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Departments of Medicine and Nutritional Sciences, University of Wisconsin, Madison, WI 53706
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMitochondrial metabolismEffects of acyl-CoA on...Effects of acyl-CoA on...Is there a common...REFERENCES |
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KEY WORDS: • acyl CoA • regulatory ligand • metabolism
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMitochondrial metabolismEffects of acyl-CoA on...Effects of acyl-CoA on...Is there a common...REFERENCES |
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,
Shrago et al. 1995
). The diagram shown in Figure 1
briefly alludes to some of the diverse sites of action of acyl-CoA
in the cell, which can influence biological processes ranging from
transport to bioenergetics, to apoptosis, to gene transcription.
Whether there is a unity in the mechanism of the acyl-CoA actions
remains to be established.
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Mitochondrial metabolism |
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TOPABSTRACTINTRODUCTIONMitochondrial metabolismEffects of acyl-CoA on...Effects of acyl-CoA on...Is there a common...REFERENCES |
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, Woldegiorgis et al. 1981
and 1982
).
The similar structure of the adenine group of ADP/ATP to that on the
CoA molecule was considered to be the important factor in the
effectiveness of the ligand. The data in Figures 2
and
3illustrate the competitive interaction of acyl-CoA with nucleotides
binding to the purified AAC from bovine heart mitochondria (Fig. 2)
and
the UCP in intact brown adipose tissue mitochondria (Fig. 3)
.
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). Results
shown in Figure 4
indicate the discrete covalent binding of the photolabel to the AAC and
UCP in brown adipose tissue mitochondria, which is protected against by
the appropriate reagents GDP, carboxyatractylate and cold acyl-CoA.
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illustrates the interaction of acyl-CoA with nucleotide binding to
the cytosolic ("C") and matrix ("M") sides of the AAC and
"C" side of the UCP. Although a definitive physiologic event
reflecting the effect of acyl-CoA on the AAC remains controversial
(Faergeman and Knudsen 1997
), one distinct possibility
is in the establishment of the ATP/ADP ratios in the cytosol and
mitochondrial matrix of the cell (Sobol et al. 1984
). It
is particularly relevant that acyl-CoA mimics exactly the classical
inhibitors atractylate and bongkrekic acid in their effects on the AAC
(Woldegiorgis et al. 1982
). On the basis of this finding
alone, it has been postulated that long-chain acyl-CoA esters are
likely the natural ligands for the carrier. Included in the scheme
(Fig. 5)
is the representation of a somewhat ill-defined but
potentially very important anion channel or megapore called the
mitochondrial transition pore (MTP) (Bernardi et al. 1994
). Functionally, the opening and closure of the MTP is
dependent upon the membrane potential, the concentration and gradient
of calcium and, interestingly, the conformational state of the AAC as
determined by atractylate and bongkrekic acid (Lequoc and Lequoc 1988
). The MTP in conjunction with the AAC and outer
mitochondrial membrane porin protein is now considered to play an
important signaling role in apoptosis by facilitating release of
apoptotic promoting factors including cytochrome C from the
mitochondria (Santos et al. 1998
). Experiments by this
group and others have shown that atractylate induces and bongkrekic
acid inhibits initiation of apop-tosis by fixing the conformation of
the AAC in the "C" or "M" state. It should thus be appreciated
that acyl-CoA could serve this purpose as a bifunctional ligand of
the AAC under physiologic or pathophysiologic conditions (Chua and Shrago 1977
, Woldegiorgis et al. 1982
).
There is no evidence that nucleotides or acyl-CoA binds to or
affects the MTP directly.
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may be obligatory in UCP function
and have specific physiologic significance in energy expenditure.
Proton conductance by the UCP is gated by nucleotides, most likely ATP,
and activated by fatty acids (Klingenberg and Huang 1999
, Shrago et al. 1995
). An important fact to
consider is that in the presence of nucleotides, which are abundant,
fatty acids are inactive and the port is closed. Figure 6
summarizes results that denote the fact that fatty acids cannot
displace tightly bound nucleotides from the UCP. By contrast, they are
competitively removed by acyl-CoA. Regulation of proton conductance
by the UCPs from brown adipose tissue may thus require the appropriate
interaction of nucleotides, fatty acids and acyl-CoA esters
(Katiyar and Shrago 1991
). The more recently described
UCPs from other tissues have not yet been characterized biochemically,
although they appear to have uncoupling activity (Boss et al. 1998
).
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Effects of acyl-CoA on gene expression |
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TOPABSTRACTINTRODUCTIONMitochondrial metabolismEffects of acyl-CoA on...Effects of acyl-CoA on...Is there a common...REFERENCES |
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).
