldstein
2005;1:309–22. JL, Brown MS. Unsaturated fatty acids inhibit transcription of the ste-
36. Sanderson LM, Degenhardt T, Koppen A, Kalkhoven E, Desvergne B, rol regulatory element-binding protein-1c (SREBP-1c) gene by antag-
Muller M, Kersten S. Peroxisome proliferator-activated receptor beta/ onizing ligand-dependent activation of the LXR. Proc Natl Acad Sci U

Downloaded from advances.nutrition.org at UNIVERSITY OF TENNESSEE JOHN C HODGES LIBRARY on November 19, 2012
delta (PPARbeta/delta) but not PPARalpha serves as a plasma free fatty S A. 2001;98:6027–32.
acid sensor in liver. Mol Cell Biol. 2009;29:6257–67. 54. Yoshikawa T, Shimano H, Yahagi N, Ide T, Amemiya-Kudo M, Matsuzaka
37. Kersten S, Lichtenstein L, Steenbergen E, Mudde K, Hendriks HF, T, Nakakuki M, Tomita S, Okazaki H, Tamura Y, et al. Polyunsaturated
Hesselink MK, Schrauwen P, Muller M. Caloric restriction and exer- fatty acids suppress sterol regulatory element-binding protein 1c promoter
cise increase plasma ANGPTL4 levels in humans via elevated free fatty activity by inhibition of liver X receptor (LXR) binding to LXR response
acids. Arterioscler Thromb Vasc Biol. 2009;29:969–74. elements. J Biol Chem. 2002;277:1705–11.
38. Staiger H, Haas C, Machann J, Werner R, Weisser M, Schick F, Machicao 55. Pawar A, Botolin D, Mangelsdorf DJ, Jump DB. The role of liver X re-
F, Stefan N, Fritsche A, Haring HU. Muscle-derived angiopoietin-like ceptor-alpha in the fatty acid regulation of hepatic gene expression.
protein 4 is induced by fatty acids via peroxisome proliferator-activated J Biol Chem. 2003;278:40736–43.
receptor (PPAR)-delta and is of metabolic relevance in humans. Diabetes. 56. Takeuchi Y, Yahagi N, Izumida Y, Nishi M, Kubota M, Teraoka Y, Yamamoto
2009;58:579–89. T, Matsuzaka T, Nakagawa Y, Sekiya M, et al. Polyunsaturated fatty acids se-
39. Haemmerle G, Moustafa T, Woelkart G, Buttner S, Schmidt A, van de lectively suppress sterol regulatory element-binding protein-1 through pro-
Weijer T, Hesselink M, Jaeger D, Kienesberger PC, Zierler K, et al. teolytic processing and autoloop regulatory circuit. J Biol Chem. 2010;285:
ATGL-mediated fat catabolism regulates cardiac mitochondrial func- 11681–91.
tion via PPAR-alpha and PGC-1. Nat Med. 2011;17:1076–85. 57. Pan DA, Mater MK, Thelen AP, Peters JM, Gonzalez FJ, Jump DB. Ev-
40. Ong KT, Mashek MT, Bu SY, Greenberg AS, Mashek DG. Adipose tri- idence against the peroxisome proliferator-activated receptor alpha
glyceride lipase is a major hepatic lipase that regulates triacylglycerol (PPARalpha) as the mediator for polyunsaturated fatty acid suppres-
turnover and fatty acid signaling and partitioning. Hepatology. sion of hepatic L-pyruvate kinase gene transcription. J Lipid Res. 2000;
2011;53:116–26. 41:742–51.
41. Rakhshandehroo M, Knoch B, Muller M, Kersten S. Peroxisome 58. Dentin R, Benhamed F, Pegorier JP, Foufelle F, Viollet B, Vaulont S,
proliferator-activated receptor alpha target genes. PPAR Res. 2010;2010. Girard J, Postic C. Polyunsaturated fatty acids suppress glycolytic
42. Georgiadi A, Lichtenstein L, Degenhardt T, Boekschoten MV, van Bilsen and lipogenic genes through the inhibition of ChREBP nuclear pro-
M, Desvergne B, Muller M, Kersten S. Induction of cardiac Angptl4 by tein translocation. J Clin Invest. 2005;115:2843–54.
