Symposium: The Role of Long Chain Fatty Acyl-CoAs as
Signaling Molecules in Cellular Metabolism
Long-Chain Acyl-CoA–Dependent Regulation of Gene Expression in
Bacteria, Yeast and Mammals1
Paul N. Black, Nils J. Færgeman and Concetta C. DiRusso2
Department of Biochemistry and Molecular Biology, The Albany Medical College A-10, Albany, NY
been numerous conflicting reports concerning the possibility that these compounds also serve regulatory func-
tions. In this review, we examine the evidence that long-chain acyl-CoA is a regulatory signal that modulates gene
expression. In the bacteria Escherichia coli, long-chain fatty acyl-CoA bind directly to the transcription factor FadR.
Acyl-CoA binding renders the protein incapable of binding DNA, thus preventing transcription activation and
repression of many genes and operons. In the yeast Saccharomyces cerevisiae, genes encoding peroxisomal
proteins are activated in response to exogenously supplied fatty acids. In contrast, growth of yeast cells in media
containing exogenous fatty acids results in repression of a number of genes, including that encoding the ?9-fatty
acid desaturase (OLE1). Both repression and activation are dependent upon the function of either of the acyl-CoA
synthetases Faa1p or Faa4p. In mammals, purified hepatocyte nuclear transcription factor 4? (HNF-4?) like E. coli
FadR, binds long chain acyl-CoA directly. Coexpression of HNF-4? and acyl-CoA synthetase increases the
activation of transcription of a fatty acid–responsive promoter, whereas coexpression with thioesterase decreases
the fatty acid–mediated response. Conflicting data exist in support of the notion that fatty acyl-CoA are natural
ligands for peroxisomal proliferator-activated receptor ? (PPAR?).
Fatty acyl-CoA thioesters are essential intermediates in lipid metabolism. For many years there have
J. Nutr. 130: 305S–309S, 2000.
● fatty acids ● acyl-CoA ● transcription ● gene regulation ● FadR
Lipids are complex, energy-rich compounds essential to all
cells. Fundamentally, most cell types retain the genetic capac-
ity to synthesize the lipids they require for membrane struc-
tures and other functions; however, many also import lipids
from the environment. Exogenous fatty acids have diverse
effects on cellular lipid metabolism and organelle structure,
function and biogenesis. Fatty acids generally repress lipid
synthesis, whereas they increase both lipid degradation and
storage (Sheen 1990, Sul et al. 1998). Early physiologic and
biochemical studies in mammals demonstrated that diets high
in calories and fat result in an increase in adipose tissue
deposition, hepatic peroxisomal proliferation and some cases
of steatohepatitis (Sessler and Ntambi 1998, Sheen 1990).
Chronic high lipid intake or altered lipid homeostasis results
in common diseases, including obesity, diabetes and coronary
heat disease. These physiologic changes occur as a result of
effects on lipid enzyme activity and gene expression. When
animals are fed a diet rich in fat, fatty acid synthesis in liver is
depressed, with a corresponding decrease in mRNA for syn-
thetic enzymes, including but not limited to fatty acid synthase
and acetyl-CoA carboxylase (Sul et al. 1998). Concurrently,
there is increased expression of degradative enzymes, particu-
larly the three fatty acid oxidizing enzymes of peroxisomes, and
in fatty acid transport proteins, including carnitine palmitoyl-
transferase I (CPTI)3(Assimacopoulos-Jeannet et al. 1997)
and fatty acid transport protein (FATP) (Martin et al. 1997).
This review focuses on the role of an essential intermediate in
lipid synthesis and degradation, long-chain fatty acyl-CoA.
The hypothesis we discuss is that fatty acyl-CoA thioesters are
important signaling molecules in the regulatory cascade lead-
ing to fatty acid–mediated alterations in gene expression
Regulation of fatty acid metabolism in bacteria by long-
When Escherichia coli are grown on long-chain fatty acids as
a sole carbon and energy source, the expression of the genes
encoding enzymes required for fatty acid degradation and the
glyoxylate shunt are increased at least 10-fold (reviewed in
DiRusso et al. 1999). Import of fatty acids occurs by a specific,
well-characterized transport system that includes an outer
1Presented at the symposium entitled “The Role of Long Chain Fatty Acyl-
CoAs as Signaling Molecules in Cellular Metabolism” as part of the Experimental
Biology 99 meeting held April 17–21 in Washington, DC. This symposium was part
of the metabolic and disease processes theme sponsored by the American
Society for Nutritional Sciences. Symposium proceedings are published as a
supplement to The Journal of Nutrition. Guest editors for this supplement were
Earl Shrago, University of Wisconsin, Madison, WI and Gebre Woldegiorgis,
Oregon School of Science and Technology, Portland, OR.