Although a homologous protein has not yet been identified in
eucaryotes, it is likely that acyl-CoA binding proteins that effect
gene transcription also exist in higher organisms. Acyl-CoAs have
been found to bind to the thyroid receptor with high affinity
(Li et al. 1993
), but a physiologic response is not
apparent. Recently, it has been reported that acyl-CoAs are ligands
for hepatic nuclear factor 4
, which effects gene transcription of a
number of liver and pancreatic islet cell proteins (Hertz et al. 1998
). Fatty acids have been found to bind to peroxisomal
proliferator-activated receptor (PPAR) isoforms and thereby effect
expression of fatty acid metabolizing proteins (Wolf 1998
). Most evidence suggests that the free fatty acid rather
than its thioester is the active agent, thus negating an acyl-CoA
modulation of this PPAR receptor. The cytosolic acyl-CoA binding
protein (ACBP) (Faergeman and Knudsen 1997
) could play a
role in gene regulation if small concentrations of the protein exist in
the nucleus of the cell. Further investigations may extend and link the
findings in E. coli to more definitive results in mammals. |
Effects of acyl-CoA on insulin secretion and insulin action |
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TOPABSTRACTINTRODUCTIONMitochondrial metabolismEffects of acyl-CoA on...Effects of acyl-CoA on...Is there a common...REFERENCES |
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). Evidence has been provided
concerning the likely possibility that acyl-CoA thioesters are the
active fatty acid intermediates producing the effects (Chen et al. 1992
). A recent experimental finding related to insulin
secretion is the activation of the ß cell KATP
channel by acyl-CoA, presumably by displacing the nucleotide that
gates the channel (Gribble et al. 1998
). The result is
an impairment of insulin secretion that may constitute a component of
the lipotoxicity attributed to lipid infiltration of the islets
(Unger 1995
). The similarity of the effects of the
acyl-CoA on the KATP and UCP channels is
noteworthy. The actual site and mechanism of the early stimulatory
effect of acyl-CoA or fatty acids on glucose-dependent insulin
secretion are yet to be defined completely (Prentki and Corkey 1996
).
In terms of insulin signaling in peripheral tissues, fatty acids impede
carbohydrate metabolism and likely play a prominent role in the
development of insulin resistance (Boden 1996
,
Chen et al. 1992
). Although the glucose-fatty acid
cycle effecting the activity of pyruvate dehydrogenase, as expounded by
Randle (1999),
receives the greatest attention as the
causative agent in fatty acid–induced insulin resistance, more recent
evidence incriminates alternative metabolic parameters with
acyl-CoA esters acting as the active effector molecule (Chen et al. 1992
, Oakes et al. 1997
).
The effects of feeding experiments (high fat vs. high carbohydrate
diet) on accumulation of acyl-CoA and development of insulin
resistance in rats have been examined (Chen et al. 1992
). Based on the content of dietary fat, the majority of the
accumulated tissue acyl-CoA esters included palmitate, stearate,
oleate and linoleate. In addition to excess weight gain in the
fat-fed rats, there was a rise in plasma insulin that correlated
directly with an increase in tissue acyl-CoA esters in liver and
muscle (Fig. 7
). The correlation was r = 0.80, P < 0.001, for liver and r = 0.78, P < 0.001, for muscle. Similar findings have been published recently by
Oakes et al. (1997)
. It was proposed that acyl-CoA
interacts with a number of key tissue proteins, particularly
nucleotide-dependent proteins, which interfere with insulin action
(Chen et al. 1992
). These proteins, which might possibly
include phosphatidylinositol 3-kinase, may be involved in the
insulin-stimulated cascade related to activation of the GLUT4
transport system (Dresner et al., 1999
, Pessen et al. 1999
).
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Is there a common consensus sequence for acyl-CoA binding? |
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TOPABSTRACTINTRODUCTIONMitochondrial metabolismEffects of acyl-CoA on...Effects of acyl-CoA on...Is there a common...REFERENCES |
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, Strieleman and Shrago 1985
). More definitively, chemical modification or
site-directed mutagenesis of specific arginine residues of the UCP
prevent acyl-CoA as well as nucleotide binding to the protein
(Katiyar and Shrago 1989
and 1991
, Murdza-Inglis et al. 1994
).
A more detailed analysis of the amino acid requirement for acyl-CoA
binding to its cognate protein has been determined for the FadR
transcription factor in E. coli (Raman and DiRusso 1995
). The important residues, glycine, tryptophan and
lysine/arginine, in FadR have also been recognized to be present as
part of the binding sequence of the AAC and UCP as well as other
related acyl-CoA binding proteins (Shrago et al. 1995
). However, except in the case of FadR, the essentiality of
a common motif is yet to be demonstrated experimentally.
In conclusion, long-chain acyl-CoA esters acting as ligands for essential proteins in a diverse number of biological processes can now be considered to play an important role in the modulation of cellular metabolism. Further work is required to determine the presence of a common binding site and similar mechanism of action in the various systems.
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FOOTNOTES |
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2 Abbreviations used: AAC, ADP/ATP carrier; MTP, mitochondrial transition pore; PPAR, peroxisomal proliferator-activated receptor; UCP, uncoupling protein.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMitochondrial metabolismEffects of acyl-CoA on...Effects of acyl-CoA on...Is there a common...REFERENCES |
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