dietary fatty acids is mediated by peroxisome proliferator-activated re- 59. Xu J, Christian B, Jump DB. Regulation of rat hepatic L-pyruvate kinase
ceptor beta/delta and protects against fatty acid-induced oxidative stress. promoter composition and activity by glucose, n-3 polyunsaturated
Circ Res. 2010;106:1712–21. fatty acids, and peroxisome proliferator-activated receptor-alpha ago-
43. Flachs P, Rossmeisl M, Bryhn M, Kopecky J. Cellular and molecular nist. J Biol Chem. 2006;281:18351–62.
effects of n-3 polyunsaturated fatty acids on adipose tissue biology 60. Chen WS, Manova K, Weinstein DC, Duncan SA, Plump AS, Prezioso
and metabolism. Clin Sci (Lond). 2009;116:1–16. VR, Bachvarova RF, Darnell JE, Jr. Disruption of the HNF-4 gene, ex-
44. Horton JD. Sterol regulatory element-binding proteins: transcrip- pressed in visceral endoderm, leads to cell death in embryonic ecto-
tional activators of lipid synthesis. Biochem Soc Trans. 2002;30: derm and impaired gastrulation of mouse embryos. Genes Dev.
1091–5. 1994;8:2466–77.
45. Hannah VC, Ou J, Luong A, Goldstein JL, Brown MS. Unsaturated 61. Yin L, Ma H, Ge X, Edwards PA, Zhang Y. Hepatic hepatocyte nuclear
fatty acids down-regulate srebp isoforms 1a and 1c by two mecha- factor 4alpha is essential for maintaining triglyceride and cholesterol
nisms in HEK-293 cells. J Biol Chem. 2001;276:4365–72. homeostasis. Arterioscler Thromb Vasc Biol. 2011;31:328–36.
46. Kim HJ, Takahashi M, Ezaki O. Fish oil feeding decreases mature sterol 62. Hertz R, Magenheim J, Berman I, Bar-Tana J. Fatty acyl-CoA thioes-
regulatory element-binding protein 1 (SREBP-1) by down-regulation ters are ligands of hepatic nuclear factor-4alpha. Nature. 1998;392:
of SREBP-1c mRNA in mouse liver. A possible mechanism for down- 512–6.
regulation of lipogenic enzyme mRNAs. J Biol Chem. 1999;274:25892–8. 63. Bogan AA, Dallas-Yang Q, Ruse MD, Jr., Maeda Y, Jiang G, Nepomuceno
47. Mater MK, Thelen AP, Pan DA, Jump DB. Sterol response element- L, Scanlan TS, Cohen FE, Sladek FM. Analysis of protein dimerization
binding protein 1c (SREBP1c) is involved in the polyunsaturated fatty and ligand binding of orphan receptor HNF4alpha. J Mol Biol. 2000;
acid suppression of hepatic S14 gene transcription. J Biol Chem. 1999; 302:831–51.
274:32725–32. 64. Dhe-Paganon S, Duda K, Iwamoto M, Chi YI, Shoelson SE. Crystal
48. Xu J, Nakamura MT, Cho HP, Clarke SD. Sterol regulatory element structure of the HNF4 alpha ligand binding domain in complex
binding protein-1 expression is suppressed by dietary polyunsaturated with endogenous fatty acid ligand. J Biol Chem. 2002;277:37973–6.
fatty acids. A mechanism for the coordinate suppression of lipogenic 65. Wisely GB, Miller AB, Davis RG, Thornquest AD, Jr., Johnson R, Spitzer
genes by polyunsaturated fats. J Biol Chem. 1999;274:23577–83. T, Sefler A, Shearer B, Moore JT, Miller AB, et al. Hepatocyte nuclear
49. Yahagi N, Shimano H, Hasty AH, Amemiya-Kudo M, Okazaki H, Tamura factor 4 is a transcription factor that constitutively binds fatty acids.
Y, Iizuka Y, Shionoiri F, Ohashi K, Osuga J, et al. A crucial role of sterol Structure. 2002;10:1225–34.
regulatory element-binding protein-1 in the regulation of lipogenic gene 66. Yuan X, Ta TC, Lin M, Evans JR, Dong Y, Bolotin E, Sherman MA,
expression by polyunsaturated fatty acids. J Biol Chem. 1999;274: Forman BM, Sladek FM. Identification of an endogenous ligand
35840–4. bound to a native orphan nuclear receptor. PLoS ONE. 2009;4:e5609.
50. Lee JN, Kim H, Yao H, Chen Y, Weng K, Ye J. Identification of Ubxd8 67. de Urquiza AM, Liu S, Sjoberg M, Zetterstrom RH, Griffiths W, Sjovall
protein as a sensor for unsaturated fatty acids and regulator of triglyc- J, Perlmann T. Docosahexaenoic acid, a ligand for the retinoid X recep-
eride synthesis. Proc Natl Acad Sci U S A. 2010;107:21424–9. tor in mouse brain. Science. 2000;290:2140–4.