2To whom correspondence should be addressed.
3Abbreviations used: apo, apolipoprotein; CPT I, carnitine palmitoyltrans-
ferase I; FATP, fatty acid transport protein; FFA, free fatty acids; HNF-4?, hepa-
tocyte nuclear factor; MODY1, maturity-onset diabetes of the young; ORE, oleate
response element; PPAR, peroxisome proliferator-activated response; PUFA,
polyunsaturated fatty acids; RXR, retinoic acid receptor; VLCFA, very long-chain
0022-3166/00 $3.00 © 2000 American Society for Nutritional Sciences.
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membrane protein, FadL, and a cytoplasmic fatty acyl-CoA
synthetase, FadD. The concerted activities of each of these
proteins result in the production of fatty acyl-CoA, rendering
this process unidirectional. The transport and activation of
fatty acids are coupled directly to transcriptional regulation of
a large number of structural genes involved in fatty acid
metabolism through the transcription factor FadR (Fig. 2).
Wild-type E. coli show a distinctive pattern of growth when
fatty acids are provided as the sole carbon and energy source
(DiRusso et al. 1999). Only fatty acids with acyl chain length
?14 C (i.e., long chain) normally support growth. Mutations
in the regulatory gene fadR allow for growth on both medium-
(C:8–C:12) as well as long-chain (?14 C) fatty acids. This is
due to the fact that only long-chain compounds inhibit FadR
and prevent repression of genes encoding proteins required for
growth on fatty acids. The genes regulated negatively by FadR
include the following: the membrane-bound fatty acid trans-
port protein (fadL) (DiRusso et al. 1993, Nunn et al., 1986);
the activating enzyme (fadD) (Black et al. 1992); the enzymes
of the ?-oxidation cycle (fadBA, fadE, fadF, fadG, fadH)
(DiRusso et al. 1992); and a protein of unknown function that
is highly expressed during stress response, uspA (DiRusso and
Nystro ¨m 1998, Farewell et al. 1996). FadR also activates the
expression of at least three genes, i.e., fabA and fabB, required
for unsaturated fatty acid biosynthesis (DiRusso et al. 1993),
and iclR, a repressor of the aceBAK operon (Gui et al. 1996).
There are at least four distinct functions associated with the
FadR protein as follows: 1) DNA binding; 2) transcriptional
repression; 3) transcriptional activation involving direct
FadR-RNA polymerase interactions; and 4) long-chain acyl-
CoA binding. FadR-long-chain acyl-CoA binding results in a
conformational change that inhibits or prevents FadR-DNA
binding (DiRusso et al. 1992 and 1998).
The DNA binding of FadR to regions within the promoters
of responsive genes and operons is inhibited by long-chain
acyl-coenzyme A thioesters but not medium-chain acyl-CoA
(C:8 or C:10), free fatty acids or coenzyme A (DiRusso et al.
1992 and 1998). The concentrations of long-chain acyl-CoA
required to inhibit DNA binding of the purified protein are in
the nanomolar range, whereas fatty acids and detergents re-
quire micromolar to millimolar amounts (DiRusso et al. 1998,
Raman and DiRusso 1995). Thus the FadR-ligand binding
domain distinguishes both the CoA moiety and the acyl chain
length of the ligand. To localize and characterize amino acids
in FadR required for binding of long-chain acyl-CoA, nonin-
expression in eucaryotes. Fatty acids (FFA) are delivered to the cell
from the environment (e.g., seeds and fruits for yeast and plants, blood
for mammals). The fatty acids are transported into the cell by a plasma
membrane fatty acid transport protein (filled oval). Upon entry it is either
bound to fatty acid binding protein (FABP) for intracellular transport or
it is activated to the CoA thioester. The acyl-CoA may interact with a
transcription factor such as hepatocyte nuclear factor (HNF)-4? directly
(route B) or may bind to or cause the modification of one or more signal
transducing proteins, which then activate a transcription factor (route
C). Alternatively, the acyl-CoA may be further metabolized [e.g., to a
prostaglandin (PG) derivative] (routes D, E or F), which then binds a
transcription factor to activate or repress transcription. Finally, the fatty
acid may interact with a cell surface receptor (R)(as yet unidentified) to
initiate a signal transduction cascade. It is most likely that several of
these routes are utilized by various cell types. Abbreviations: VLCFA,
very long-chain fatty acids; PUFA, polyunsaturated fatty acids.
