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Department of Biochemistry and Molecular Biology, The Albany Medical College A-10, Albany, NY 12208-3479
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRegulation of fatty acid...Alteration of gene expression...Evidence that long-chain acyl...Is the free acid...REFERENCES |
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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).
KEY WORDS: • fatty acids • acyl-CoA • transcription • gene regulation • FadR
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRegulation of fatty acid...Alteration of gene expression...Evidence that long-chain acyl...Is the free acid...REFERENCES |
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, 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 synthetic 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, particularly the three fatty acid
oxidizing enzymes of peroxisomes, and in fatty acid transport proteins,
including carnitine palmitoyltransferase 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 leading to
fatty acid–mediated alterations in gene expression (Fig. 1
).
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Regulation of fatty acid metabolism in bacteria by long-chain acyl-CoA |
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TOPABSTRACTINTRODUCTIONRegulation of fatty acid...Alteration of gene expression...Evidence that long-chain acyl...Is the free acid...REFERENCES |
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). Import of fatty acids occurs by a specific,
well-characterized transport system that includes an outer 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
).
|
). 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 transport protein (fadL)
(DiRusso et al. 1993
, Nunn et al., 1986
);
the activating enzyme (fadD) (Black et al. 1992
); the enzymes of the ß-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 Nyström 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 require 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, noninducible mutations in the FadR gene were
selected after chemical 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 superrepressor
FadRS219N was overexpressed, purified and
characterized in vitro. DNA binding of FadRS219N
was unaffected, whereas acyl-CoA binding was reduced 10-fold.
Alanine substitution 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
(Raman 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 localized by
affinity labeling of the full length protein and an amino terminal
deletion derivative, FadR1–167, with a
palmitoyl-CoA analog,
9-p-azidophenoxy[9-3H]nonanoic
acid-CoA ([3H]APNA-CoA) (DiRusso et al. 1998
). After labeling, the full length FadR and the
deletion derivative were each digested 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 corresponds to amino acids 187–195 in FadR (DiRusso et al. 1998
).
Isothermal titration calorimetry was used to estimate affinity of
the wild-type full-length FadR, a HIS-tagged derivative of FadR
(FadR6XHis) and
FadR1–167 for 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 compounds >12 C in length, and no binding was detected for the
medium-chain ligand C:8-CoA. Full-length wild-type FadR and
FadR6XHis bind oleoyl-CoA and
myristoyl-CoA with similar affinities
(Kd = 45 and 63 nmol/L and 68 and 59
nmol/L, respectively). The Kd for
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.
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Alteration of gene expression in Saccharomyces cerevisiae by exogenous fatty acids |
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TOPABSTRACTINTRODUCTIONRegulation of fatty acid...Alteration of gene expression...Evidence that long-chain acyl...Is the free acid...REFERENCES |
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). The sole site of
fatty acid degradation 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.
In yeast, imported long-chain fatty acids are converted to
CoA 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
peroxisome 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 contained a putative ORE. Northern hybridization
analysis confirmed 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
(Rottensteiner 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
, McDonough 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
). Characterization 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.
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Evidence that long-chain acyl-CoA effect changes in gene expression in mammals |
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TOPABSTRACTINTRODUCTIONRegulation of fatty acid...Alteration of gene expression...Evidence that long-chain acyl...Is the free acid...REFERENCES |
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). 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 retinoic
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 peroxisomes. Chronic administration of these compounds also results
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 be
adipocyte specific, PPAR (also known as PPARß, FAAR and 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 asymptomatic (Gonzalez 1997
). They exhibited normal numbers of peroxisomes and levels
of systemic lipids and lipoproteins. However, peroxisomes do not
proliferate in response to synthetic 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
ß-oxidation pathway, exhibit a mimicking of the effects of chronic
administration 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 VLCFA accumulate, e.g., in AOX mice such as in
X-linked adrenoleukodystrophy 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
evaluated DNA binding and transcriptional activation of hepatocyte
nuclear factor 4 (HNF-4) by long-chain acyl-CoA (Hertz et al. 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 KD of 1.2–3.4
µmol/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 activation 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 compounds 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
experiments 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 stimulate 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)
monitored the change in expression of peroxisomal
acyl-CoA oxidase mRNA abundance upon administration of PUFA and a
peroxisomal proliferative compound to rats. They found that increased
peroxisomal acyl-CoA oxidase mRNA abundance upon treatment with a
potent PPAR activator, 5,8,11,14-eicosatetraynoic acid; however, PPAR
activation did not reduce fatty acid synthase, 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 transcription 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.
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Is the free acid or acyl-CoA the regulatory molecule? |
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TOPABSTRACTINTRODUCTIONRegulation of fatty acid...Alteration of gene expression...Evidence that long-chain acyl...Is the free acid...REFERENCES |
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. 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 strains deficient in acyl-CoA binding protein
(ACB1p) (Schjerling et al. 1996
). Similarly, the
alterations in response noted in cells that overexpress thioesterase in
E. coli (Cronan 1997
) and
mammalian cells (Hertz et al. 1998
) each give
valuable, albeit circumstantial evidence for a role for acyl-CoA.
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FOOTNOTES |
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3 Abbreviations used: apo,
apolipoprotein; CPT I, carnitine palmitoyltransferase I; FATP, fatty
acid transport protein; FFA, free fatty acids; HNF-4, hepatocyte
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 fatty acids.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRegulation of fatty acid...Alteration of gene expression...Evidence that long-chain acyl...Is the free acid...REFERENCES |
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