Gene regulation by fatty acids 133

 68. Lengqvist J, Mata De Urquiza A, Bergman AC, Willson TM, Sjovall J, receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflam-
Perlmann T, Griffiths WJ. Polyunsaturated fatty acids including doco- matory changes in the interaction between adipocytes and macro-
sahexaenoic and arachidonic acid bind to the retinoid X receptor al- phages. Arterioscler Thromb Vasc Biol. 2007;27:84–91.
pha ligand-binding domain. Mol Cell Proteomics. 2004;3:692–703. 86. Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME. Tlr-4 deficiency
69. Stafslien DK, Vedvik KL, De Rosier T, Ozers MS. Analysis of ligand- selectively protects against obesity induced by diets high in saturated
dependent recruitment of coactivator peptides to RXRbeta in a fat. Obesity (Silver Spring). 2008;16:1248–55.
time-resolved fluorescence resonance energy transfer assay. Mol Cell 87. Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara
Endocrinol. 2007;264:82–9. SM, Schenka AA, Araujo EP, Vassallo J, Curi R, Velloso LA, et al. Loss-
70. Suzuki K, Takahashi K, Nishimaki-Mogami T, Kagechika H, Yamamoto of-function mutation in Toll-like receptor 4 prevents diet-induced obe-
M, Itabe H. Docosahexaenoic acid induces adipose differentiation- sity and insulin resistance. Diabetes. 2007;56:1986–98.
related protein through activation of retinoid x receptor in human cho- 88. Covington DK, Briscoe CA, Brown AJ, Jayawickreme CK. The G-protein-
riocarcinoma BeWo cells. Biol Pharm Bull. 2009;32:1177–82. coupled receptor 40 family (GPR40–GPR43) and its role in nutrient sensing.

Downloaded from advances.nutrition.org at UNIVERSITY OF TENNESSEE JOHN C HODGES LIBRARY on November 19, 2012
71. Wietrzych-Schindler M, Szyszka-Niagolov M, Ohta K, Endo Y, Perez Biochem Soc Trans. 2006;34:770–3.
E, de Lera AR, Chambon P, Krezel W. Retinoid x receptor gamma 89. Kebede MA, Alquier T, Latour MG, Poitout V. Lipid receptors and islet
is implicated in docosahexaenoic acid modulation of despair behav- function: therapeutic implications? Diabetes Obes Metab. 2009;11:
iors and working memory in mice. Biol Psychiatry. 2011;69:788–94. Suppl 4:10–20.
72. Anderson EJ, Thayne K, Harris M, Carraway K, Shaikh SR. Aldehyde 90. Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, Kedzierski
stress and up-regulation of Nrf2-mediated antioxidant systems ac- RM, Yanagisawa M. Short-chain fatty acids stimulate leptin produc-
company functional adaptations in cardiac mitochondria from mice tion in adipocytes through the G protein-coupled receptor GPR41.
fed n-3 polyunsaturated fatty acids. Biochem J. Epub 2011 Aug 31. Proc Natl Acad Sci U S A. 2004;101:1045–50.
73. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi 91. Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK,
K, Yamamoto M. Oxidative stress sensor Keap1 functions as an adaptor Hammer RE, Williams SC, Crowley J, Yanagisawa M, et al. Effects of
for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. the gut microbiota on host adiposity are modulated by the short-chain
Mol Cell Biol. 2004;24:7130–9. fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad
74. Gao L, Wang J, Sekhar KR, Yin H, Yared NF, Schneider SN, Sasi S, Sci U S A. 2008;105:16767–72.
Dalton TP, Anderson ME, Chan JY, et al. Novel n-3 fatty acid oxida- 92. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter
tion products activate Nrf2 by destabilizing the association between HC, Rolph MS, Mackay F, Artis D, et al. Regulation of inflammatory
Keap1 and Cullin3. J Biol Chem. 2007;282:2529–37. responses by gut microbiota and chemoattractant receptor GPR43.
75. Groeger AL, Cipollina C, Cole MP, Woodcock SR, Bonacci G, Rudolph Nature. 2009;461:1282–6.
TK, Rudolph V, Freeman BA, Schopfer FJ. Cyclooxygenase-2 generates 93. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S,
anti-inflammatory mediators from omega-3 fatty acids. Nat Chem Biol. Ogi K, Hosoya M, Tanaka Y, Uejima H, et al. Free fatty acids regulate
2010;6:433–41. insulin secretion from pancreatic beta cells through GPR40. Nature.