Possible routes of fatty acid-mediated control of gene
mediated control of Escherichia coli
FadR. In the absence of acyl-CoA, the
FadR homodimer binds to DNA in a
sequence-specific manner to repress
the transcription of negatively con-
trolled genes and to activate transcrip-
tion of positively controlled genes.
Binding of long-chain acyl-CoA (LC-
acyl-CoA) causes a conformational
change that results in alteration of the
DNA binding domain such that amino
acid and base pair contacts are no
longer favorable. The acyl-CoA binding
region of the protein is illustrated as a
dotted section. Amino acid residues
that confer a superrepressor pheno-
type when altered are as shown.
Model of acyl-CoA–
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ducible mutations in the FadR gene were selected after chem-
ical mutagenesis of plasmid DNA (Raman and DiRusso 1995).
These fadR alleles, called superrepressors, encode proteins that
are able to bind to DNA to repress transcription of the fadB
gene or activate fabA, but are not inactivated by long-chain
acyl-CoA. As a result, cells carrying these fadR alleles are
unable to grow on fatty acids of any chain length. One super-
repressor FadRS219Nwas overexpressed, purified and charac-
terized in vitro. DNA binding of FadRS219Nwas unaffected,
whereas acyl-CoA binding was reduced 10-fold. Alanine sub-
stitution of amino acid residues adjacent to S219 identified
Y179, Y193, G216, E218, W223 and K228 as also required for
maximal derepression of fadB by long-chain fatty acids (Ra-
man and DiRusso 1995). These preliminary studies led to the
prediction that the acyl-CoA binding region was localized in
a carboxyl-terminal domain of the protein. This conclusion
was supported further by the phenotypic analyses of protein
fusions between the DNA binding domain of LexA (amino
acids 1–87) and amino acids 102–239 of FadR (Raman et al.
1997). The resulting protein fusion retained the DNA binding
specificity of LexA and was inducible by long-chain fatty acids
demonstrating the ligand binding function contributed by FadR.
The acyl-CoA binding domain of FadR was further local-
ized by affinity labeling of the full length protein and an amino
terminal deletion derivative, FadR?1–167, with a palmitoyl-
([3H]APNA-CoA) (DiRusso et al. 1998). After labeling, the
full length FadR and the deletion derivative were each di-
gested with trypsin and tryptic peptides separated by HPLC.
One labeled peptide common to both the full-length protein
and the deletion derivative was identified. The amino terminal
sequence of the labeled peptide was SLALGFYHK, which corre-
sponds to amino acids 187–195 in FadR (DiRusso et al. 1998).
the wild-type full-length FadR, a HIS-tagged derivative of FadR
(FadR6XHis) and FadR?1–167for acyl-CoA (DiRusso et al. 1998).
The binding was characterized by a large negative ?H° (?16 to
?20 kcal/mol). The binding specificity, as expected, was for
medium-chain ligand C:8-CoA. Full-length wild-type FadR and
FadR6XHisbind oleoyl-CoA and myristoyl-CoA with similar af-
finities (Kd? 45 and 63 nmol/L and 68 and 59 nmol/L, respec-
tively). The Kdfor palmitoyl-CoA binding was higher (about
fivefold) despite the fact that palmitoyl-CoA is 50-fold more
efficient in inhibiting FadR binding to DNA than myristoyl-CoA
(DiRusso et al. 1992). These apparently conflicting data indicate
that the interaction of acyl-CoA with FadR is complex; although
the shorter-chain compounds C:12 and C:14 bind with high
affinity, they are not expected to result in a change in protein
conformation required to either prevent DNA binding or release
the protein from the DNA.
Alteration of gene expression in Saccharomyces cerevisiae
by exogenous fatty acids
Yeast are a valuable model system with which to study fatty
acid transport, activation and gene regulation because they
can grow on long-chain fatty acids as a sole carbon and energy
source. Yeast also require exogenous unsaturated fatty acids in
the natural environment when growing anaerobically because
the O2-dependent fatty acid desaturase (Ole1p) is inactive
(Walenga and Lands 1975). The sole site of fatty acid degra-
dation for energy production is the peroxisome. Biogenesis and
proliferation of this organelle occurs when yeast are grown on
fatty acids as a carbon and energy source (Elgersma and Tabak
1996). In stationary phase, yeast accumulate fatty acids and
store them as triacylglycerides in a lipid body. Thus, unlike
bacteria, yeast modulate not only their metabolism but also
organelle structure and function in response to fatty acids.
thioesters by the fatty acyl CoA synthetases Faa1p and Faa4p
(Johnson et al. 1994). Recent evidence indicates that, similar to
E. coli, FadD, either Faa1p or Faa4p, is required for import of fatty
acids (Black and DiRusso, unpublished data). Thus transport is
coupled to activation. The fatty acyl-CoA may be incorporated
into phospholipids or triglycerides, used as a substrate in protein
acylation or can be used as a carbon and energy source.
Regulation of transcription by fatty acids in yeast has been
the subject of intense research in recent years. Growth on
long-chain fatty acids causes induction of the genes encoding
structural proteins and enzymes of peroxisomes (Elgersma and
Tabak 1996, Igual et al. 1992, Kos et al. 1995). Two fatty
acid–responsive transcription factors are essential for peroxi-
some biogenesis, Oaf1p/Pip1p and Oaf2p/Pip2p (Karpichev
and Small 1998, Rottensteiner et al. 1996). Oaf1p and Oaf2p
form a heterodimer, which interacts specifically with promoter
DNA containing an oleate response element (ORE), which is
CGGNNNTNA(N9–12)CCG (Luo et al. 1996, Rottensteiner
et al. 1997). Karpichev and Small (1998) recently conducted
a database search for yeast genes and identified 40 that con-
tained a putative ORE. Northern hybridization analysis con-
firmed that 22 are induced by oleate and regulated by either
Oaf1p or Oaf2p or a heterodimer of Oaf1p and Oaf2p. Most,
but not all of the genes encode peroxisomal proteins. OAF2
transcription is itself increased when cells are grown in oleate,
and the increase in expression is dependent upon Oaf1p (Rot-
tensteiner et al. 1997). The expression of one gene encoding
a protein of undetermined function, YOR002c, is dependent
upon Oaf1p and Oaf2p whether oleate is or is not provided in
the growth media, thus demonstrating the complexity of
Oaf1p/Oaf2p–dependent gene regulation. The gene encoding
?9-fatty acyl-CoA desaturase in yeast, OLE1, is repressed by
monounsaturated and polyunsaturated fatty acids (PUFA) in an
Oaf1p/Oaf2p–independent fashion (Choi et al. 1996, McDon-
ough et al. 1992). At this time, the transcription factor(s)
mediating repression have not been identified, although two
groups have reported the isolation of mutations that eliminate
repression (Fujimori et al. 1997, McHale et al. 1996). Char-
acterization of the products of these mutant alleles should help to
define their function in fatty acid–mediated repression of OLE1.
Fatty acid–dependent gene regulation (both activation and
repression) in yeast requires the activity of fatty acyl-CoA
synthetases Faa1p or Faa4p (McDonough et al. 1992). At this
time, it is not known whether the reduction of transcriptional
control is due to an inability to form acyl-CoA, the natural
ligand, or to a defect in fatty acid import.