76. Wang R, Kern JT, Goodfriend TL, Ball DL, Luesch H. Activation of the 2003;422:173–6.
antioxidant response element by specific oxidized metabolites of lino- 94. Steneberg P, Rubins N, Bartoov-Shifman R, Walker MD, Edlund H.
leic acid. Prostaglandins Leukot Essent Fatty Acids. 2009;81:53–9. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis,
77. Galli C, Calder PC. Effects of fat and fatty acid intake on inflamma- and impaired glucose homeostasis in mouse. Cell Metab. 2005;1:
tory and immune responses: a critical review. Ann Nutr Metab. 245–58.
2009;55:123–39. 95. Edfalk S, Steneberg P, Edlund H. Gpr40 is expressed in enteroendo-
78. Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam P, Bray G, crine cells and mediates free fatty acid stimulation of incretin secre-
Hwang DH. Differential modulation of Toll-like receptors by fatty tion. Diabetes. 2008;57:2280–7.
acids: preferential inhibition by n-3 polyunsaturated fatty acids. J 96. Wang J, Wu X, Simonavicius N, Tian H, Ling L. Medium-chain fatty
Lipid Res. 2003;44:479–86. acids as ligands for orphan G protein-coupled receptor GPR84. J Biol
79. Lee JY, Sohn KH, Rhee SH, Hwang D. Saturated fatty acids, but not Chem. 2006;281:34457–64.
unsaturated fatty acids, induce the expression of cyclooxygenase-2 97. Hansen KB, Rosenkilde MM, Knop FK, Wellner N, Diep TA, Rehfeld
mediated through Toll-like receptor 4. J Biol Chem. 2001;276: JF, Andersen UB, Holst JJ, Hansen HS. 2-Oleoyl glycerol is a GPR119
16683–9. agonist and signals GLP-1 release in humans. J Clin Endocrinol
80. Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N, Hwang Metab. 2011;96:E1409–17.
DH. Reciprocal modulation of Toll-like receptor-4 signaling pathways 98. Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G,
involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M,
and polyunsaturated fatty acids. J Biol Chem. 2003;278:37041–51. et al. Deorphanization of a G protein-coupled receptor for oleoyletha-
81. Wong SW, Kwon MJ, Choi AM, Kim HP, Nakahira K, Hwang DH. nolamide and its use in the discovery of small-molecule hypophagic
Fatty acids modulate Toll-like receptor 4 activation through regulation agents. Cell Metab. 2006;3:167–75.
of receptor dimerization and recruitment into lipid rafts in a reactive 99. Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M,
oxygen species-dependent manner. J Biol Chem. 2009;284:27384–92. Sugimoto Y, Miyazaki S, Tsujimoto G. Free fatty acids regulate gut in-
82. Schaeffler A, Gross P, Buettner R, Bollheimer C, Buechler C, Neumeier cretin glucagon-like peptide-1 secretion through GPR120. Nat Med.
M, Kopp A, Schoelmerich J, Falk W. Fatty acid-induced induction of 2005;11:90–4.
Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links 100. Miyauchi S, Hirasawa A, Iga T, Liu N, Itsubo C, Sadakane K, Hara T,
nutritional signalling with innate immunity. Immunology. 2009;126: Tsujimoto G. Distribution and regulation of protein expression of the
233–45. free fatty acid receptor GPR120. Naunyn Schmiedebergs Arch Phar-
83. Erridge C, Samani NJ. Saturated fatty acids do not directly stimulate macol. 2009;379:427–34.
Toll-like receptor signaling. Arterioscler Thromb Vasc Biol. 2009;29: 101. Tanaka T, Katsuma S, Adachi T, Koshimizu TA, Hirasawa A, Tsujimoto
1944–9. G. Free fatty acids induce cholecystokinin secretion through GPR120.
84. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links Naunyn Schmiedebergs Arch Pharmacol. 2008;377:523–7.
innate immunity and fatty acid-induced insulin resistance. J Clin In- 102. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu
vest. 2006;116:3015–25. WJ, Watkins SM, Olefsky JM. GPR120 is an omega-3 fatty acid recep-
85. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai tor mediating potent anti-inflammatory and insulin-sensitizing ef-
S, Kotani H, Yamaoka S, Miyake K, Aoe S, et al. Role of the Toll-like fects. Cell. 2010;142:687–98.

134 Georgiadi and Kersten