Evidence that long-chain acyl-CoA effect changes in gene
expression in mammals
It has been recognized for many years that fatty acids have a
significant effect on RNA abundance of genes encoding proteins
involved in fatty acid metabolism in mammals. In general, fatty
acids suppress fatty acid synthetic enzymes, including acetyl-CoA
carboxylase, fatty acid synthase, ATP-citrate lyase and apoli-
poprotein (apo) A-I expression, whereas they increase expression
of genes involved in peroxisomal biogenesis, ?-oxidation and
several fatty acid transport proteins including CPT I and FATP
(reviewed in Sessler and Ntambi 1998). Many of these effects can
be traced to the activities of the nuclear orphan receptor family
members called peroxisomal proliferator-activated receptors
(PPAR). The PPAR factors function as heterodimers with reti-
REGULATION OF GENE EXPRESSION
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noic acid receptor (RXR) family members. There are at least
three isotypes of PPAR (?, ? and ?), which exhibit different
patterns of expression and regulation of target genes (see Clarke
et al. 1997, Kliewer and Willson 1998 and Reginato et al. 1998).
PPAR? is most highly expressed in liver, intestine, kidney and
brown adipose tissue and is highly activated by the synthetic
compounds known collectively as peroxisomal proliferators.
Treatment of animals with peroxisomal proliferative drugs results
in the proliferation of hepatocyes and a 10-fold increase in per-
oxisomes. Chronic administration of these compounds also re-
sults in liver tumors. The natural ligands for the PPAR family
have been difficult to discern (Krey et al. 1997, Lin et al. 1999,
Wolf 1998). This is due in part to the fact that each responds in
varying degrees to a broad range of natural compounds, including
long-chain saturated, unsaturated and PUFA. PPAR? and
PPAR? are each highly expressed in adipose tissue but in a
different developmental sequence. Although PPAR? appears to
NUC1) is expressed in a number of tissues, particularly neuronal
tissue. PPAR? and PPAR? are activated to a limited extent by
synthetic peroxisomal proliferators by comparison to PPAR?
(Reginato et al. 1998, Staels et al. 1998).
Recently, transgenic mice deficient in PPAR? have been
generated. Surprisingly, the mice were essentially asymptom-
atic (Gonzalez 1997). They exhibited normal numbers of
peroxisomes and levels of systemic lipids and lipoproteins.
However, peroxisomes do not proliferate in response to syn-
thetic peroxisomal proliferators nor do animals develop tumors
upon chronic administration of those compounds (Aoyama et
al. 1998). In contrast, animals deficient in peroxisomal acyl-
CoA oxidase, the first enzyme in the peroxisomal ?-oxidation
pathway, exhibit a mimicking of the effects of chronic admin-
istration of synthetic peroxisomal proliferative drugs (Fan et
al. 1998). The animals have elevated numbers of peroxisomes
and develop steatohepatitis and liver tumors by 15 mo of age.
This is suggested to be the result of sustained activation of
PPAR? that is assumed to be due to the accumulation of a
PPAR? natural ligand (Aoyama et al. 1998). Candidates for
the proximal ligand include long-chain acyl-CoA and very
long-chain fatty acids (VLCFA), which accumulate to high
levels in transgenic animals. There is no direct evidence to
distinguish either the CoA thioester or the free acid form as
the natural ligand. However, in other conditions in which VL-
CFA accumulate, e.g., in AOX mice such as in X-linked adre-
noleukodystrophy or in mice lacking VLCFA-CoA synthetase,
peroxisomes do not proliferate nor do liver tumors develop.
In eukaryotes, there is only one case providing compelling
evidence for regulation of a transcription factor’s activity by
long-chain acyl-CoA. Recently, Bar-Tana and co-workers eval-
uated DNA binding and transcriptional activation of hepatocyte
1998). HNF-4? is a member of a transcription factor family
involved in hepatocyte differentiation and cellular metabolism
(Duncan et al. 1998, Fraser et al. 1998). Mutations in HNF-4?
cause two forms of diabetes, maturity-onset diabetes of the young
(MODY1) and MODY3 (Furuta et al. 1997, Gragnoli et al. 1997,
Sladek et al. 1998). Binding of palmitoyl-CoA to purified
HNF-4? is saturable with an apparent KDof 1.2–3.4 ?mol/L and
is specific for the CoA thioester of the long-chain fatty acid
(Hertz et al. 1998). The measured affinities are much lower than
that estimated for purified E. coli FadR but within the normal
physiologic range of liver cytosolic long-chain acyl-CoA.
Palmitic acid and free coenzyme A (CoASH) had no effect on
binding using purified protein in a direct filter-binding assay.
Coexpression of thioesterase in transfected cells inhibited activa-
tion of a CAT reporter construct under the control of the apo
CIII gene promoter in an HNF-4?–dependent manner, whereas
coexpression of acyl-CoA synthetase potentiated activation. The
regulation of HNF-4? activity was dependent upon acyl chain
length, i.e., 16:0 resulted in activation, whereas shorter saturated
compounds had no effect; unsaturated and polyunsaturated com-
pounds inhibited apo CIII-CAT expression. The mechanism of
acyl-CoA–dependent regulation of HNF-4? activity may be to
control dimerization of the transcription factor, which in turn
controls the protein’s DNA binding activity. In the same exper-
iments demonstrating direct binding and regulation of HNF-4?
by long-chain acyl-CoA, activity and binding of acyl-CoA to
PPAR? was evaluated. In these experiments, PPAR? activity
was stimulated by 18:0 and 18:3 acyl-CoA. However, when
acyl-CoA synthetase was cotransfected with PPAR?, activation
was inhibited. These results appear to contradict the suggestion
above that increases in intracellular long-chain acyl-CoA stimu-
late PPAR?-dependent gene activity in the acyl-CoA oxidase-
deficient mice (Aoyama et al. 1998).
Although PPAR? and HNF-4? are the most highly visible
candidates for transcription factors regulated directly by fatty
acids, a substantial body of evidence has been accumulated that
indicates that other unidentified factors may be involved in the
regulation of some genes. PUFA and peroxisomal proliferators
have different and separable effects on genes such as fatty acid
synthase (Bing et al. 1997) SCD1 (Miller and Ntambi 1996) and
the rat S14 gene (Bing et al., 1997). Clarke et al. (1997) moni-
tored the change in expression of peroxisomal acyl-CoA oxidase
mRNA abundance upon administration of PUFA and a peroxi-
somal proliferative compound to rats. They found that increased
peroxisomal acyl-CoA oxidase mRNA abundance upon treat-
ment with a potent PPAR activator, 5,8,11,14-eicosatetraynoic
acid; however, PPAR activation did not reduce fatty acid syn-
thase, whereas PUFA was effective. The results from experiments
such as these point to the complexity of fatty acid–dependent
control of transcription in mammals. Two candidate transcrip-
tion factors include steroid receptor element binding protein
(Thewke et al. 1998) and thyroid hormone receptor (Thurmond
et al. 1998). Additionally, they indicate that other factors and/or
mechanisms of regulation have yet to be uncovered.
Is the free acid or acyl-CoA the regulatory molecule?
As summarized above, there is clear evidence that exoge-
nous administration of fatty acids to bacteria, yeast or mam-
mals results in alterations in mRNA synthesis such that fatty
acid synthesis is reduced, and fatty acid transport and degra-
dation are increased. In most cases, it is also clear that ?-ox-
idation is not required to form the proximal natural ligand
because administration of 2-bromo-palmitate and other sub-
stituted fatty acids result in a response similar to free fatty
acids. These compounds are substrates for acyl-CoA syn-
thetase and may be activated to a CoA thioester like the
natural fatty acids. Therefore, as long as pools of both free fatty
acid and acyl-CoA are present within a cell, it is not easy to
distinguish which class of compounds is the proximal effector.
Additionally, it appears that activation in many cell types
occurs concomitantly with import; thus, eliminating acyl-CoA
synthetase, as in the case of the yeast faa1 faa4 strains, does not
prove that activation per se is required for regulation of gene
expression apart from fatty acid transport. The best evidence
that acyl-CoA thioesters mediate regulation of gene expres-
sion directly comes from direct binding studies such as those
conducted with E. coli FadR and HNF-4?. Additional in vivo
evidence includes the demonstration that intracellular acyl-
CoA or fatty acid pools change simultaneously with a change
in gene expression. This was shown to be the case in yeast
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Polyunsaturated fatty acid regulation of
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Requirements for unsaturated fatty
REGULATION OF GENE EXPRESSION
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